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Okay guys, I'll just set up my slides of things before we do anything else? I do have a, a slide. Oh Just going in the background. There's going to be some questions dotted throughout the talk just to try and make it a little bit less dry because I appreciate path can be sometimes. So if people do want to jump on uh the slider, they can submit questions throughout equally, you can put them on the team's chat, you can um you, you can shout at me whatever is easiest for you guys. So there will be like screenshots of the slider at the point in time when it's necessary. Um But just so that, you know, so as is the standard, I can't see the chat when I'm presenting. Um But if you guys want to like raise a hand or um you, it's probably the easiest way. Um Perfect. So it's on and said I'm just gonna be chatting through the second half, I believe of your immunology content. Uh Please do give me a shout if you can't hear me or anything like that as well. So in terms of what we're going to cover today. Um I'm mainly gonna be talking through hypersensitivity reactions. So, the different types um um and the kind of clinical correlates for those are them be going into transplant or more specifically transplant rejection, how we can kind of monitor and treat that? Um And then a sort of largest portion of this lecture is gonna be about how we modulate the immune system for our own benefit. Um So whether that be boosting the immune response or trying to dampen it down. Um And then if time allows, I do have some slides, just a couple on HIV. Um But equally, this isn't something that's tested as much as the other section. So if we need to kind of skim through it, we absolutely can. Um And you guys can kind of have a look through in your own time. Uh So if there are no burning questions, I'll get going. Um So the first areas cover is about hypersensitivity. So for any kind of immune response, any immune reaction in the body, we can think of it as either protecting us from something, view that virus cancer, etcetera, or we can think of it's causing damage and your hypersensitivity reactions are all going to fall into this damage category. Uh Let me put on my highlighter actually or laser pointer just in case. Um So within this section, you've got your autoimmune autoinflammatory diseases, which I believe will probably covered um the previous immuno content. So, talking about kind of the different diseases and the mono genetic poly genetic patterns that I won't be going into any of that. You were pleased to hear. Um But what I will be talking about is allergy, which is the bottom one and those type of reactions. So very briefly, all hypersensitivity reactions or all immunopathology. So damage within the body because of the immune system can be broadly classified into one of these. So these were initially used just to talk about kind of skin reactions that we saw. But now we can expand them to cover all of the reactions that we see. Uh And I'm kind of going to be talking through the processes behind each of these as well as the clinical examples of them and any other kind of key concepts that you guys need to know. So the first one obviously is your type one reactions. So for these, these are I G mediated and I'll come onto kind of what I G the role I G plays in these shortly um I G media mediated immediate reactions. So if we take, for example, are peanuts are allergen here, what we need to kind of get a type one reaction is we need a first exposure which the end result of is sensitization. So you will be sensitized to peanuts at the end of this. So we intake are peanut allergen somehow. Uh and what happens is the antigen presenting cells in your body will pick up that allergen and they will take it to your lymph nodes and in the lymph nodes, as I'm sure you guys will be aware of in terms of microorganisms, they'll present it to the T cells. And because of the cytokines that happen to be floating around at that point in time, they'll develop down this T helper to pathway. So your naive cells will become T helper too or most of them. And those will do two things. So they'll release I L4 which causes B cell class switching. So all our nice B cells will stop producing I G G or I GM or anything else and they will start producing I G E specific to your peanut. So it's capable of binding your peanut protein. Uh and then your IgE will go and it will find mast cells and it will bind to them and it will prime them or sensitize them ready if your body ever encounters peanut ever again. And the second thing these cytokines do is I L5 will promote a sinful development and proliferation. So at the end of this first exposure, what you'll be left with is you have your I G E which is bound via the F C region to your mast cells. And you have lots of these cinephiles ready for if this ever happens again. So at the end of that, your, your sensitized, there's IgE present in your blood, but you're not necessarily allergic, what you need for an allergy is the second exposure, which can happen months, possibly even years later. As soon as this happens, the allergens, at least two of them bind to your IgE on your mark cells and that triggers the whole early phase response. So what we know is an allergic reaction happens because of allergens binding to I G E on mast cells. And that causes them ourselves to release everything they have inside they're Granules. So the main thing people think about here as history, me, uh histamine is what's going to cause your vascular permeability to increase. So all the fluid can kind of use out of your capillaries, it causes your rash, uh it causes your itchy sensation. Um And in some people, obviously, it can cause smooth muscle contraction. So that's why they feel the bronco spasm in anaphylaxis. So there's just a little summary here as well of kind of that process. So it's important just that you guys have the distinction in your head between being sensitized to something which is just the presence of IgE to a certain protein in your blood versus actually being allergic, which is when it causes this clinical symptoms. And in terms of the allergic disease that we know we need to be aware of. So I'm sure you guys by this point in your medical careers will kind of be familiar with anaphylaxis. So put the common triggers here. Obviously, it's a life threatening. Uh And the next slide just summarizes the treatment for anaphylaxis as well. But this is obviously the most of the most immediate version. Another one which is perhaps less well known but kind of important for you guys to understand is oral allergy syndrome. So people with oral allergy syndrome, as the name would suggest, typically only get symptoms within the mouth. Um and the kind of mechanism behind this is if you imagine somebody inhales pollin and just like we saw in the previous slide, they start making IgE antibodies to that pollin. Um But pollen actually shares part of its protein with pair, for example. So you can imagine that if I was to then go and eat a pair, the antibodies that were meant for pollin could cross react and bind pair as well. So this is what we see. There are some connections, for example, birch can connect apple and pear. Um And we can see that in particularly adults rather than Children and just a sort of side note or caveat to that is that these allergens are all sort of heat to label. So if you were to cook pair, for example, and put it in a crumble or something like that, you're not gonna get the same allergic reaction. And then we have other types which are your mix and your non IgE mediated. So these, you kind of need to know a little bit less detail. You don't necessarily need to understand the underlying pathology but just important to be able to give an example. So, atopic dermatitis, for example, is a mixed picture and then your non IgE mediated, which is where your lymphocytes causing the destruction. Um is a prime example, would be your celiac disease. And this is typically a more kind of chronic picture. So it's not necessarily an immediate anti allergen exposure causing symptoms, but it's over a kind of sub acute period of time. Um, as I said, obviously, just worth being aware of your anaphylaxis treatment they did for, are you at least kind of try and bring in the specialties together with pathology and apply them both together? Um So you may well find yourself seeing questions which kind of bring in both areas. Um And I've put a link through to the guidelines there as well as well as some other kind of key concepts on allergy treatment. So using anti histamines or even immunotherapy as well. Um, in terms of how we investigate allergic disease, um, there are a couple of different or a few different investigations. I'm gonna be going through these ones which I feel like are the most important to have an understanding of. Uh, so the first one is skin prick testing. Uh So what this will do is essentially will take an allergen, be it peanuts soy, whatever it may be and it will combine it with a dilute ins and apply it directly to the skin. And then as you can see on this picture, what we do is we basically just measure the size of the wheel or the kind of reactive area, uh the swollen area compared to a negative control, which will give the dilute on its own. Uh And we also use a positive control, which will be histamine, which as you can imagine will always cause this response to somebody's skin even if they're not allergic, um reasons why this is good. So as you can imagine, it's quite easy to do. It's cheap. And there's a high negative predictive value, which essentially means that if I don't react to an allergen through this test, it's quite unlikely that I'm allergic to it. Uh but the downside and sort of possible contraindications, they could give you in questions to do a skin prick testing are that it is obviously difficult to interpret if somebody has a skin disease. So for example, a child with severe X men or something like that, uh will not be able to skin protecting equally. If people for some reason can't stop their anti histamines, they won't be able to do this type of testing. Um And there is also a risk of anaphylaxis. So if you have a very high risk patient, it's unlikely that you will be happy to give them this kind of testing. And then the next type is I G E or your sometimes hear it referred to as rast R A S T blood testing. So this is not necessarily a confirmation of allergy as such. You'll remember a couple of slides back. I said there's a difference between sensitization to having IgE in your blood versus an allergy clinically. But what this does is it kind of gives us a risk profile. So there are a couple of different factors on the blood that we can look at to decide if someone very likely to have an allergy. So we can, for example, look at how high affinity the IgE is. So how well it binds are strongly, it binds to the allergen. Uh We can look at obviously the levels of I G factors like that and together those will form a kind of risk profile for that individual. And we can say