Chapters Transcript The Immunologically Complex Patient Course: Advanced Heart Failure Cases and Controversies Our last talk is by Doctor Habal who has joined us in the last year and is known as the queen of immunology across the United States and we are going to uh talk about the immunologically complex patient and after that, we will open it up for questions. Thanks so much. Um, so what I want you to just start off with briefly were three of what I think are very common scenarios that we see patients with chronic rejection or CAV, um, potentially needing a retransplant CPRA of 92%. A patient who comes to us with a history of multiple pregnancies and a CPRA of 100%. And then the complex congenital patient, maybe 3 sternotomies in a homograft, who interestingly has a CPRA of 0%. So what I would say here is, is that all of these patients have been exposed, their immune systems have been exposed to non-self human leukocyte antigens, and so they've all essentially been primed by these antigens, and therefore are all at elevated immunological risk. Of course, what makes them different here is the um presence or absence of circulating HLA specific IgG termed anti-HLA antibodies in the clinical realm. And so what I think this really highlights is the need to think about the cellular sources of these antibodies. And we often think about long-lived plasma cells, these cells that reside in the bone marrow in protected niches and environments can potentially secrete antibodies for decades on end. But it's important to think too that B cells in the context of T cell help can rapidly differentiate um into short-lived antibody secreting cells that also contribute to the circulating antibody repertoire. And what this highlights is that there's a dynamic nature to the humeral response, and it also highlights the fact that it involves cells that have potentially antibody independent roles. And so when we think whether we're talking about pre-transplant or post-transplant, immunologically quote unquote complex patients, I think that this plays an important role. And so with that sort of cellular uh framework in place, what I wanted to do is just focus a little bit on the pre-transplant patients who have circulating anti-HLA antibodies. And the key thing that I wanted to highlight is that where you start matters. And when I say that, I'll just make reference to autoimmunity. I think we've all ordered ANAs on our patients and you get a tighter result back, and that tighter is relevant to the interpretation and whether or not you're gonna call rheumatology. And I'd argue that the same thing is true for anti-HLA antibodies because they too come in a broad range of titers. And these, I would argue, are clinically relevant to the approach to the sensitized patient. To take that a little bit further, what we now know is that all CPRAs of 100% are not by any means equal, and that's something that's really being pushed forward by work from Anat Tambour's group, who's also gone on to suggest that titers actually provide better quantification of antibody strength. And so I just want to take you briefly through this um figure here, which shows essentially 20 patients who have a CPRA of 100%. That's in neat serum, which essentially means the undiluted serum where you typically get your results from the immunogenetics lab. And on the X axis here at the bottom, what she's done is essentially taken this serum and diluted it out. Diluted at 1 in 41 in 16, 1 in 64, all the way to 1 in 16,000. And then for each of those titers, calculated the CPRA. And what's I think really important to consider here and what this shows nicely, is, is that all CPRAs of 100% are indeed by no means the same. So if you look at the top two patients here, as you start to tighter out the serum, you see that these antibodies rapidly come down and so does the CPRA. On the other hand, for patients down here in 19 and 20, regardless of how many times you try and dilute out this serum, the CPRA stays fixed at 100%. And so this is gonna have implications for your pre-transplant patient, both in terms of the intensity of any kind of treatment you're gonna try and also for deciding on what kind of antibodies you might even be able to cross at transplant. And so I wanted to continue on with that, but raise one additional sort of concept, and that is um sensitization phenotypes, which can broadly be defined in in the following. So you can have a patient who's highly sensitized, and by that I then mean have high tighter antibodies to a few common specific antigens such as the A2 allele that probably 40 to 50% of us have in this room. On the other hand, you have patients who are broadly sensitized, and you often see this in pregnancy. To many, many, many different alleles. And then probably the most common are patients who sort of have this mixed phenotype. I'll just take you through this um briefly. Um, so if you think about the broadly sensitized patient here, so the neat CPRA, which is the undiluted CPRA that you get from, from your, your lab usually is roughly 98%. And if you tighter that out just a little bit to 1 in 8, it's still above 90%. So maybe you say, OK, I'm gonna try a little bit of some sort of desensitization. And what you can see is, is that your undiluted CPRA that you standardly get does not show that there's