Biennial Report of the Director

Research in Diseases, Disorders, and Health Conditions
Chronic Diseases and Organ Systems

Since the first successful kidney transplant between identical twins in 1954, transplantation has become the treatment of choice for end-stage organ failure. Despite tremendous progress, however, major barriers still remain to the overall success of transplantation. These include immunological incompatibility between donor and recipient, acute rejection, chronic graft dysfunction, and complications from requisite long-term use of immunosuppressive drugs. NIAID supports basic and clinical research that focuses on the immunologic processes underlying transplant rejection and acceptance, ways to reduce or eliminate the need for immunosuppressive drugs, and the development of new, less toxic anti-rejection therapies.

It has been observed that some liver transplant recipients who stop taking their immunosuppressive drugs because of other health problems have continued to have a well-functioning liver without rejection. During FY 2010 and FY 2011, NIAID sponsored a clinical study to establish the feasibility of immunosuppression withdrawal in pediatric living donor liver transplant recipients. In this study, 20 children who were transplanted with a lobe of liver donated by a parent, and who had been doing well on immunosuppressive drugs for many years, were selected for study. Over a period of 6 months, the doses of their anti-rejections drugs were slowly reduced until finally the drugs were stopped altogether. The results will be published in FY 2012.

As a result of Highly Active Anti-Retroviral Therapy (HAART), persons in developed countries who are diagnosed with HIV infection early in the course of the disease have a life expectancy of 75 years, and may develop conditions treatable by kidney transplantation. NIAID sponsored research on outcomes of kidney transplantation and immunosuppression in people infected with HIV. In a multi-center study, 150 people with well-controlled HIV infection underwent kidney transplants, and were treated with standard anti-rejection drugs along with HAART. The results, published in FY 2011, showed that patient survival rates at 1 year and 3 years were 95 percent and 88 percent; 90 percent of the transplanted kidneys were still functioning well one year after the transplant, and 74 percent were functioning 3 years after the transplant. A higher-than-expected rejection rate was observed: 31 percent at one year, and 41 percent at three years. HIV infection remained well controlled. This research demonstrates that people with well-controlled HIV infection can have acceptable outcomes after kidney transplantation, and that more research is needed to determine the best immunosuppressive regimen for them.271

“Transplantation tolerance” refers to the condition in which a person can have a healthy, well-functioning transplanted organ without needing to take immunosuppressive drugs. Eliminating the need for immunosuppressive drugs is an important goal of transplantation research; however, there is currently no simple test that would tell doctors which patients might do well if they stopped taking their drugs. NIAID-sponsored research in which investigators identified the largest reported cohort of tolerant renal transplant recipients, as defined by stable graft function and receiving no immunosuppression for more than 1 year, and compared their gene expression profiles and peripheral blood lymphocyte subsets with those of subjects with stable graft function who are receiving immunosuppressive drugs, as well as with healthy controls. The results, published in FY 2010, showed that Tolerance of a transplanted kidney was strongly associated with a B cell signature using several blood and urine tests. Tolerant subjects showed increased expression of multiple genes that control B cell development. A set of just 3 of these genes distinguished tolerant from nontolerant recipients. These results point to a critical role for B cells in regulating the body’s response to a transplanted kidney and might prove useful in determining which transplant recipients could do well with less or no anti-rejection medication.272

NIH will continue to support transplantation research along the entire spectrum from basic discovery to phase III clinical trials. In addition to a portfolio of investigator-initiated research projects, NIAID supports solicited research through cooperative groups. The Genomics of Transplantation Cooperative Research Program examines how patterns of gene expression and individual genetic variations are associated with clinical transplant outcomes. The HLA Region Research Consortium studies how the HLA region, a highly variable region of an individual’s DNA, is associated with many immune-mediated diseases, including transplantation rejection and graft failure. The Nonhuman Primate Islet/Kidney Transplantation Tolerance program evaluates the safety and efficacy of existing and new techniques that can help transplant recipients tolerate transplanted tissues and have improved long-term outcomes. Programs for human transplantation studies include the Clinical Trials in Organ Transplantation and Clinical Trials in Organ Transplantation in Children consortia; The Transplantation in HIV study; the RELIVE Consortium, studying the outcomes of living organ donors; The Clinical Islet Transplant Consortium; and the Immune Tolerance Network, a program that evaluates novel, tolerance-inducing therapies for transplantation as well as autoimmune diseases and asthma.

271 Stock PG, et al. N Engl J Med. 2010;363(21):2004–14. PMID: 21083386.
272 Newell KA, et al. J Clin Invest. 2010;120(6):1836–47. PMID: 20501946.