okay, it's likely that they're allergic to this. But obviously, we can't say for certain and you would use this if for some reason, things like skin prick testing or intradermal testing, which is a similar method aren't possible for the reasons I mentioned before. And then the kind of gold standard that we use or that could be used is an oral food challenge. Um So this is exactly as it sounds, the patient will essentially just consume increasing doses or increasing amounts of whatever it is that they are suspected to be allergic to. Um As you can imagine, this is quite high risk intervention is a high risk of anaphylaxis. It also takes a lot of time. Um, and particularly if you have young Children, it can be quite difficult to decipher if they are actually getting symptoms. So in theory, it's the gold standard, but it's not necessarily always stuff. Um, and this is just a kind of confirmation of what I was saying about how we compare the size to decide if someone is likely to be allergic. I do have on my slides, not that I'm going to go through. But when you have them for yourself, a summary of all the other investigations as well, but these are kind of the main ones I would take away. Um I will pause in case there's any questions or anything like that, but the sounds of it, I think we're okay. Cool. OK. So type two reactions then um so the kind of prerequisite for this type of reaction is that there needs to be some kind of breaking of central tolerance in your body. So you guys might be familiar with the idea that any cell that's capable of recognizing our own proteins should really be destroyed somewhere in its developmental pathway. For some reason sometimes that doesn't go to plan and we end up with these kind of angry autoreactive B cells or T cells which are capable of recognizing our own proteins and kind of harming our own body. So in this case, it's a B lymphocyte B cell and it will produce antibodies usually of the I G class um to some kind of antigen within the host. So this might be an intrinsic antigen. So something that is naturally just inside my cells on the surface of my cells or sometimes it can be an extrinsic antigen. Um And what I mean by that is that sometimes if I take a medication, for example, um through a variety of processes, tiny sort of peptides from that medication can end up on the surface of myself. Myself might present a bit of penicillin peptide, for example, but it's simply um and so I might have a B cell in my body that's capable of recognizing that antigen. And in doing that, it will start to attack myself as they're displaying it. So then these antibodies decide to attack the host cells in your body and they'll cause things like fake cytosis, they'll activate your complement pathways and all the kind of other arms of your immune system. And um that you may have learned about previously. But ultimately, the response is that specific cells within your body that are displaying that specific antigen will be destroyed. And and a couple of examples just to familiarize yourself would be things like good pastures disease. So in this case, the antigen that's being recognized and killed is a type of collagen in your basement membrane. And you may or may not be familiar with kind of the clinical presentation of that, which is that people may have hemoptysis, they may have renal disease, etcetera. Uh Another one, pemphigus, vulgaris, which can cause some skin blistering. Uh sort of caveat to that process is um when the antibody binding doesn't necessarily cause destruction, but it just sort of gets in the way of the normal running of things. So it will either block a receptor or it will over stimulate the receptor. So a classic one that I'm sure you will know because you went to imperial um is brave disease. So that will over activate the TSH receptor when it binds to it. And it will cause clinical hyperthyroidism, myasthenia gravis, similar, but you can think of it sort of the opposite. So it will prevent the receptor from functioning and prevent the action potentials. And that's why you get that fatigue bubble with muscle weakness. So type three is similar in some ways. But the key difference is that the antigen that's being recognized is soluble. So instead of being attached to my host cells, it's just kind of floating around somewhere in my bladder in my body. Um and, and the same thing happens. So your B cell creates antibodies against this soluble antigen and together they form an immune complex, which is quite simply just the antigen plus the antibody together and they formed clumps. And as you can imagine, if things clump together and get stuck somewhere in your body that can cause issues and it can cause a lot of inflammation. Um and the way that that typically happens in type two reactions is by activating complement in a very large scale. And that's why you guys may or may not be familiar with the fact that we can use C three and C four to uh complement components to measure disease activity in Lupus. For example, lupus is a type three reaction. So if you have low levels of C three and C four, it means it's all being used up because there's a lot of information going on, it's being consumed. Um and complement will act as an uh felt to file a toxin apologies. Um And so similar to our type of reactions. Basically, this will cause a Dema it will cause um swelling, inflammation, michael's skin reactions, etcetera. And you'll also get a recruitment of other inflammatory cells. So you'll get figure sites that come to the area and they try and figure cytose all those immune complexes to get them out of the way, clear them. Um But unfortunately, it doesn't work for some reason in these cases. And so what you actually get is those figure sites in term in the process of trying to absorb the immune complexes will just release all their enzymes. And you can imagine that that then causes even more information. Um and it causes necrosis as well. Specifically, it causes something called a fibrinoid necrosis, um which is just a sort of histological pattern that we can see on the microscope slides. And you can imagine that the specific symptoms you get kind of depends where your immune complexes are being deposited in your body. But typically we see that they go to the kidneys, the joints and the blood vessels. So that makes sense then that when we look at type three reactions, type three diseases like lupus, these are kind of the areas where you're seeing symptoms. And I've also got the antigens here that are being targeted. So remember, these are all soluble antigens somewhere in the body type four reactions, which is our last type. So these are your delayed hypersensitivity reactions you might hear them referred to. Um and I always think these are kind of most similar to your normal immune response to viruses, for example, or bacteria. So it's quite similar to that process. So you have an antigen here. In this case, it's a molecule from a poison ivy plant and this is quite small molecules. So it can essentially move its way through your skin and it will get picked up by one of the patrolling dendritic cells which will take it to the lymph node and it will activate your naive T cell that's capable of recognizing this antigen. And when that happens, depending on the cytokines that are around and depending on which T cell it happens to show it to, it can go down to pathways, so it can go down to CD four pathway. Um and CD four is, they're not cytotoxic. They can't kill things themselves directly. But what they can do is they can recruit lots of macrophages and then the macrophages are basically what causes all the damage. So they'll create ross or reactive oxygen species which can kill damaged cells. They'll release license signs, they'll release lots of inflammatory cytokines and they'll recruit more and more immune cells. So that's the way the damages occurring when you activate CD four cells. If you activate CD eight T cells within this lymph node, these are a bit more involved. So they will directly cause apoptosis and cell death themselves. Um So they have things like perforin. They have grands, I'm, which can do the killing directly. But at the end of the day, the kind of a result is that you get the same cell and tissue destruction. Um And these are just examples of different types of delayed type hypersensitivity or type for reactions. One to possibly draw your attention to is the tuberculin skin test here, which you'll obviously realize is not a disease per se, but it's a way that we can kind of manipulate this reaction in the body to um see if somebody has previously been exposed to TB or A B C G vaccine. So at the end of that section, I've just got a couple of questions for you guys to do just to make sure that that's hopefully making sense. Um And you're kind of following me so far because I appreciate it's um a little bit heavy, maybe a little bit dry as well. So I have a slider for you guys to just answer a little pole. Um And we'll see how it goes. So let me go back to the previous one. So I just got a question here. Basically, what type hypersensitivity reaction is also called cytotoxic hypersensitivity because it involves antibody media to destruction of specific cells within the body. So hopefully, you know, there are only really four or five options. So it's just a case of working out which number. And then when a few more people have answered, we can have a look and we can have a chat through it, check that there's nothing in the teams as well. Cool. Okay. I'll give it a few more seconds and then we can look. Okay. Cool. So there's a range but I think the majority of people definitely went for type two, which is correct. So to kind of explain this in a bit more detail because I appreciate the question was maybe using some words, I didn't the explanation. The reason this is type two is because it involves an antibody and it involves antibody mediated destruction of specific cells. So you might remember that when I was talking about type two, I said it recognizes a specific antigen on the outside of a specific cell. So for example, with our good pastures, it recognizes collagen, which is specifically on a type of cell. Whereas with our type three, the damage is not really sell specific, it can damage anywhere in the body. Um It will just damage wherever the immune complexes happen to end up. So that's kind of the key difference between type two and type three. So type two is your cytotoxic antibody dependent reaction. Type three is immune complex dependent. Hopefully that makes a little bit clearer. The next question. So in type one hypersensitivity reactions I G E binds to what expressed by masked cells is also expressed by baseballs in the center pills. But the main thing is mast cells. So what is it that the IgE is binding to to cause those cells to be kind of primed? Apologies also if you can hear the noise from outside. Mhm Okay. I'll give it a little while longer and then we can have a look at what people have suggested. Okay. Yeah. Perfect FC receptor FC region. Exactly. Yeah. F C component. Perfect. Yep. So