The Epigenetics of Organ Transplantation


Dr. Daniel Salomon discusses the state of organ transplants, what obstacles exist, and how epigenetics might be central to improving long-term health in patients.

 

The Challenges in Transplantation

My background is in transplantation medicine, transplantation immunology. And my interests are to change the way we manage patients. There’s a huge series of challenges right now. We’re using very toxic medications, we have essentially no objective metrics to measure the efficacy and safety of these drugs. So we’ve become very good clinicians over the last 25 years, and that’s a big positive for our patients.

But the challenge to science, challenge to immunology today is going to be to develop the new science develop objective metrics for these things. Incorporate them in the clinical practice and really change the way we practice medicine. What’s interesting about transplantation as a field is that it is unique in one respect. It is the essential collision of two genomes.

So there’s a donor genome, which represents the transplanted organ, or transplanted cells, and there’s the recipient genome. A lot of what’s going on is reflected in this intersection. So the immune response of course, is the recipient’s immune response. So a lot of the genetics of the recipient determines the degree of the immune response. But it’s not that simple, because the target of that immune response is the organ. And the function and integrity, structural integrity of the organ is critical to the success of the transplant.

So you really do want to understand how the organ, the donor’s genome also responds. So there’s some interesting opportunities in the epigenetic studies of transplantation that really don’t exist anywhere else, because it’s the potential of studying the epigenetics and the changes of transplantation on the epigenetics of the donor organ, as well as understanding the changes and challenges of the epigenetics in the recipient’s immune response.

 

“What’s interesting about transplantation as a field is that it is unique in one respect. It is the essential collision of two genomes.”

Now, our drugs work on the recipient’s immune response. Currently, what’s interesting is that despite the fact that 50% of our outcome is determined by the organ and the organ’s response to the transplant, we don’t have any drugs, or really almost no measures of how the organ is responding to the transplant. So it becomes very crude.

If the organ starts failing, usually that’s too late for us to do anything as physicians. Then we recognize that there’s been progressive tissue injury. So the challenges of transplantation now for epigenetics would be to incorporate this new field into understanding on one hand, the immune response of the recipient’s genome, and on the other hand, understanding the response to tissue injury and immunity that’s being leveled against the organ.

The Epigenetics of Transplantation

And that’s going to be determined by the cells and the donor genome. So that’s an interesting area, an interesting conflict. And really attracted me to this area. In terms of the epigenetics of transplantation, the immune response is leveled at the transplant, starting at the time of transplantation. But it’s not the same. It changes over the first three is six months post transplant is one aspect to the immune response.

And then there’s this chronic, long term phase of community. Interestingly, when I first started in the field in the early 1980s, the biggest problem we had was acute rejection. Now we’ve done a really, really good job in treating acute rejection, but what we’ve not done anything about in the last two decades is changing the rate of chronic rejection.

So in some ways, the focus is more and more on these chronic changes. So the real question is, can we use epigenetics to understand these two aspects? This nexus of these two genomes so on one hand, we would want to say, can I take the blood from a patient? Determine the epigenetic profile of the constituent immune cells and determine exactly how they’re going to respond.

 

“…in the end your patient lives and dies based on how well you protected the organ, not how well you immuno suppressed the patient.”

 

How likely they are to attack the organ, how much damage they’re going to do, and therefore how adequate is the immuno suppression that I’m giving them. And that’s one challenge. And the second challenge is can I take a biopsy of the tissue at key times and determine how well I’m actually affecting the immune system? How well I’m protecting this organ.

Because remember, in the end your patient lives and dies based on how well you protected the organ, not how well you immuno suppressed the patient. With the decision that we would get into studying the epigenetics of transplantation immunity, you’ve got to start somewhere. And so where we decided to start was on the recipient immune response.

So we had published last year what we considered a very important observation. We looked at the response of the recipient to the organ at multiple times within the first three months. So we’re looking at this early phase of transplantation to which I referred earlier. This is the genesis of any immune response, and it therefore would be determinative of what you would see over the next 10 years. And I already told you chronic rejection, what happens over the next 10 years is what we’re interested in. So the real question is, why have we been successful in reducing the incidence of acute rejection so much, and not been successful at all in reduce the incidence of chronic rejection?

There has to be a hole. There has to be a failure in this system somewhere that we’re not getting. So our first question has been, where is that failure? So what this first study showed is that there are two kinds of cells in the immune response. Naive cells that have recently come out of the phymas and are essentially just encountering antigen for the first time, and there are memory cells. And these cells are basically our memory of all immune interactions we’ve had in our lives. And of course if you did’t have memory cells, you would die the next time you got a cold. So the memory cells, we demonstrated, are operatively resistant to the immuno-suppressive drugs that we’re giving. That led us to the hypothesis that it is memory cells that are the problem.

It is our inability to successfully immuno-suppress memory immune responses with our current set of drugs, is why we’ve done so well with the acute rejection but failed in reducing the rate of chronic rejection. So we set up a series of epigenetic studies in order to answer the question, what’s different between naive and memory cells?

And what are the mechanisms on these memory cells that are specifically resistance to the immunosuppressive drugs? If you knew that, you would immediately have two benefits. First, you would have a measure that you could measure in a patient. You could take a patient who’s doing great, and you could ask yourself at an epigenetic marking viewpoint, do these patients have successful suppression of their memory response? If they do, you can tell the patient, you’re going to do great. You’ve got a great chance here. Very low risk of having problems with chronic rejection. In contrast, we are thinking that years before they actually damage the kidneys, we should be able to see the epigenetic profiles of uncontrolled memory immune responses.

And if we could discover that, then you would know that those are patients that would be candidates for increases in medication, or even switches to completely new medications. Now, the second thing you get from that is if you can tell the drug companies that the next generation of immunosuppressive drugs has to be against memory, but not only that, we can tell you which genes by epigenetic profiling are the problem, then that’s the mechanisms.

Those are the actual molecular pathways that the next generation immunosuppressive drugs can be targeted against. So those are our two interests. Develop a set of biomarkers based on epigenetic profiling that tells us whether or not we’re successfully or not successfully suppressing the memory cells, and second, discover what the pathways are.