Immunosuppression after
Lung Transplantation


By Ramsey Hachem, M.D.

Washington University School of Medicine Barnes-Jewish Hospital
Division of Pulmonary and Critical Care

September, 2006

The immune system’s main purpose is to recognize and respond to foreign invading organisms.  To do this, it must be able to respond to viruses, bacteria, and fungi that it has never come in contact with in the past.  In addition, it must be able to distinguish between an invading organism and the individual’s own organs and tissues.  During development, the immune system acquires the ability to recognize and attack an almost infinite array of cellular patterns.  However, to avoid attacking oneself, immune cells that recognize an one’s own tissues and cells are deleted early in life.  Failure to delete these cells may result in autoimmune disorders.  After an organ transplant, the recipient’s immune system recognizes the transplanted organ as foreign and attacks it; this is recognized as rejection, and the transplanted organ would fail completely within a few days if this immune response were not suppressed.

In the past 30 years, tremendous progress has been made in understanding the immune system and developing drugs to suppress specific immune responses.  However, rejection remains a major problem after organ transplantation and the leading obstacle to better long-term outcomes after lung transplantation.  Induction therapy consists of potent immunosuppressants typically given in the first few days after transplantation to minimize the risk of early rejection, but its role in lung transplantation remains controversial.  In fact in recent years, less than one-half of lung transplant recipients in the Registry of the International Society for Heart and Lung Transplantation received any induction therapy, and usage has been split between two classes of drugs, polyclonal anti-lymphocyte preparations and monoclonal interleukin-2 receptor antagonists.  While no large-scale multi-center clinical trial has been done, several small studies have shown that induction reduces the incidence of early acute rejection.  However, critics of induction therapy highlight the lack of significant differences in long-term outcomes such as chronic rejection and survival and the increased incidence of infections in patients who receive induction.  Because of this controversy, individual transplant programs decide whether to institute induction therapy as part of their immunosuppressive protocols.  There is currently an ongoing placebo controlled multi-center clinical trial evaluating the efficacy and safety of a new polyclonal anti-lymphocyte agent, but no consensus in the transplant community is expected until the results are available.

Likewise, there has been no consensus about the ideal maintenance immunosuppressive protocol.  The earliest lung transplant recipients were managed with the triple drug regimen consisting of cyclosporine, azathioprine, and prednisone, but over the past 20 years additional agents have been introduced including tacrolimus, mycophenolate mofetil, and sirolimus.  Cyclosporine and tacrolimus have similar mechanisms of action; they both inhibit the normal function of an intracellular regulatory molecule known as calcineurin.  This impairs the expression of several critical immune cell activation genes.  In addition, the two drugs also have similar side-effect profiles consisting of high blood pressure, kidney dysfunction, neurological complications, and hypercholesterolemia.  Furthermore, both agents have narrow therapeutic ranges and variable absorption, thus measuring blood levels is necessary to ameliorate toxicity.  However despite these drawbacks, cyclosporine and tacrolimus form the cornerstone of the immunosuppressive therapy that makes organ transplantation a reality.  Azathioprine and mycophenolate mofetil also have similar mechanisms of action; azathioprine inhibits the proliferation of immune cells in the bone marrow and decreases the number of circulating immune cells.  Mycophenolate mofetil has a more selective anti-proliferative effect on lymphocytes, the specific immune cells that mediate rejection.  Sirolimus is a new immunosuppressive drug that is structurally similar to tacrolimus but has a distinct mechanism of action; it impairs lymphocyte proliferation and is used primarily in combination with cyclosporine or tacrolimus.  The side effect profile of sirolimus consists of gastrointestinal symptoms such as nausea, abdominal pain, and diarrhea, edema and hypercholesterolemia, but by itself, it does not impair kidney function.

Obviously, as the number of immunosuppressive medicines has grown so has the number of possible combinations.  The majority of lung transplant recipients are managed with the various combinations of three drugs consisting of cyclosporine or tacrolimus, azathioprine, mycophenolate mofetil, or sirolimus, and prednisone.  No consensus exists about the optimal combination and the choice of agents for a given recipient is usually individualized based on the clinical situation and expected side effects.  Finally, while some low risk kidney and liver transplant recipients have been weaned completely off prednisone, this has not been routinely done for lung transplant recipients because of the higher incidence of acute and chronic rejection.

While immunosuppressive therapy has made lung transplantation a clinical reality, these agents carry a life-long risk of infection, various metabolic side effects, and cancer; in addition, they do not completely abolish rejection.  Thus, ideal therapy would consist of donor-specific immune tolerance with preservation of the normal immune responses.  Not surprisingly, tolerance has been called the “holy grail” of transplantation and remains the focus of intense research.  Whether inducing donor-specific tolerance will become a clinical reality remains to be seen, but it offers hope for the future of organ transplantation.