the IgE that's created in response to your peanut or whatever it is that you consumes, binds to the F C region or via the F C region to your mar cells. And that means the mar cells are primed ready to go in case you have a second exposure. Fabulous. OK. So back to the pathway. The next thing this is just the answer to summarize. The next I'm going to talk about is transplant, specifically transplant rejection. If you guys are not familiar or you need reminding of the type of graphs and things like that in transplant. Um I have included a glossary at the end of this side, we'll just keep times and immunology. So if you want to have a look through that, that might help clear things up. But I'm going to assume that we kind of have a baseline understanding of how transplant works in terms of were taking organ or tissue and we, we moved someone else's body. So the two types of rejection you can think about as being T cell mediated and B cell mediated or antibody mediated. You might also see the word humeral being used bit less commonly in terms of how rejection happens. So you can think of it in three basic phases. The first one is that the antigens on your graft say it's a graft, kidney need to be recognized. Somehow they need to be recognized as foreign proteins that's not belonging to the recipient. And then once that happens, you need to have activation of your immune system and specifically the parts of your immune system which are capable of recognizing and binding that antigen. And then phase three is basically all the damage that gets done. So all the effects of functions. So sort of sight, sight of toxicity or your inflammatory cytokines, everything like that. And the important kind of determinants of whether somebody is going to reject the graft or not. So the main one is your HLA type. So you're human leukocyte antigen and you may see that you've kind of interchangeably with MHC. Um and the other one is your A B O blood group. So obviously, if I have a positive blood group, there will be part of that present in the vessels, in whatever organ I donate to someone. And so if we are a match in terms of a V O blood group that can cause problems in terms of rejection down the line. So thinking about HLA kind of what it is and how it can cause problems. Um Again, you guys may or may not know this stuff already, but it's encoded on chromosome six. It's a set of genes that essentially help us in terms of recognizing different viruses, organisms as regions. Um and they're very variable between people. And that's normally a good thing because it allows us to recognize lots of different things. But it also means that there's a potential to have different HLA types to somebody that you're donating to. And that's where the problem can arise. So we have two different types of HLA, we have class one, which is your A B C and you have HLA class two, which is your GERD QTP. Um You'll see that ABC is present on everything in your body. Whereas this class too is typically only cells involved in the immune system, the antigen presenting ones because they need to have it to present to your T cells, but it can be upregulated as well and by other cells. So if the cells become infected or cancerous or something like that, they might got to up regulate. And as I said, if you have a mismatch between yours and somebody else is HLA, that's a kind of source for potential rejection. They might start for antibodies against your HLA. um and they can sort of attack the graft. So thinking about kind of how we avoid that or how we predict it. We can look at yours and your donors or yours and your recipients. Um HLA type and we tissue type them preop um several times as well as POSTOP and we particularly care about the D R group. So this is the most important factor in terms of transplant rejection. So if ever you have a question about which is most significant, it's always gonna be D are followed by B and followed by A and you may know that HLA is inherited by your parents. So it's a simple sort of Mendelian inheritance pattern. You inherit half from one biological parent, half from the other. And so that therefore means that each sibling that you have, if you have any has a one in four chance of perfectly matching your HLA. So it's 25% chance of them perfectly matching 25% chance of them having no matches at all. And then there's a 50% chance of them being half a match with you. And to kind of put that into perspective, if I was just to take a random stranger off the street, there's around a one in 100,000 chance that they would match with you. So that sort of makes a bit of sense in terms of why we look at someone's immediate family when we want the donor. And if that's still not really making sense, just to kind of explain it a bit more. So, say that I am the recipient of a kidney. Um This is my donor who's giving me the kidney. I said, the A B and D are the most important groups. So we're just gonna haplotype or tissue type of these for now. Um So we can see here that I've inherited a one from my mom, let's say, and I've inherited a two from my dad, whereas the donor is inherited a one from their mom as well. Great, we match, but they've inherited a 11 from dad. So you can see that these two here are different. So we've got one mismatch from each other. And similarly, you can look at your B groups and you can see here that we also have one mismatch in terms of our B H L A, but our D L HLA matches perfectly. So we have no mismatches here. So our total number of mismatches across these three groups would be too, obviously, you can see that the maximum mismatches would be six in which case, we would ideally never transplant that organ. Um And and the perfect match would mean that all six of these are the exact same, which would be ideal. So hopefully, that helps you kind of understand where things could go wrong and why you might have projection of an organ. Obviously, we can't always perfectly match someone and we do see draft direction. So we also need to think about kind of how that happens and also how we can stop it. So the first time we're gonna think about is T cell rejection. So as I mentioned, the first thing it needs to happen is the foreign antigens on that donor kidney need to be recognized. Um The T cells do this in a number of different ways. So we have the direct pathway whereby some of my antigen presenting cells will still be present on that donor kidney. They might happen to be within the tissue or in the blood vessel. And so my donor A pcs will present my peptides, my MHC to an immune cell in your body and you'll obviously recognize, hang on a second, that's not mine, that's not normally here. And then you have these two indirect and semi direct pathways which are a bit different. So if these, what happen is if we start with semi direct the recipient antigen presenting cells, so a dendritic cell, for example, floating around your body will present my MHC to your immune system. So the only thing that's actually coming from me from the donor is the MHC. And we think this happens when cells kind of swap MHC between themselves. Um I wouldn't be able to go into the detail of kind of why or how that happens. But you can think of it essentially as like when bacteria sort of swap genes that help with the resistance. So we swap MHC with each other. So a cell that belongs to you has somehow ended up with some of my M H D and my protein and the indirect pathway is similar. But instead of presenting the whole MHC that belongs to me or belongs to the donor, instead it just picks up kind of little peptides, little parts. And this can happen sometimes when the graft cells die and they release the proteins out into the environment. So obviously in most organs in the body, there's kind of a level baseline level of cellular death and regeneration. Um And so what happens is when those cells die, they might release little peptides and your recipient dendritic cell which was just kind of floating along at that time happens to pick up some of those peptides and it will present it to your immune system. So usually three slightly different methods. But at the end of the day, the same thing happens, your immune system recognizes that something is abnormal. There, there's something foreign uh in your body and the T cells will become activated and then the cytotoxic t cells and the macrophages similar to our type four hypersensitivity will essentially destroy those cells destroy that graft. Um And it will begin to fail and then antibody mediated rejection or B cell mediated. Again, we have the same kind of process. So we have recognition of the antigens. Something is abnormal, something's foreign in the body and then the B cells will proliferate and they'll mature and they'll be able to create antibodies. So in terms of what antibodies they're actually creating, the first type is anti HLA. So remember I mentioned that if my HLA differs from my donor and my recipient, it's possible that antibodies can form against the different molecule because it's obviously something their body's never encountered before. They don't know what it is, they want to attack it, same as you were to kind of flu virus or something entering into your body. Um And these aren't naturally occurring. So you won't naturally have these in your body because obviously you've never seen someone else's HLA, that's not a standard thing that happens. But what can happen is if we give someone a blood transfusion or if you're pregnant with the foetus, that has a different HLA group to you, obviously, because that can happen, you can form these antibodies. Um So these are called preformed anti HLA. So when I give somebody a donor kidney, if they already have anti HLA in their body, for one of these reasons, they might start to attack it straight away. So we'll see that sooner or they can have post formed antibodies. So for some reason, if the kidney that we transplant begins to fail, um the graph damage will cause widespread release of HLA and peptides and then your body will start to make antibodies against that because you don't like that. Anti A B for example, um is naturally occurring. So that's a bit different. You think about how we have to match blood groups? Are we doing transfusions? Exactly the same principle. So there are low levels of your blood group in your vessels within a kidney or liver or anything else. So the same thing can happen if I am blood group A, I might have antibodies against B. And so if you give me a beast um type kidney, I might start to attack it. And the kind of end result of this process is that eventually one of these antibodies will bind to the endothelium on the graft. So it binds within the blood vessels and it will cause vascular disease. And that's what ultimately makes the graft fail. So if you ever have a question about kind of the location of antibody mediated rejection, you always want to say something to do with the vessel or the endothelium or the capillaries. And again, that has a kind of specific pattern under the microscope. But the kind of buzzwords here really