By Ramsey Hachem, M.D.
Washington University School of Medicine Barnes-Jewish Hospital
Division of Pulmonary and Critical Care
September, 2007
The purpose of the immune system is to defend the body against infections. There is a myriad of bacteria, viruses, parasites, and fungi that can infect the body, and the immune system has to recognize these and attack them. During its development, the immune system goes through a process of “negative selection” in the thymus, where immune cells that react with the person’s own body are deleted. This is to prevent one’s immune system from attacking their own body. However, this process is incomplete and small numbers of self-reactive immune cells may escape it. Under normal conditions, several mechanisms suppress these self-reactive immune cells in the periphery, but If they are stimulated at a later time they can lead to autoimmune disorders. Autoimmunity is a self-directed immune reaction. Lupus, rheumatoid arthritis, and type 1 diabetes are all examples of autoimmune diseases. They obviously have different manifestations but share the fundamental problem of the immune system attacking and damaging the self. Lupus has various manifestations but the immune system can damage the skin, kidneys, lungs, and the brain. The joints are the primary focus of autoimmunity in rheumatoid arthritis and the insulin producing pancreatic cells are attacked in type 1 diabetes.
After an organ transplant, cells of the immune system recognize the transplanted organ as “foreign” and attack it. This immune response is termed alloimmunity, and without immunosuppressive therapy, the transplanted organ would fail completely within a week or two. Indeed, immunosuppressive therapy has advanced the field of organ transplantation tremendously and has made it a clinical reality for thousands of patients. Not surprisingly, clinical studies in organ transplantation have focused on improving immunosuppressive therapy, and multiple new drugs have been developed over the past 30 years. However, rejection rates after lung transplantation have not improved substantially, and chronic rejection remains the leading obstacle to better long-term outcomes. Indeed, the transplanted lungs are more susceptible to rejection than other transplanted organs such as kidneys, hearts, and livers. One possible explanation for this observation is that the lungs are constantly exposed to the outside environment such that inhaled substances, including infectious organisms, can stimulate the immune response and trigger rejection.
In recent years, animal studies and some preliminary human studies have suggested that autoimmunity may be playing a role in rejection after lung transplantation. This new paradigm proposes that self-reactive immune cells are present in many healthy people but these are suppressed by regulatory immune mechanisms under normal conditions. However, at the time of the transplant, the lungs are injured by the process of ischemia and subsequent reperfusion. In other words, there is a period of no blood flow through the lungs after they have been harvested from the donor; then, blood flow is restored at the time of implantation into the recipient. This sequence is known to be injurious to the lungs and other organs. This ischemia-reperfusion injury is very common after transplantation and can expose normally sequestered self-proteins in the lungs. This can then stimulate and expand populations of self-reactive immune cells, which may then cause an injury pattern that is indistinguishable from rejection. Immunosuppressive therapy, which is directed at suppressing alloimmunity and preventing rejection, can promote the expansion of these self-reactive immune cells after they have been exposed to self-antigens that would ordinarily be sequestered by suppressing the regulatory mechanisms that keep self-reactive immune cells in check under normal circumstances (or outside of organ transplantation). This paradigm implies that ironically the very therapy that is meant to prevent rejection may actually play a role in promoting it. However, it is well accepted that organ transplantation would not be feasible without today’s immunosuppressive therapy. Indeed, advancements in immunosuppressive therapy have reduced the incidence of rejection and improved outcomes, albeit these improvements have not been substantial compared to the immunosuppressive therapy of 20 years ago.
So, what does this all mean and how do we put these seemingly competing ideas together? The more we learn about the immune system, the more we appreciate its complexities and its multiplicities. This new paradigm of autoimmunity playing a role in rejection is probably true, but the clinical events that trigger it and the biological mechanisms that promote the expansion of self-reactive immune cells are still unclear. In addition, the role that immunosuppressive therapy plays to promote these events is also still uncertain. So, much work is yet to be done to sort this out, but we hope that this may improve our understanding of the mechanisms that cause rejection and may present a new avenue for potential treatments. But for now, the current immunosuppressive therapy is the best that we have.