been any effect. And so then the question logically becomes, did this drug have any effect? Did it work? Should I continue? Should I try something else, or should I just give up altogether? But what you can see is that even at a 1 in 8 tighter, you've had a 12% drop in your CPRA. So then maybe you do a little bit more. And as you can see here, you can drop your CPRA to 66%, and that's something like 1 in 8, you might then consider listing this patient and um using some sort of peri-ransplant risk mitigation strategy, be that plasmaphoresis or some of the complement inhibitors to try and get them through transplant. This figure here essentially shows the same thing. It just adds one additional dimension, which is that the CPRA entirely depends on what MFI or mean fluorescence intensity you use to define it. And what you can see here in the uh yellow line, actually in all of them, doesn't really matter what you do at the beginning before treatment, they all have the same CPRA of 95%, let's say. Um, but as you treat, you start seeing these curves separate out and if you need to use a neat MFI of 10,000, you see a market drop. And where this has relevance besides the bedside is in how we talk to each other within the country or or uh internationally because we could have very, very different interpretations of essentially the same patient. So I'll just take you through um a second case, which is the, which highlights nicely the concept of mixed sensitization. So for these patients, it can be really helpful to break up the antibodies into uh groups. So those that have low titer, um, as shown here, the undiluted serum MFIs are around 5000, and they rapidly dilute out as you dilute out the serum. The intermediate group tighter. That nearly reaches saturation um in undiluted serum, but shows a nice steady decline as you tighter it out. And then finally, the high tider group, where even if you're out at 1 in 128, your MFIs are still well above 10,000. And these would classically be what I would consider to be avoids. So then you decide to treat the patient, and as you can see, not unexpectedly, all the low tighter antibodies respond very nicely, and that's relevant because if you have a broadly sensitized or a mixed sensitized patient, you're probably gonna have to cross quite a few and the risk is cumulative. So then for the intermediate tighter group, what you, you have to define what your goal is and often we would define this as trying to bring down the antibodies at a 1 in 16 tighter, which we know correlates to a 1.5 volume plasma exchange. And so what you can see here is that you've essentially been able to drop from a 1 in 128 tighter to a 1 in 16 tighter. And then finally for the high tider group, I would argue that you've never really anticipated that you were going to cross them, but academically, it's kind of interesting to ask, is there something fundamentally different about the cells that make these high tidor antibodies, or is it just a matter of the overall concentration? And what you can see here is that indeed they too have responded. It's just that it wouldn't be enough that you would necessarily want to transplant against. So essentially this allows you to bring the effective CPRA down from 99 to about 60%. So, in the final minute or so, I just wanted to uh consider a few of the, the basic fundamental thoughts about um therapeutic interventions, and instead of mentioning any in particular, I think it's nice to think about key basic principles. So, I would argue that targeting the cellular response is critical. Um, and mitigating consequences of disrupting immune homeostasis, which is kind of a fancy way of saying avoid being rebound, um, basically with the principle that if you remove one of these populations of cells, the immune system is naturally going to try and compensate and so you have to think of ways to sort of get around that. And then based on on that, you're probably gonna need a multi-drug regimen, of which we're arguably quite lucky because we have the opportunity to repurpose drugs both from oncology. And from autoimmunity. And so there's certainly not a lack of different possibilities, but the key is to choose rationally. And so if we think about antibodies coming from antibodies secreting cells or plasma cells that um derive from B cells that have differentiated in the context of T cell help and the potential interactions with the innate immune response, I think it gives us a nice framework to start doing them. Finally, hopefully I've um emphasized the importance of having clear definitions of your goals, be that efficacy versus effectiveness, as in, is the drug working or have we achieved our target. And then finally, something that I think is really important is defining mechanisms of sensitization and their response to treatment. And I would argue that rigorous bedside to bench translational models are going to be critical. And so finally, I just wanted to um acknowledge the whole heart transplant team and particularly our nurse practitioners. Any of these immunologically complex patients are certainly challenging to take care of our immunogenetics cops and my research team and thank you. Published May 10, 2024 Created by Related Presenters Marlena Habal, MD View full profile
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