are that it's to do with the vessels. And then in terms of how we treat that. So the main thing is that we want to kind of screen for it, we want to be able to predict when it and when and if it's going to happen. So in terms of antibody mediated, we want to check does a person have any of those anti HLA or anti A B antibodies before we give them the organ during the allocation process? So once they've been assigned a kidney or whatever, or then it may be. And then we also want to check again after we've given them the kidney. So remember I said that sometimes antibodies conform once it's already been transplanted, we want to check if that's happening. It's always good to get ahead of a rejection before it kind of starts taking hold and your graph starts failing. And then in terms of T cell. So this is a little bit trickier I guess to pick up. But the main thing we look at is how well the organ or the graph is functioning. So again, with the example of kidney, if you start to see that the creatinine is dropping or increasing, if you start to see that the, the E G F R is dropping, um if the urine output is decreasing, if anything's go going on, that suggests poor organ function. You can do a biopsy and that will ultimately confirm the diagnosis. So for both of these, actually, it's the biopsy at the end of the day that will definitively confirm the diagnosis because you're looking down a microscope. And you can see for example, that there's um disease within the vasculature within the endothelium or in the case of T cells, you can see that there's lots of T cells, lots of inflammatory cells within that zone. Um And then the other thing we can do obviously is we can give it immuno suppressants. So that's kind of the whole purpose of immuno suppressants when we give a transplant is to prevent this happening. So we have this induction agents which given beforehand. Um So we can give anti thumbs like globulin. Um We can give anti C D 52 we can give anti CD 25 obviously, the exact regimen will decide, will be decided by your hospital and also what organ you're receiving. Um But it's just good to kind of have an awareness of the possible agents we might use. And then you also have your baseline immuno suppression. So once you've received your graft, you will typically be on the calcineurin inhibitor, which I'll go into it a bit more later, you'll be on mycophenolate, Matile or azaTHIOprine and then you may have steroids as well and then specific treatments for if we are, if we do identify rejection. So T cell you'll be given basically steroids is the main thing here. IV. And then oral and if it's B cell rejection, then we're thinking about things like plasma exchange and I V I G as well as anti B cell agents. Two anti CD 20 we can give to target B cells and stop them producing antibodies. The main thing obviously, it's easier to try and prevent it than it is to treat it. And then the final part of transplant to be aware of is the idea of stem cell transplant. So I appreciate this is quite a lot of text. This is just to kind of compare the two types of stem cell transplant that we can do. So we have autologous or kind of thinking of it as patient's own stem cells and we have allergenic, which is an HLA matched donor similar to how we would donate an organ. So which type you go for? Essentially depends on, well, firstly what kind of militancy or what disease the person has, but also their age and their fitness. Um and sort of whether they'll be able to handle each of these treatments essentially. So key things to kind of understand the difference is that with an autologous transplant, you obviously take the patient's own stem cells, you freeze them, you go to them this high dose chemo or whatever treatment they need for their cancer or their disease. And then once they've had that, you then fall and you could re infuse their own stem cells. So the perks of that are that obviously, you don't need to give them immuno suppressants because you're just putting their own cells back to their body. So they're not going to reject them. There's a lower infection risk. Therefore, because you're not immune suppressing them. Obviously, if you have stem cells, you can do autologous stem cell transplant. It's readily available. You don't need to bother trying to match them. And this is what I was suggesting about how fit or how old somebody is. So elderly typically find these regimes easier. Um So the high dose chemotherapy here and the lack of immuno suppression is a lot easier for people to cope with versus this type. The downside is that if you imagine in a blood cancer, sometimes the malignant cells can get into your bone marrow. And so if I'm just re infusing your same bone marrow, you might relapse further down the line. Um So there's no what we call graft versus leukemia effect here because it's just your own cells which might reintroduce malignant cells alongside them versus then your allergenic type. So as I said, it's an HLA matched donor. So we basically completely destroy the patient's bone marrow. And then when we introduce the new stem cells, they just take over and now they own, they colonize the blood marrow, the bone marrow, sorry. And, and this does have a graft versus leukemia effect. So what I mean by this is that there will be some uh blood cells, some white blood cells and immune cells within the stem cells that are capable of attacking, finding and attacking any leftover malignant cells. So even kind of later down the line, once we've done this stem cell transplant, we can see that there's less chance of the leukemia happening again, relapsing or recurring if we do this type of stem cell transplant. Um and obviously the graft because you're taking it from somebody unrelated, they don't have cancer in their stem cells. So the graft will be free from anything um sort of militant, but it does mean that you have a risk of something called graft versus host disease. So to kind of go through this graft versus host disease is essentially where those donor lymphocytes, donor white blood cells recognize and attack the recipient HLA So it's kind of the opposite of organ rejection if that helps you to um to contextualize it. And so these donor lymphocytes attack your own body and you can get sort of skin rashes, you can get chronic diarrhea, you can get a lot of really awful symptoms. And actually, once this starts happening in the body, it's irreversible. So we can try and dampen down the reaction, but it can never be cured, so to speak. So this is really significant risk associated with allergenic types. And obviously, because we'll also need to immune a press them in, you know, suppress them. Uh They may get opportunistic infections and they may get uh infertility or other side effects as well. Again, apologies if you can hear the sound from outside. Um Hopefully you're still with me. So that's the kind of whistlestop tour of transplant rejection. Again, we're going to do the same thing. So I just got a couple of questions on it is a different slider. So I'll just put that up now. Um Is this one here and we'll do the same thing again. So the question I have this time is uh if a 35 year old man needs a renal transplant because he's had a diagnosis of renal cancer, renal malignancy. I won't need to rank the following potential donors from most preferable to least preferable. So one should be the best option. Five should be the worst option in terms of graft outcome. And then these are all the options we have to take potential kidney from. So that's the first question um and not open up teams as well just to see if there's anything there. Okay. So I appreciate this one might take a little bit longer because it's a little bit fiddly. Um So that's fine. Obviously, if anyone has any additional questions, please feel free to a mute or type in the chat or anything like that and we'll go through this one in a couple of minutes. Mhm Apologies. If people are getting frustrated with my, um, desktop rearrangement as well. It's not my laptops. I'm getting used to it, but hopefully we're doing okay. Okay. I think there's a couple of people still typing uh, or rearranging and then we'll have a look at what people have said. Okay. Okay. So let's have a look. Perfect. So, the first thing to say, I guess about this question is, um, that obviously in real life we would tissue type all these people and we would have an exact idea of who was the best match, but we don't have that information here. So we're kind of just working this out based on our baseline understanding of what each person's H L A connection should be. In theory based on just epidemiological and inheritance information. So you all or most people have correctly said that the first or the best option would absolutely be a twin. So in theory, a monozygotic or identical twin would have an identical HLA to you or to this man. So that would be the best option. Obviously, I was a little bit mean, perhaps I didn't actually say what type of twin it is. Um But even if this was a dizygotic twin or um non identical twin, there is actually some interesting evidence which suggests that twin is more likely to carry your same HLA versus a normal sibling. So even if this had been a non identical twin, this would actually still be the best option. So why don't I want to put that? Um And then the next option people have correctly said is a sibling. So you'll remember that. I said that siblings have a 25% chance of being a perfect match to you. Obviously, they have a 50% chance of being a half match, so to speak and a 25% chance of not being a match at all. But when you compare that to a parent, a parent can at maximum have only 50% or a half match with you because the other half comes from your other other parents. So sibling is definitely the best option, parent closely follows. Uh And then you guys correctly worked out that between an unrelated live and cat of Eric or uh deceased donor live is a better option. We'd have, we typically prefer live donors. Uh There tends to be a better graft survival. Uh This could possibly be related to things like ischemia um or things like that. So we typically see better outcomes with live. So that's absolutely the correct order. The next question um is about which of the following investigations would be able to give us a definitive diagnosis of humoral graft rejection after a hepatic or a liver transplant. So which option would allow me to diagnose humeral graft rejection? You guys have a think about that one and then again, we'll go through it in a little while. Okay. Okay. So I think we're on similar numbers that we had last time. So we'll have a look. Yeah, perfect. So most people went for liver biopsy, which is absolutely correct. So going through this, not necessarily one by one, but just a bit more detail. So things like prothrombin time A L T even CT Abdo, these could all suggest to you that the liver graft wasn't doing well. So prothrombin time, for example, you might see um this could suggest that your liver is not at the synthetic function of your liver is not good. We