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Rejection: why does it happen?

In this video talk to Dr Nick Jones, an immunologist at The University of Birmingham about the process of rejection.
INTERVIEWER: Can you introduce yourself and tell us your role at the Institute for Immunology and Immunotherapy? DR.
NICK JONES: So, my name’s Nick Jones. I’m a senior lecturer at the Institute of Immunology and Immunotherapy, and I really concentrate on teaching at the undergraduate level and medical students, both general immunology and transplant immunology. My research interest is really in looking at the ways in which the immune system recognises foreign organ transplants, and in particular, looking at ways in which we may be able to manipulate those immune responses to allow grafts to survive.
INTERVIEWER: What are the challenges that the transplant recipient faces after transplantation surgery? DR.
NICK JONES: So, I think once the recipient does get over the quite traumatic surgery, which is certainly the case with liver transplants, then obviously the next step is maintaining the organ in place in the face of the inevitable immune response against the foreign organ transplant.
INTERVIEWER: Is there a difference in how our immune system experiences a liver transplant compared to transplants of other organs? DR.
NICK JONES: So, I think all organs will be susceptible to immune responses and potentially immune-mediated rejection, if those immune responses are left unchecked. But certainly, the immune responses that you get to the liver are unique in many ways. First of all, the sheer mass of tissue for a liver transplant, compared to a kidney transplant for example, often results in potentially a bigger immune response, but the T cells, which are the main cells responsible for rejection, get overstimulated, and therefore start to delete themselves. As well as the size of the liver, there’s the normal function of the liver, where it’s exposed constantly to oral, sort of food-based proteins, as well as from potentially commensal bacteria.
So, the organ itself is not very permissive to support immune responses. So, taken together, it appears that the liver is able to resist the process of rejection a bit better than other organs. And it’s also highly regenerative compared to a kidney, for example. So, it may be able to take on a certain amount of damage and repair that damage.
INTERVIEWER: What are the main mechanisms involved in transplant rejection? DR.
NICK JONES: So, certainly transplant rejection is a multi-faceted process involving most arms of the immune system, but what’s absolutely central is that it’s mediated by this collection of cells called T cells that recognise certain foreign proteins that are expressed on transplanted tissue. The main focal collection of foreign proteins that seem to be targeted are proteins belonging to the major histocompatibility complex, or MHC, in part because they are normally involved in T cell recognition of foreign proteins, but also they are the most polymorphic. They’re the most different between people proteins known to man.
INTERVIEWER: Can you tell us a little bit about transplant tolerance and how we can achieve this? DR.
NICK JONES: So, transplant tolerance is easily defined. It’s defined as the survival of a transplanted organ in the absence of immunosuppression. And actually, the liver itself appears to be naturally tolerogenic for reasons I’ve already alluded to. So, about 20% of patients, after a liver transplant, if they’ve maintained their graft for, say, 10 years, are likely to be naturally tolerant. However, most patients are obviously not tolerant, and certainly not tolerant at the beginning. So, we’ve been learning lessons, really, from the way in which we control our own responses to our own tissues, in order to tap in and develop therapies that might be used to develop tolerance to foreign proteins that are expressed on donor allografts, for example.
And some of the ways that are being explored are simultaneous bone marrow transplant, along with certain doses of chemotherapeutic agents. There’s costimulatory molecule blockage. So, what we know about T cells is that the signal that a T cell receives upon engagement of a foreign protein is not enough for a productive response. What’s also required is another set of proteins that are being labelled as being costimulation. We know that if we can go in and block these costimulatory molecules at the time of recognition, then rather than promote any productive T cell response, these T cells may switch themselves off and promote a state of tolerance.
INTERVIEWER: How does immunosuppression work, and what is its role in the context of liver transplantation? DR.
NICK JONES: So, immunosuppression is really an umbrella term for many drugs that interrupt the normal function of the immune system, which is of course what you want to try to prevent rejection. So, I think broadly, you can categorise them as being derived from biological agents, such as monoclonal antibodies, and antibodies are used predominantly during the period immediately post-transplant to deplete the recipient of T cells that may go on to reject the transplant. There are other molecules that are targeted by pharmacological agents, such as the calcineurin inhibitors, cyclosporine and tacrolimus, and those seek to interrupt the signaling in the T cells that the T cells need to acquire function.
There are other agents, such as azathioprine and MMF, which interrupt DNA synthesis thus stopping the T cells from dividing, which is an important part of the immune response. And then there are other agents that may interrupt other signalling pathways, again, predominantly the T cells.
INTERVIEWER: Dr. Nick Jones. Thank you very much.

In several previous steps we have mentioned the need for patient to take immunosuppressive drugs after the transplant. These reduce the ability of the recipient’s immune system to damage the new liver, and so are vital to maintain the health of the new liver. We need to think a bit more about this process of organ rejection as it remains a huge challenge in the field of transplantation.

Your task: Watch this short video in which Dr Zania Stamataki interviews Dr Nick Jones, an immunologist at The University of Birmingham about the process of rejection.

He will explain how the liver is unusual when it comes to immune recognition and has an inbuilt ability to resist damaging immune responses. You may find that watching Zania’s video about the immune system in Step 1.9 will refresh your memory about some of the different immune cells types.

Share your thoughts on this video in the comments.

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Liver Transplant: the Ins and Outs

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