Translational impact of NIH-funded nonhuman primate research in transplantation

Abstract

The National Institutes of Health (NIH) has long supported using nonhuman primate (NHP) models for research on kidney, pancreatic islet, heart, and lung transplantation. The primary purpose of this research has been to develop new treatments for down-modulating or preventing deleterious immune responses after transplantation in human patients. Here, we discuss NIH-funded NHP studies of immune cell depletion, costimulation blockade, regulatory cell therapy, desensitization, and mixed hematopoietic chimerism that either preceded clinical trials or prevented the human application of therapies that were toxic or ineffective.

Fig. 1.. The transplantation research cycle.

The cycle begins with mechanistic diagnosis of the clinical problem of tissue rejection in human transplant patients. It progresses to a hypothesis regarding potential solutions. The next step involves testing in vitro experimental solutions and selecting the most promising new therapies for in vivo evaluation in murine models of organ transplantation. This is followed by more discriminating experimental evaluation of the therapy in nonhuman primate (NHP) transplant models. Successful NHP therapies progress to controlled human clinical trials before FDA approval for general clinical use in transplant patients.

Fig. 2.. Timeline for development of belatacept.

Blocking the CD28-CD80/CD86 costimulatory pathway has evolved from a mechanistic in vitro experimental tool to in vivo application for solid organ and islet transplantation, first in murine models and then in NHPs. In NHP transplant models, it was recognized that continuous therapy to prevent organ rejection would be more clinically useful than induction of tolerance and that a higher affinity molecule (belatacept) would be preferable to CTLA4-Ig. The FDA approved belatacept for kidney transplantation in 2010, 24 years after CTLA4-Ig was originally developed.