Complement and organ transplantation

Published on April 30, 2018   51 min

Other Talks in the Series: The Complement System

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My name is Steven Sacks, and I'm a clinical nephrologist with a particular interest in transplantation. My interest in complement stems from local complement synthesis, and I want to try and develop some of the ideas that have sprung up around that particular aspect of cell biology.
Transplantation has been a highly successful procedure but it's not totally successful. There are two particular barriers which still hold up the procedure in terms of long-term outcome. The first of these is what I've called metabolic and physical injury which sums up a lot of different stimuli that occurred during the transfer of the organ, and in particular the kidney, from the donor to the recipient. That results in a number of different forms of stress which are just conveniently labelled as metabolic and physical injury. The second aspect is a recognition of a donor organ as non-self. That triggers a series of events which can be summarized into two things, one is the cell-mediated rejection and the other is antibody-mediated rejection. Each produces its own form of injury, that when these are together they can shorten the half-life of kidney by up to eight years. In other words, about 50 percent of the grafts are lost by 67 years if both are present together and if neither of those insults are present, then the kidney last for many years longer, perhaps about eight or nine years longer than that on average.
A number of observations have shaped my thoughts about complement. So these are not necessarily the only observations that could be called landmark in the history of how complement is linked to transplantation, but they certainly sparked my interest. The first truly successful transplant carried out in Boston was in 1954, and so there was about a 15 year space before the first real observation linking complement the transplantation was made, and this was out of Paul Terasaki's laboratory. They found the presence of antibodies against the donor organ which when they interacted with the endothelium surface of the donor organ, led to the activation of the complement cascade and destruction of a transplant. Within about space of the next 10 years, further advances had been made so that it became clear that the complement system was not only a factor of antibody-mediated damage in the organ, but was important and played an instructive role in priming the antibody response. These observations came from a series of elegant studies carried out by Mark Pepys and colleagues, in Cambridge in the 1970s. Basically, they found that for non-complement antigen, so these were experimental antigen models in complement depleted animals. It was very difficult for the animals to make a fully mature immunoglobulin response. It was later on that James Marsh working in our laboratory identified a similar effect in the context of transplantation which I'll come back to later. But nonetheless, that was a rather important observation that sparked my interest. But I was particularly drawn in the 1990s with some seminal observations by Doug Fearon, and he noticed that the complement system was necessary to fully mediate a scheme in response in the heart, so that in the absence of complement and complement treated animals, the animals were protected from ischemic injury in coronary artery ligation models for example. Later, came further insights on chronic rejection which is the drawn out process by which graft slowly fails towards the end of its life. This is a very variable phenomena and is linked to acute rejection also to ischaemic injury. But nonetheless, the mechanism was unclear and it was only through studies of complementary position inside the transplant organ in which were made by Feucht that new insights were brought about just to the mechanism of chronic rejection. In other words showing that it was linked to antibody deposition on the vascular micro capillaries. My interest really took off before 2002 but the data were published in about 2002, which were focused on the studies of local complement synthesis. In the first such study, it became very clear that if transplantation was carried out where the donor organ was deficient in complement reduction then, this led to long-term graft survival. This actually opened up a whole series of observations which I'll be coming to a little bit later on.