Bellur S. Prabhakar

Professor and Head,

Ph.D., The Johns Hopkins University

Room: E705A MSB, Tel: 312-996-4945


Dr. Prabhakar’s laboratory is currently pursuing studies related to thyroid autoimmunity. His studies are unique in that his laboratory has been able to study two distinct diseases namely, Hashimoto’s thyroiditis (HT) and Graves’ disease (GD), both of which are organ specific autoimmune diseases with thyroid serving as the target organ. However, the autoimmune responses themselves are unique in that autoantibodies directed against the thyrotropin receptor predominates in GD and T cell responses against thyroglobulin is characteristic of HT. His studies have aimed at understanding the molecular pathogenesis of thyroid autoimmune diseases and apply lessons learnt from those studies to develop novel therapies to prevent and/or treat ongoing disease. A major aspect his studies involves studying the immune responses that are critical for the development of the disease using two different animal models; one for experimental autoimmune GD (EAGD) and the other for experimental autoimmune thyroiditis (EAT). His studies on the EAGD have focused on the development of an animal model that has features associated with GD. His laboratory has explored the involvement of Th1 or Th2 cytokines in the pathogenesis of the disease. These studies clearly showed that mere suppression or increase in the production of IL-4 well into disease development is not sufficient to affect the disease outcome, but total abrogation of IL-4 (i.e. IL-4 knockout mice) could prevent the development of the disease. This indicated the importance of IL-4 for the disease development.

His study on EAT is focused on the effects of modulation of dendritic cells using Flt3L or GM-CSF on the development of the disease. These studies showed that GM-CSF can not only completely prevent the development of EAT but can suppress the ongoing disease. Similarly, mice treated with a bi-specific antibody with specificities for CTLA-4 and TSHR could prevent the development of an effective immune response against thyroglobulin and development of EAT. Careful analyses of immune response in these experimental systems revealed that antigen specific regulatory T cells are up-regulated and are responsible for the suppression of the disease. Interestingly, the predominant cytokine responsible for suppression in GM-CSF treated mice was IL-10 while TGF beta predominated in the bi-specific antibody treated mice. Further studies are underway to fully delineate the underlying mechanism of action of these modalities of treatment.

Similar studies are being conducted to understand the role of regulatory T cells in the NOD animal model of type1 diabetes (IDDM). IN one of the studies, his laboratory has been able to demonstrate induction of regulatory T cells that can completely suppress the development of diabetes in NOD mice. Other studies have demonstrated that treatment of mice with a bi-specific antibody with specificities for CTLA-4 and a relevant alloantigen (anti-MHC class-I) can allow significantly longer survival of allo-islet transplants in diabetic mice and help maintain normal blood sugar levels. These studies are quite exciting and are likely to be very productive and could lead to the development of novel modalities of treatment for type-1 diabetes and preventing allo-graft rejection.

As part of his long-standing interest in type-1 diabetes, his laboratory cloned a novel human gene (IG20) that is differentially expressed in human insulinomas and can encode four different splice variants. These variants have been characterized through both gain and loss of function studies. The most fascinating aspect of gain of function studies is that one of the splice variants (DENN-SV) is over expressed in tumors and cells expressing exogenous DENN-SV are resistant to a number of cancer therapies including gamma-radiation and TRAIL. In contrast, another variant (IG20) is expressed at very low levels or not at all expressed in tumor tissues, and expression of exogenous IG20 renders cells highly susceptible to the above mentioned treatments and suppresses cell proliferation. In contrast, loss of function studies using SiRNA have shown that knockdown of a third isoform, MADD, can render cancer cells highly susceptible to spontaneous as well as TRAIL induced apoptosis. These observations indicate that MADD is required for cancer cell survival. The anti-cancer effects noted in our studies is mediated primarily through the modulation of death inducing signaling complex leading enhanced caspase production. Efforts are underway, using both knockout and transgenic mice, to fully understand the physiological function of these proteins.