News from St. Louis Second Wind Lung Transplant Association

INDUCTION IMMUNOSUPPRESSION

AFTER LUNG TRANSPLANTATION

Ramsey R. Hachem, M.D.
Washington University School of Medicine
Barnes-Jewish Hospital

Division of Pulmonary and Critical Care

The immune system has the primary role of detecting and responding to infectious microbes. This elicits the immune response to the allograft after a transplant, and chronic rejection has clearly emerged as the leading obstacle to better long-term outcomes after lung transplantation. Immunosuppressive treatment is necessary after transplantation to reduce the risk of rejection, although it does not prevent rejection altogether. Immunosuppression is broadly categorized as induction and maintenance treatment. Induction is intensive immunosuppression given immediately after the transplant, whereas maintenance immunosuppression is continued lifelong and gradually tapered over time. The role and use of induction immunosuppresion after lung transplantation is controversial. In fact, less than 50% of recipients reported to the International Society for Heart and Lung Transplantation (ISHLT) Registry received induction treatment in recent years.

The rationale behind induction immunosuppression is to minimize the risk of acute rejection in the early period after transplantation, which is the highest-risk period for rejection. There is ample evidence that acute rejection is a leading risk factor for chronic rejection, and it seems reasonable that preventing acute rejection may mitigate the risk of chronic rejection. In addition, induction often allows a delay in the initiation of tacrolimus or cyclosporine. Acute renal insufficiency is sometimes an early complication after transplant, and both tacrolimus and cyclosporine are toxic to the kidneys and can further worsen the kidney damage. So, in some cases, delaying the initiation of tacrolimus or cyclosporine by one or two days is preferred, and induction provides a margin of safety in the absence of a calcineurin inhibitor. However, the decision to use induction immunosuppression and the choice of agents is usually a center-specific decision, and different centers have different protocols and favor certain agents.

Multiple induction immunosuppressants exist. Historically, polyclonal anti-thymocyte globulins, or ATG, were commonly used. Two specific ATG agents are available, a horse and a rabbit preparation. The drug is developed by immunizing horses or rabbits with human lymphocytes, the immune cells responsible for rejection. The animal then makes antibodies directed against human lymphocytes, and these antibodies are retrieved from the animal, purified, and administered to patients. This results in a pronounced depletion of circulating lymphocytes and intensive immunosuppression. In recent years, however, monoclonal antibodies have been developed that are specific to certain important cell surface molecules on lymphocytes that are responsible for activation and proliferation. The most frequently used agents, known as interleukin-2 receptor antagonists, block the interleukin-2 receptor. This molecule is critical to the proliferation of lymphocytes in response to an infection or organ transplant. An older monoclonal agent, known as OKT3 binds another cell surface molecule on lymphocytes, the CD3 complex, that is critical to lymphocyte proliferation. Most recently, a chemotherapy drug, alemtuzumab, which binds to the CD52 molecule on lymphocytes and other immune cells and results in a prolonged and profound immunosuppression has been used in transplantation.

In medicine, the ideal test of a drug's efficacy and safety is a randomized controlled trial, where patients are randomly assigned to treatment with the study drug or placebo, and the investigators are blinded to the treatment assignment. In some cases, where a certain treatment or drug is known to be effective and considered the standard of care, but an alternative agent is being studied, the two are compared head to head in a randomized controlled trial. This study design minimizes potential biases that might influence the outcomes. However, randomized controlled trials are difficult to conduct because of cost, time investments, and inherent biases among different centers about their protocols. Indeed, few clinical trials have been conducted in lung transplantation evaluating the efficacy and safety of induction immunosuppression. A small study compared an ATG preparation to placebo and showed that ATG reduced the incidence of acute rejection. However, in the long-term analysis, there was no significant difference in the incidence of chronic rejection or survival between the two groups. Over the past five years, there has been an ongoing large multi-center clinical trial comparing the efficacy of another ATG preparation to placebo, and the results are pending.

There have been multiple non-randomized studies comparing different induction agents, but these have been inherently limited by their retrospective design and unavoidable biases that influenced the treatment assignment and may have also influenced the overall outcome. Furthermore, the majority of lung recipients worldwide are not treated with induction immunosuppression because of the concern for significant side effects such as serious infections or the development of post-transplant lymphoproliferative disease. Clearly, this remains a controversial topic in lung transplantation, and individual centers will continue to favor their own immunosuppression protocols. However, randomized controlled trials are necessary to identify the best treatments and improve outcomes after transplantation.