obviously do use this in terms of liver disease, but it's not specific in terms of giving me a definitive diagnosis of graft rejection. It doesn't tell me that the reason the liver is struggling is because of graft direction. Similarly, for A L T, um this is just kind of a marker of the hepatocytes. Uh It's very nonspecific. Um So I'm glad that nobody went that uh CT ABDO again, you could possibly see some signs of ischemia of vascular disease. But we don't know that that's because of graft rejection. So the thing that we absolutely need to do is we need to take a biopsy. Uh and we need to see under the microscope whether there's any histological evidence of graft rejection, which hopefully you guys will remember from the slide, if it's antibody mediated or humeral will be within the vasculature. So, within the endothelium is where we will be looking to find the science projection. Perfect. So, um the next section, if anybody has any questions, um is going to be on therapeutic. So I'll just check my teams finally. Uh No. So this question is quite heavy. It's quite memory based. Um I appreciate that I'm not going to be able to just teach you every single drug, uh, and its target today. Uh And it will take a bit of work in terms of sort of flash cards and things like that in your own time. Um But I would say these therapeutics do definitely come up in terms of the exam. So it is good just to kind of understand what the differences between them and what diseases that used for. But before we get into those details, I kind of just wanted to talk about this balance in terms of the immune system. So at any one time in your body, you have inhibitory signals which are trying to dampen down your inflammation and immune response. Um And you're also having inflammatory or activating signals which are kind of telling you to activate your T cells are released cytokines or, you know, figure cytose things that they don't like that are floating around, you know, be it pollin or viruses or whatever else. And obviously, depending on if you're on well at the time or, you know, if you're an allergic person or something like that, you're kind of teeter between these two signals. But roughly your body will keep you in equilibrium. Um And any infection or disease you have will resolve and it'll keep you balanced. But the issue comes when somebody kind of teachers too far in one direction. So the first option we have is that they're in an anti immune state. So for some reason, their body is not able to mount the correct amount of inflammation or immunogenicity. Um, so it might be related to sort of HIV infection. It might be related to cancer. And there's a lot of clever different ways that the immune system and the tumor cells can kind of evade the immune system and can dampen down our ability to respond. Um or it might be a genetic reason. So I think in your other lecture, you would have talked about kind of the primary immune deficiencies where you can lack certain components um of your immune system and you can be susceptible to infections. So, obviously, these people are very susceptible, as I mentioned to abductions, things like that. So what we want to do is boost their immune system, we give them immune boosting therapy. If you want to think of it that way, we try and level out that cease all that balance. So the ways that you need to be familiar with to do that our vaccination, replacing whatever it is that's missing in the body, giving them cytokines and then checkpoint inhibition. So we're just gonna go through each of these in turn. So I'm sure you guys are familiar with vaccination or immunization, but kind of just to recap the key concept here. So vaccines obviously use your immune memory. Um That's kind of the principle that they rely on, which is essentially where following resolution of an infection or exposure to whatever antigen it maybe you sort of retain information about that antigen that is leaves your body capable to respond in a better and quicker fashion. Should you ever encounter it again? So this is maintained by, for example, having this preformed pool of antibodies, they're ready to go. If you do get, you know a cold again, Rhinovirus, whatever it may be, and you also have a residual pool of specific T and B cells which are already activated, already ready to go and recognize that antigen and kill it or do whatever needs to be done. And to be a good vaccine, we generally say that it obviously needs to be able to create that immunological memory. So you want to be able to inject or give the vaccine, it causes an initial immune reaction, but it also allows the body to remember it for ideally a long time or forever. It also needs to be safe. So you don't really want to be having any adverse reactions and needs to be practical as well. So you may have seen discussion's around COVID time about the sort of cold chain and things like that ideally, we want it to be as simple as possible to administer, to maintain these vaccines. Um And another thing just to kind of talk about is this idea of adjuvants. It's something you need to be familiar with. Um So sometimes whatever virus or bacteria is that we want to um immunize someone against doesn't kind of enact much of a, an immune response from somebody for some reason. Uh we sometimes see it in uh elderly people or other people. Um And what we can do to enhance that is we can give an adjuvant and this will boost the response. So it will provoke more of a response without changing the specificity. So you'll still react to that specific strain, but you'll just get more of a response, um which is obviously ideal and we can do it in two different ways. So the first way is that we can just give more antigen over a longer period of time. So we would call it a depo or a depot adjuvant. Um So it kind of self regulates the antigen exposures will allow it to sort of slowly leak out over an extended period of time all the while you're creating more T cells B cells, et cetera. And then the other type is the stimulant, um adjuvant. So these are where there is some kind of chemical or compound which triggers the immune system, boost it even more. Um uh sort of anger that in some way so that it reacts then more to the initial antigen that you're giving. Uh an example of adjuvants would be something like aluminium salts. And there's more notes about kind of specifically what achievements fit more category in the notes, but I won't go into too much detail here. So this is a disgustingly detailed table about different vaccine types. Um Unfortunately, kind of do need to know at least the examples for each. Um It's very simple to remember. I don't think it would challenge any of you. It's just a case of memory, sadly, so I would say just sort of flashcards, but I'm just gonna kind of pick out the key concepts here that can be tested. Um And that I did notice kind of recurring throughout the past five years or so passed papers. So the first thing is the idea about live attenuated vaccines um and the reversion. So if you're just modifying a live vaccine to make it a little bit less virulent, it obviously does have the capacity to revert back to it's very virulent, very dangerous self. And for most people, that isn't necessarily a huge issue, they might be able to cope with the infection even if it does occur. But for immuno suppressed or immunocompromised people that can be really dangerous. Um And so we generally don't give live attenuated vaccines to immuno suppressed people. So you may see questions about uh for example, uh HIV positive patient, you know what vaccines can we give them? What can we not? Um And it's important just to kind of be aware of that concept. Uh The next thing is about this idea of inactivated vaccines. So the kind of flip side of the comment I just made is that these are safe immunodeficient people. Um So they don't have any capacity to revert, they're safe for everybody. Um We can definitely give these if somebody is taking, you know, immunosuppressive medication or something like that. And then the other thing just to highlight is the conjugate vaccines. So these are good for encapsulated bacteria. So you're in capital encapsulated bacteria, you might be familiar with as the NHS bacteria. So in Syria, uh haemophilus and strep, uh these are particularly used in Children as well. So you'll come across them impedes, but also um inpatient, you've had a spinal mentally will often give this type of vaccine because they're particularly susceptible to these types of bacteria. Uh And you may well see kind of more questions coming in about DNA vaccines. So there was a lecture about this in my year a couple years ago, obviously relating to COVID. Um it's worth just being aware of kind of what the concerns are with these type of vaccines rather than necessarily the specific types because that's quite new. So the next thing we can do is we can replace the components of your immune system that are missing. Um So we've obviously talked about stem cell transplant and won't really go into that again. Um But we can also replace antibodies. So if somebody doesn't have antibodies, for whatever reason, we can give them two different types, we can give them human normal immunoglobulin. Um And this is collected from a number of donors, it's all pulled together. And the idea being that it will contain I G G to a wide range of organisms and allergens that those people will have been exposed to over their lifetime. So we're not looking to protect against any one specific thing. We kind of just want to provide a baseline, uh varied protection to lots of different things that this person might encounter. Uh And you would give this when somebody lacks antibodies because of a primary deficiency. So the sort of genetic diseases like hyper I G N, but you might also give it if somebody's had, for example, a bone marrow transplant or they have a blood cancer. Um And they're particularly, they're picking up infections or they're not getting better things like that. And the other type of immunoglobulin or antibody we can give is the specific type. So you can think of this as a form of passive immunization or um post exposure prophylaxis really. So we only use this if somebody has had some kind of exposure uh and they're not already protected against it. Uh So we want to give them the antibodies quickly to prevent them from uh sort of picking up that disease. So an example would be if you have a needle stick injury from somebody who's happy positive, you might get HEP B uh I V I G to protect you from developing hepatitis B later down the line. Um And there are obviously only specific things that we have that type of immunoglobulin for. So it's worth just kind of familiarizing yourself with these view conditions here or diseases here. And then the final thing that we can replace or give somebody R T cells. So there are a couple of different types of T cell transfer that we can do. Um we can do tumor infiltrating and we can do car T cells are kind of the most uh I guess interesting but also complex. Sometimes for people, I do have a