Zhibin Chen, MD, PhD

Assistant Professor of Microbiology & Immunology
Room 3035 (Office), 3039A (Lab)
Rosenstiel Medical Sciences Building
1600 NW 10th Ave.
Miami, FL 33136

Research Interests: Immune tolerance and its applications to autoimmune diabetes and islet transplantation

Immune tolerance mechanisms
Vertebrates have evolved an adaptive immune system to fend off myriads of infectious agents. The central players in the system, T- and B-lymphocytes, express clonally unique receptors reacting to specific antigens. These receptors are generated somatically through random recombination of V, D and J gene segments, a process that can potentially create an astronomic number of specificities, but also, inevitably, reactivity to self tissues. Exquisite collaborations among diverse mechanisms prevent the immune system from attacking self tissues. For T-lymphocytes, prominent roles have been attributed to central tolerance, illuminated by the role of Aire in thymic deletion of autoreactive T lymphocytes, and peripheral regulation, exemplified by the function of Foxp3 in generating CD4 +CD25 + regulatory T (Treg) cells.

Dominant suppression by Treg cells holds exciting promise of adoptive cellular therapies. We are interested in the mechanisms of Treg-cell-mediated inhibition of autoimmunity, particularly in type 1 diabetes. Using mouse models of autoimmune diabetes, we have identified a key function of Treg cells in suppressing inflammatory pathology during immune destruction of pancreatic islets, and are studying how Treg cells enforce this protective role.

Immune tolerance has to function in a real world full of infectious agents. The role of Treg cells in controlling immunopathology perhaps indicates the evolutionary shaping of these immune cells against microbial infections. In many infectious diseases, microbial agents themselves do not cause substantial destruction, but out-of-control inflammation in responses to infections leads to pathological damage of tissues. Coxsackievirus B infection, which has long been implicated as a possible trigger in type 1 diabetes, is an example. In animal models, infection with Coxsackievirus B leads to severe pancreatic inflammation that is mediated by the adaptive immune system. We are interested in using this model to study the role of immunoregulations in controlling infection-induced inflammatory pathology in the pancreas.

Knockdown diabetes with RNAi
Common human diseases are thought to be predisposed by complex genetic variations. In an era of genomic sciences, large scales of gene expression analyses and genetic studies will continue to discover variations that are associated with diseases and health. Many of these variations will be on the levels of gene expression or copy numbers, but definitively establishing the causal roles of such variations remains a challenge. The cytotoxic T-lymphocyte antigen-4 (CTLA4 ) gene is such an example. CTLA4, a negative regulator of T-cell activation, plays a critical role in peripheral tolerance. Genetic variants that lead to reduced CTLA4 expression are linked to human type 1 diabetes as well as the disease in mouse models.

RNAi, commonly called “knockdown”, refers to gene silencing mediated by small interfering RNA (siRNA). With its potential to reduce gene expression to a spectrum of levels, it represents an ideal tool to study the effect of gene dosage. We generated CTLA4 “knockdown” mice, using lentiviral RNAi transgenesis. This “knockdown” model not only yields a unique insight into CTLA4-mediated immunoregulation in pathogenesis of type 1 diabetes, but also offers us a novel tool to study CTLA-based immune tolerance. The technical advantage of lentiviral RNAi transgenesis will also enable us to address the role of other genes implicated in the cascade of diabetes development, and identify targets for prevention and treatment of type 1 diabetes.

Immune tolerance induction for islet transplantation— a realistic approach to cure type 1 diabetes.

Type 1 diabetes is a devastating disease. Curing this disease has been a dream for generations of children, parents, and researchers. There are many promising venues leading to this goal. With the solid outcome from recent clinical trails of islet transplantation by multiple international centers, however, islet transplantation appears to be the most realistic approach in the nearest future to cure type I diabetes.

One of the critical limitations in islet transplantation is the current requirement of lifelong immunosuppression to maintain graft survival. These anti-rejection agents ensue risks of infections and malignancies, and thus prevent islet transplantation to become a treatment for many patients, particularly children. For patients to have a permanent acceptance islet grafts but be free from life-long immunosuppression, specific immune tolerance to the grafts must be induced.

Our studies, together with works from many other groups, have demonstrated critical roles for CTLA4 and Treg cells in immune controls of type 1 diabetes. Teaming up with the world leaders in the field of islet transplantation at Diabetes Research Institute, we are applying the knowledge and unique reagents, developed from studies of immune tolerance in autoimmune settings, to investigate tolerance induction to islet transplants.

Selected Publications
Adrian Liston, Andrew Farr, Zhibin Chen, Christophe Benoist, Diane Mathis, Nancy R. Manley, Alexander Y. Rudensky. Lack of Foxp3 function and expression in the thymic epithelium. J. Exp. Med . 204: 475-480, 2007.

Zhibin Chen , John Stockton, Diane Mathis, Christophe Benoist. Modeling CTLA4-Linked Autoimmunity with RNA Interference in Mice. PNAS . 103: 16400-16405, 2006.

Zhibin Chen , Ann E. Herman, Michael Matos, Diane Mathis and Christophe Benoist. Where CD4 +CD25 + Treg cells impinge on autoimmune diabetes. J. Exp. Med . 202: 1387-1397, 2005.

Zhibin Chen , Christophe Benoist and Diane Mathis. How defects in central tolerance impinge on a deficiency in regulatory T cells. PNAS. 102:14735-14740, 2005.

Sarah L. Dunn, Marie Björnholm, Sarah H. Bates, Zhibin Chen, Matthew Seifert and Martin G. Myers, Jr. Feedback Inhibition of Leptin Receptor/Jak2 Signaling via Tyr 1138 of the Leptin Receptor and Suppressor of Cytokine Signaling. Mol. Endocrinol. 19: 925-938, 2005.

Mark S. Anderson, Emily S. Venanzi, Zhibin Chen, Stuart P. Berzins, Christophe Benoist and Diane Mathis. The Cellular Mechanism of Aire Control of T Cell Tolerance. Immunity . 23:227-239, 2005.

Natalia Matin-Orozco, Zhibin Chen, Laurent Poirot, Elisabetta Hyatt, Andy Chen, Osami Kanagawa, Arlene Sharpe, Daine Mathis, Christophe Benoist. Paradoxical dampening of anti-islet self-reactivity but promotion of diabetes by OX40 ligand. J. Immunol. 171: 6954-6960, 2003.

Mark S. Anderson, Emily S. Venanzi, Ludger Klein, Zhibin Chen, Stuart P. Berzins, Shannon J. Turley, Harald von Boehmer, Roderick Bronson, Andree Dierich, Christophe Benoist, Diane Mathis. Projection of an immunological self shadow within the thymus by the AIRE protein. Science . 298: 1395-1401, 2002.

Zhibin Chen , Sergei B. Koralov, Garnett Kelsoe. Complement C4 inhibits systemic autoimmunity through a mechanism independent of complement receptors CR1 and CR2. J. Exp. Med . 192: 1339-1351, 2000.

Zhibin Chen, Sergi Koralov, Mariya Gendelman, Michael C. Carroll and Garnett Kelsoe. Humoral immune responses in Cr2 -/- mice. Enhanced affinity maturation but impaired antibody persistence. J. Immunol. 164: 4522-4532, 2000.

Zhibin Chen, Sergei Koralov and Garnett Kelsoe. Regulation of humoral immune responses by CD21/CD35 (review). Immunol. Rev . 176: 194-204, 2000.