Research

To investigate how Tregs prevent autoimmune diabetes and transplant rejection in a mouse model system, we are observing the actions of Tregs injected into both diabetes-prone mice as well as mice that are recipients of transplanted organs such as skin and islets.  We are analyzing how these Tregs affect the initiation of an immune response in the lymph nodes, the invasion of the immune cells in the tissue, and the final killing of the islets by immune cells in disease-prone mice or the destruction of the transplanted organ.

We use a novel two-photon laser-scanning microscopy to monitor these events in intact tissues and to directly visualize the Treg interaction with other components of the immune system.  We are further investigating the molecules utilized by Tregs to achieve their control over the immune system's activity.

Despite the great potential seen in islet transplantation as a therapy for type 1 diabetes, immune and non-immune-mediated islet graft loss poses a significant barrier to sustainable insulin independence.  The acute sensitivity of isolated islets to immunosuppressive drugs is a major factor in graft loss.  We are therefore not only examining the immune response to transplanted islets, but also the effect of immunosuppressive drugs on long-term function of islet grafts using an in vivo imaging approach.  Results from this study will be valuable in identifying less toxic immunosuppressive regimens for islet transplantation.

As the immune system's main mechanism for suppressing unwanted inflammation and ensuring self-tolerance, Tregs are becoming a major focus for translational research in the fields of immunology and transplantation.  Basic research in animal models in the past decade has demonstrated that it is possible to isolate and expand Tregs, and then use them to treat autoimmune diseases and inflammatory disorders.  We are currently optimizing protocols to expand human Tregs to prevent organ transplant rejection in patients.

The advantage of using Tregs is that they are long-lived and act specifically to suppress cells rejecting the graft but not other cells, thus minimizing the need for long-term generalized immunosuppression.  In patients undergoing Treg-therapy or other novel drug treatment, we need to have a battery of standardized assays to assess the status of the patients' immune system to determine whether they have developed tolerance to the grafts.  Thus, we are using blood samples from healthy volunteers to develop protocols to expand human Tregs for therapeutic use and to develop standardized tests for monitoring the status of alloimmune responses.

A collaborative effort with Drs. Peter G. Stock, MD, PhD, Flavio Vincenti, MD, Sang-Mo Kang, MD, Zoltan Laszik, MD, PhD, and Ryutaro Hirose, MD, this initiative is part of an NIH prospective multi-center study on the safety and efficacy of liver and kidney transplantation in HIV positive patients.  Preliminary data indicate that HIV positive recipients of both liver and kidney transplants have surprisingly higher rejection rates than their HIV negative counterparts.  The observed patterns of rejection in these patients reveal two important features: first, the rejection seems to be the result of an inherent enhanced response to transplant antigens, and second, the immune responses are resistant to immunosuppression, which is reminiscent of a memory response.  In this study, we aim to address the hypothesis that HIV positive patients have preformed memory immunity to alloantigens that are resistant to conventional immunosuppressive treatment.