slide that goes to a bit more detail about these. Um again, which is will be within the final, but I'm not going to show today. But essentially, this is just where the T cell is taken removed from the body of the patient. Um And it's either just expanded in the lab or it's altered genetically somehow and then expanded and then it's reintroduced with an enhanced capacity to recognize and kill whatever it's targeted. So obviously, you can see that it could be a virus that it's targeting, it could be a tumor cell. Um The idea being that we do already have cells in our body that could recognize and kill viruses and cancer. But sometimes things can get in the way of that process. So we're just trying to boost the capacity of the T cells to do that by genetically modifying them. Uh And then they go in and do that thing and kill off whatever salad is that they need to. The next thing we can do is give cytokines to help people. So obviously, if we're trying to boost the immune system, it will be pro inflammatory cytokines. One example is I L2, which can be given to boost the T cell response, for example, in a renal cancer. Um so similar to the car T cells and we're just trying to increase the body's capacity to recognize and kill off that cancer. Somehow, another one is Interferon alpha. So you can remember this as A B C if you like. So interferon alpha can be given for HEP B and C and it can also become CML. Um and it has an antiviral but also an anticancer effect. Obviously, as you can see here and then Interferon gamma, you may have come across uh in your previous immunology lectures. So this can be used in chronic granulomatous disease just to increase the capacity and the function of your macrophages um and try and kind of reduce the symptoms. And then one which I always found a bit confusing, I guess at the time when I was learning, it is Interferon beta. So this is actually given in M S. So you can think of it as dampening down the immune system rather than boosting it. Um This is given in relapse and remitting type of M S just to halt the progression of further demyelination in the body. And then the last thing we can do to boost the immune system is a checkpoint inhibition, um which you guys may have come across in your sort of team or cancer of aspects of the course. So you can kind of think of checkpoints as breaks in your immune system. So as I mentioned with the kind of see, saw there will always be inhibitory signals at any point in time. And if we take away those inhibitory signals, obviously, that will allow the immune system to kind of boost itself and go unchecked in theory. So we can do that by targeting a couple of different molecules. First, one is CTLA four. So this is in the form of ipilimumab or we can target PD, programmed death, one or programmed death ligand one. And this is in the form of nivolumab. Uh both of these work slightly differently. But the end result is basically that T cells survive and T cells become activated and then the T cells can go and kill whatever cancer cells it is, they need to. So just to kind of show you that in a pictorial form here we have PD ligand PD one and you can see that when these binds along with the T cell receptor, the tumor cell essentially survives and the T cell may um Actos or kind of get the signal that it's not needed. Whereas here, when we block this interaction, you can see that the T cell activates, uh it may proliferate, you may recruit other immune cells. And the end result is that the tumor cell is killed, which is obviously what we want. And these can be used in mainly Melanoma but also some other metastatic cancer. So renal cell cancer as well. Okay, I will pause for a second in case anybody has any questions or just needs a moment and then we'll have a think about how we can dump and down the immune system. So uh as I said before, you can also have a proinflammatory state. So you can have auto information, autoimmune disease allergy, which we obviously talked about today. And if somebody does have those things, what we might want to do is give them a union suppressants to balance out the signals. So the first immunosuppressant going to talk about is steroids. So you can see in this diagram here, obviously, you can ignore the kind of detail of it, but we're within the nucleus of the cell. And you can see that the steroids are acting at the transcription level. So this is why steroids have really widespread um mechanism of action. They have widespread effects in the body, it's why we can give them for lots of different diseases. Uh But it's also why steroids don't work immediately. So if you start someone on Orapred, for example, it may take a while for there to be any improvement. Um And that's because if you imagine how long it takes to transcribe a green and then see all of the downstream effects of that gene through kind of cell signaling pathways, etcetera. You can obviously take some time. Um and apologies that this is a bit small, but this is basically just summarizing all the different effects that steroids have in the body on the immune system. So key things to pick out. Um you see here that they reduce the expression of cytokine genes. So the pro inflammatory cytokines won't be expressed as much. You also see that they affect antibody production as well. Uh And here you can see that they actually prevent neutrophils from leaving the blood vessels and entering the tissue. Um Obviously, what that does mean is that the neutrophil count kind of temporarily does increase sometimes when we give people steroids. So you may see that the white cell count actually increases after starting them on uh prednisoLONE or something like that. The next type of immuno suppressant we can give is antiproliferative agent. So, targeting a slightly different part of the cell uh target cell cycle or DNA synthesis. So this may be because it's um sort of antifolate or something like that and it stops the cell from reproducing. Obviously, it makes sense that these are sort of predominantly affecting cells that rapidly reproduce. So that is a lot of cells in your immune system. Uh And that's why that they work successfully as immuno suppressants. So three to be aware of our mycophenolate, mofetil azaTHIOprine and uh cyclo as well. So that's kind of all there is to say about those, I'll go through the side effects of all of these together at the end. And these are cell signaling inhibitors. So to pick out the two pathways you have em tour here and you have calcium urine and can I can hear. So, calcineurin inhibitors essentially will interact with these cell signaling pathways to reduce the amount of I L2 that's expressed by cells. Um And you may remember seeing on the previous slide that we can give somebody I L2 in renal cell cancer to boost T cells. So it makes sense that if we have reduced I'll to, we're getting reduced t cell activity and reduced immune system activity. So this would be something like tacrolimus or tacrolimus. Uh And you can see here as well the indications for this type of medication and then your mental inhibitors uh similarly. So these will dampen down the immune system. Uh and these are used again in transplant, things like Rapamycin. Um None of these are particularly tricky concepts. It's sort of just memory. Um But hopefully at least kind of going through today and then going through it more in your own time will help to sort of uh solidify things. You can kind of just see how they all linked together and target different aspects of the immune system. And then the next part just going to move my um little bar apologies because blocking my diagram. Um So these are your cells surface antigen target ear's. So you can see that they affect T cells, B cells and other cells in the body. So the first one to talk about is the CeleXA mob. So this here binds to see D 25. So we can see her that your molecule binds CD 25. It will inhibit T cell proliferation. Uh and it can be used in rejection prophylaxis. So it stops the T cells from functioning. You can also see a batter set. So that would be symbolized by this one here. Obviously, they don't look like this in your life, but it's kind of just a simplified way of thinking about them. So this is a fusion protein again blocks T cell activation. Uh And it does that by preventing this molecule here, this C D 80 86 from binding to its target. So normally CD 80 will bind CD 28. Uh And you might recognize that CD 28 is the costa military signal needed to activate a T cell. So if the T cell isn't getting this CD 28 signal, it won't become poorly activated and it won't be able to carry out its effective functions. So that's how it stops T cell activation. And this one is used in rheumatoid arthritis. And then the cell surface antigens we can target on B cells. So, C D 20 is the key one and this is riTUXimab. So this recognizes and binds CD 20 and essentially will trigger antibody or sort of cell license of the B cells. So it will reduce the amount of mature B cells circulating, it will reduce antibody production. Um And we can use it in non Hodgkin's lymphoma as well as other hematological cancers. And then the final one just to be aware of is vedolizumab. So this targets alpha four V to seven integrion. Um And this one is slightly different. So it prevents the leukocytes from escaping from the blood vessels. So if they can't escape from the blood vessels, they can't enter the tissues, then you won't get the inflammation that there are aiming for. Um And so this is used in IBD. So as a kind of memory aid, I guess I always remember this as a fed Lizzie mob and I thought of someone being fed as somehow being related to IBD. I mean there are so many antibodies and things like that to learn. So anything that can help you is um is worth it. I always thought. And then this is just a summary, um which I'm not going to go through in detail of the cytokine agents we can use. So another class, but um you know, suppressant you can see for each of them what the target is. So what side kind they're blocking or inhibiting. Uh and you can see what they're used for. So for example, Infliximab is the type of TNF alpha inhibitor. Uh and it can be using the inside arthritis. It could be used in psoriatic arthritis, etcetera. So not only does this tell you kind of what medications are used in what diseases? But it also gives you an indication of what slight kinds are key to the development of that disease. So it can be kind of used in two ways it stable. And similarly here another kind of memory aid for you to remember if it helps feel free to think of your own for any and all of these natalizumab. Um I do remember people thinking about in terms of M S. So we think about a typical epidemiology wise M S patient is being a young Scandinavian lady called Natalie. So that might help you remember that natalizumab is a cytokine inhibitor used in M S. It might not, but that's fine. And then the last type of, you know, suppression we can use um is plasma exchange or plasmapheresis. So this is a little bit different in that it's not a medication that we give to patient's. But what we do is we take their blood. Um and we put it through a cell separator or plasma separator. And essentially this will remove any pathogenic antibodies, uh auto antibodies that are causing disease within that person. And then we can either just return the blood as it was, but minus the antibodies or sometimes we replace it with albumin. Um So if we are replacing with album in, we would consider it exchange. Whereas if we're not, we would just call it plasmapheresis. That's the only kind of significant difference between the two. And it makes sense that since we're taking away antibodies, this is obviously useful for diseases where antibodies are the cause. So thinking about your antibody mediated disease is this was things like good pastures, my senior gravis um but also your sort of transplant rejection, incompatibility. So this is something we can do. Uh once we've identified a graft rejection, uh one thing to be aware of with plasmapheresis techniques is that sometimes when we return the plasma, even though we've taken out the pathogenic antibodies, the immune system can recognize that and it can sort of go into hyperdrive, so to speak or overdrive. Uh and it can have a rebound antibody production. So a way of mitigating that is we sometimes give an anti proliferative agent. So something like mycophenolate mafia till to avoid this happening and just to make sure that we don't kind of undo all our hard work. Um As I mentioned, uh there are some key complications for all of these types of drugs. So all of the immuno suppressants can obviously cause lots of different side effects. Um It's important to be aware of some of them because they're either so important or so dangerous or because they're just a little bit rare and unusual. So it's worth making the association in your head. So in terms of generic um side effects that we can have with immunised presents, you can split these into infection, malignancy and autoimmunities. So with infection, obviously, if we're dampening down someone's capability to respond to an infection or a threat, we see that these patient's will either get more severe infections or they will get atypical organisms. So they might get bacteria that we wouldn't expect to see or they might have reactivation of viruses that normally wouldn't affect me or you but can cause severe disease. And then in terms of malignancy, we can see uh skin cancers, we can see lymphoma and other sort of viral associated um malignancies as well. And then the last one might seem a bit counterintuitive because if we're damping down the immune system, you'd think we'd be treating all communities. But you can kind of think of this as if we're trying to modulate the immune system, we've kind of just dysregulated all it's uh feedback mechanism. So it kind of just freaks out, it doesn't really know what to do. Um You get an overall dysregulated system. And so part of that can manifest as autoimmune disease and then specific things to be aware of. So steroids. Uh I'm sure you guys probably familiar with the idea that if somebody is on high dose steroids for a long time, they eventually will get adrenal suppression. So it's very dangerous to stop them, uh stop their steroids as their body cannot produce any steroids for itself. And then in terms of your antiproliferative. So, cyclophosphamide is associated with hemorrhagic cystitis. Just a connection to be aware of um that they could give you in a patient post transplant or something like that. Mycophenolate mofetil is associated with PML. So progressive multifocal leuko encephalopathy. Um and this is quite a unusual sort of varied disease. It essentially involves demyelination of your central nervous system and it can present with all sorts of movement disorders, personality changes, et cetera. Um and it's really linked to the reactivation of JC virus or human papilloma virus. I believe it is. And then azaTHIOprine or a CT. The key thing with this one that they love to test in the exams is the risk of bone marrow suppression. So this is a risk for anybody taking azaTHIOprine. But there are certain people in the population who have a specific polymorphisms. So a genetic change in their body which means that they can't metabolize this drug properly. And so there are a very, very high risk of bone marrow suppression. So what we need to do before we start anybody on as a fire brain is, you have to check their T P M T, which is an enzyme involved in the uh metabolism of the drug. You check the T P M T levels or you do a genetic screen essentially to check for that polymorphism. And then another thing to be aware of again, just because it's kind of a bit of a bizarre side effect is avascular necrosis of the jaw. So this can be seen when you start somebody on denosumab, which is a treatment that targets the rank and rank ligand pathway. So it's used in osteoporosis to prevent the bone being resolved. So again, something just to review in your own time kind of, you don't have to remember absolutely every side effect for every single drug in the world. But it's worth just being able to pick out some of these key kind of either unusual or really dangerous ones. Okay. So this is the last question, the last few questions for me. Um And then I can either go through HIV sides depending on what people want or we can leave it there. So I will go to the last slide, er um and we can have to go at these ones. So I will open the pole. So this question is about what antiproliferative agent used in the pro flexographic ejection requires a pre treatment. Genetic testing of TPMT, go to the teams as well to make sure there's nothing. I'm just looking for a medication for this one. Okay. I'll give it a few more seconds. I mean, have a look at what people have suggested. Okay. Perfect. Yeah. So most people gone for azaTHIOprine or something of that nature. Yeah. So, azaTHIOprine is absolutely correct. So, azaTHIOprine, remember I said risk of bone marrow suppression for some people with a certain type of genetic polymorphism. they're at an even higher risk. So you need to check their TPMT levels or you check their genetics directly. RiTUXimab is used in hematological cancer. So it's anti CD 20 to my knowledge, we do not check TPMT or other enzymes before riTUXimab. But you obviously might want to do generic screens. For example, if somebody has um undiagnosed TB background TB, you wouldn't want to give them um any kind of immunosuppressive really. So you might want to do other checks, but you wouldn't necessarily do TPMT. And then the second question um is about which of the following blood abnormalities we would suspect or expect. Sorry. So let me hide the results. So if I start my patient on a course of oral prednisoLONE, which of the following blood results is most likely to be seen one week later. Basically, what can all prednisoLONE course? Mhm. Mhm. Okay. I'll get a few more seconds again and then we'll have a look. Okay. Perfect. Yeah, most people have gone for white cells 26. So hopefully, that was because you realize that the white cells were raised and you may have remembered from my side about steroids that steroids can cause a transient neutrophilia. So they can cause an increase in your neutrophil count. Um That's actually because they just block the neutrophils from being able to escape the blood cells, the blood vessels into the tissue. Um But obviously, that looks on a blood test like you have more neutrophils. So you might see an increased white cell count, obviously, more specific or a better answer would have been if I'd put raised neutrophil count, but that might have made things a bit too easy for you guys. Uh CRP. So CRP may well be raised. Obviously, if we're giving someone steroids, they may have an inflammatory condition. Um The CRP could be raised. Um But it's possible that a week later the CRP will have started coming down. So this isn't necessarily what the question was getting at and then the other abnormalities um are not necessarily associated with steroids. So, anemia, not necessarily uh reduced renal function. Uh steroids are more uh steroids obviously can affect lots of different things in your body's, but they're not necessarily associated with the renal failure. Okay. So that is the end of what I wanted to get through today. As I mentioned, there are some a couple of sides on HIV. If people feel particular passionately, either way that they do or don't want to go through them. Do let me know you can do it on the slider as a Q and A if you want or you can post in the team's chat. What people would prefer for me to do? Um Either to go through them or to leave it there and you guys can review in your own time. I won't be offended by the way because I appreciate it's a long talk and you go through the HIV sides, please. Ok. So one vote to go through them. Is there anyone oppose that? Anyone agree? Otherwise we'll make a start. Obviously, you guys can leave. Sorry while everyone's having a think if you could please fill out feedback for Becky and that would be really helpful. Perfect. Thank you. Um Yeah, obviously if we do go through them and you guys get fed up any point, you, you are more than welcome to leave to that is absolutely fine. Okay. So I'll make a start. Um leave as um when you need to, it's only a couple. So HIV. Um I just kind of wanted to talk to you guys about the natural progression of HIV um the diagnosis and then we're gonna have to think about drug targets as well. So you guys may be familiar, let me get my little laser pointer back if I can. You don't. There we go. Ok, the laser pointer. So after somebody is exposed to HIV, um via needle state, sexual contact, vertical transmission, whatever it, maybe they have an acute phase. So, during this acute phase, you can see in the red line, your HIV one, we're thinking about HIV one because that's the most common type. Um, we predominantly HIV HIV one and almost all the literature will be meaning that even when it says HIV, so your HIV, one count shoots up. But then actually what happens is your immune system is able to get it under control and it starts to drop down and it becomes stable. And while that's happening, your CD four cells are actually dropping, they're being infected by the HIV, but they do recover a bit and then they become a bit more stable. So that's fine. So in this acute phase, you'll be Ciro converting. So you'll be starting to produce antibodies against the HIV virus. Um and you may also have symptoms. So you may have things like my algia flu, etcetera. Um You may not notice them but you may have those symptoms and then time will pass and you'll be in this chronic phase. And so this can happen for a number of years. If you're very unlucky, it can happen, you know, over a matter of months, 12 years, some people will be in this chronic phase for I think 10, 20 years. And what's happening in this period of time is that your viral load is pretty much stable, but it does start to creep up towards the end, right. So it reaches a threshold where it just manages to overtake your CD four cells. And whilst you're in this kind of middle ground here, just trend um sort of uh just taking a long, essentially in this middle ground, you may have symptoms. So you may have things like recurrent thrush, for example, canted diocese, you may have um TV, infection can be associated with HIV positivity. Uh You may have some of the most unusual conditions like uh oral Harry Leukoplakia, which is 62 E B V or you may have nothing at all and you may actually feel completely well. Um And often this is the period during which people get a unexpected HIV positive result because they feel completely fine. But as I mentioned, eventually everyone reaches a point where your HIV viral load kind of um takes over your CD four count. And this is typically when your CD four count reaches between 200 to 500 obviously, the threshold is different, different countries, places, etcetera. But when you reach that threshold, you've essentially acquired acquired immunodeficiency syndrome. So, aids and once you've reached this point, you'll start developing unusual severe infections. You might have uh malignancies such as composing sarcoma. Uh you will become very unwell usually. Um and you can even develop sort of neuropsychiatric conditions as well. And then from this point on people will potentially their viral load will shoot up. They become very ill, very quickly. Uh and they may pass away or this may take a bit more time. Um But this is the kind of typical cycle we see and at any point in that period, if we want to detect someone's HIV, if we want to diagnose it, then we can do a number of different tests. So the first ones are looking at antibodies. So these will be serological tests or serology and they basically look at your body's response to the HIV. So we're not detecting HIV directly, but we're looking at how you've responded to it. Um obviously, to be able to text antibodies, your body needs to have made them. So if for some reason, somebody can't mount an antibody response, thinking if they have one of those sort of rare primary immune deficiencies or if it's simply too early for you to have created antibodies. So it's before this 15 day period, these tests will come back negative even if you're HIV positive. So it's just something to be aware of provided, we do them after the 45 day period and you're otherwise healthy, this will come back positive. But we also don't do serology in babies or Neo Neitz. Um And the reason for that is that you will have antibody transfer from the pregnant person. So across the placenta, across the breast milk. So even if a baby is not actually infected with HIV, you will see antibodies in their blood that might make you think they are. So we use these other types of methods in neonate and the other types are looking for the antigens. So we confirm that there are viral particles within the body or we confirm that there's genetic material. So we have to kind of different types of tests. We have the antibody based tests and we have the virus based tests and we can depend, we can determine which we do based on the kind of patient characteristics. But typically, what we do is we do in Eliza, which is a neurological test first line. So that's the kind of standard and then we do a western blot after that as a confirmation test. Um you feel free to look into the details of kind of all those tests involved, but I won't bore you with them for now. Um The next thing to be aware with HIV is kind of just the life cycle. And whilst I definitely didn't learn all of the different drug names, I think it's good to be aware of kind of the different classes and at least what stage of the life cycle they're trying to attack or trying to prevent happening because I think that helps you then think about kind of resistance and lots of other concepts in HIV medicine. So the first thing obviously the HIV needs to do is needs to bind to your host cell. So your CD four T cell, the first thing it does, it binds by a CD four and then it will also bind via some other receptors. So one of them is CCR five. Hence, our CCR five inhibitor can hopefully prevent that stage from happening. And then if it does manage to bind, the next thing it will do is it will fuse with the host cell membrane. But obviously, we have fusion inhibitors which can try and stop that from happening. So that's the next stage that we can attack with drugs if both of those things fail and it manages to get into the cell. And the next thing it will do is it will need, it's R N A, it's genetic material to be reverse transcribed into DNA so that it can be incorporated into your D N A. And so we have two different drug classes which target this stage. So we have the N R T I S O, the nuclear died and we have the non nuclear side. Um So two different drug classes which are essentially doing the same thing. So they're preventing the reverse transcriptase enzyme from taking the HIV genetic material and turning it into DNA. Um And I've just highlighted one drug here to offer there because this is the medication that is used in pre exposure, prophylaxis, prophylaxis. So, prep uh if you ever come across patient's taking prep, so they'll take this daily if they are very high risk of being exposed to HIV. Um And hopefully that will prevent them being infected. And then the next stage again, if all of these somehow managed to fail and HIV is um you know, continuing on its journey, its life cycle is integration. So you can see here this orange genetic material has come from the virus, it's integrating with your nice blue turquoise G N A. Um So we can try and prevent that happening with something like raltegravir. Um If that fails again, we've got a couple more options. So we don't actually at the moment have anything that targets replication or assembly or at least not to my knowledge or that I was ever taught. But we do have protease inhibitors which are kind of final hail mary to try and prevent budding of the complete viral particle out of the cell before it can go and infect any other cells in the body. So this would be something like right on over. Um So those are kind of the drug targets and what each of them is aiming to do. But I guess the general concepts for you to also be aware of with HIV medicine are firstly that everybody needs to be started on antiretrovirals, highly active antiretrovirals as soon as they are HIV positive, obviously provided that they consent to that we no longer wait for patient's to be at certain CD four or viral load threshold. Everybody should be started on it uh immediately. And what we generally start is two drugs from this class, the N R T I S and one protease inhibitor or P I. So they should be taking three different agents um which might seem like a lot. But essentially the principle behind that is that taking three different medicine, which target slightly different areas means that there is less chance of resistance developing. And what we do know about HIV is that because it mutates very quickly, it's very easy for it to develop resistance. So anything we can do to try and prevent that is definitely important. Um So that is all I wanted to say about HIV. Obviously, if people have any questions about HIV or indeed anything else in the lecture, then fill three to um proper message either on the slide oh or the um team stat. Uh And I can try and answer any of them. Mhm If people don't have any questions, so thank you very much for listening. I hope it was helpful. Um And obviously these slides will I presume be sent out to you or put on the website? So you guys can have a look at the additional notes I was mentioning as well. Okay, let's have a look. So um do the do the allergy theories come up in exams? So um they come up in the sense that you might be tested on sort of uh what type of hypersensitivity, different diseases are. So, for example, if they gave you good pastures. They might ask you what type of hypersensitivity. It was um you would probably also be expected to have an awareness of kind of what the basic processes for each of them. So for example, that type one is I G, that type two is antibodies. That type three is immune complexes. Obviously, it's up to you how much time and energy you want to put into learning every single um detail of each of those processes. But they definitely can come up. And I would say to be honest, they're probably more common, at least on my exposure to the past paper questions than things like HIV. I think there are only one or two concepts really that I've ever seen tested on HIV. Hopefully that helps. Uh The next question is about how much did the initial immune modulating drugs come up and how do they present? So again, I can obviously only go from my experience um with the exam, uh which actually was, they were quite kind in my year. So they, for example, after riTUXimab, they would write anti CD 20 which kind of helps you work out what it's targeting and therefore what it might be used in. Um That is by no means a promise that they'll do it for your year group. Um So again, you know, is just a case of putting a bit of time into flash cards and like rote learning, which is not the most fun I appreciate, but that is kind of the whole pathology course, to be honest with you. Um So they can literally just test like which of these agents is used in rheumatoid arthritis. And it will give you a list of, you know, different antibodies you need to kind of just know off the top of your head which, which it might be. Um next question. Sorry, I meant like the hygiene theory of food allergies. Yeah. So this, this was stuff that came up in the lectures. Um, and I think it's interesting. So the idea of like the atopic March, etcetera, but I had never seen it tested in the exams. I don't really know how they would test it in a kind of SBA or VSA setting, um, worth being aware of, but there's not really much to it in terms of revising, I guess, would be my, my perception, but obviously take that with a pinch of salt as with anything else. Um, do we have to learn the number's like anti I L 17 A or anti CD 25 or just be able to recognize them? Yeah. So that, I guess it's kind of ties into what I was saying before. They actually did tell us both. So they gave us both the drug name and the target when we wrote questions when we had questions in our year. So, like we're talking about brackets, anti CD 20 brackets, anti TNF alpha. Um, that's no guarantee. I'll do it for you, but that obviously made it a lot easier. Um, um, that being said, I don't think I knew they were going to do that. So I think I probably did try and learn or the site of kinds and things like that. Um, I think they will stick in your head more than you might expect. Now, um, kind of as you're just reading through the lectures, like you probably will absorb more than you think, but maybe leave it for later down the line. Like I would try and understand the basic concepts first, uh and the more like high yield stuff like, um, hopefully that has helped if anybody has any other questions, obviously feel free to email me or I'm sure an or somebody can pass it on to me. Um But yeah.