Dr. Bellur Prabhakar
Autoimmunity: A major focus of our research effort has been to identify, clone and characterize autoantigens implicated in different autoimmune diseases. More recently, our work has focused on understanding the role of dendritic cells in modulating immune responses with a particular emphasis on regulatory T cell induction and maintenance. Treating mice with experimental autoimmune diseases with low doses of GM-CSF causes selective expansion of CD8a- myeloid dendritic cells and retains them in a semi-matured status (tolerogenic BMDCs). Antigen presentation by these DCs resultedin selective expansion of Tregs which suppressed the disease. This modality of treatment has been successfully used to prevent and suppress ongoing, experimental autoimmune thyroiditis and myasthenia gravis; and to prevent type-1 diabetes in NOD mice. Tolerogenic BMDCs express OX40L and Jagged-1 and signaling mediated by both these ligands are essential for Treg expansion. Interestingly only FOxP3+ Tregs express cognate receptors OX40 and Notch3, and blocking signaling mediated by these receptors also abrogates BMDCs ability to expand Tregs. Use of BMDCs from MHC class II-/- mice showed that G-BMDCs induced Treg expansion occurred in the absence of canonical TCR engagement. More recently, we have shown that soluble OX40L and Jagged1 are sufficient to cause functional Treg expansion and delay/prevent the onset of diabetes. Furthermore, we have extended our findings by elucidating human Treg expansion by treating human thymocytes and splenocytes with soluble human OX40L and Jagged1. Currently, through NIH and JDRF funding, we are exploring the possibility of expanding human Treg in vivo by treating NSG mice with soluble OX40L and Jagged1. Cancer Biology: Anaplastic thyroid cancer (ATC) accounts for 50% thyroid cancer related deaths and the mean survival of patients with ATC is less than 6 months. Current treatment modalities do not significantly alter this outcome. Therefore, a treatment that can selectively kill cancer cells that are unresponsive to radioiodine treatment is highly desired. MADD protein is an Akt substrate and pMADD confers resistance to TRAIL induced apoptosis of cancer cells. Knockdown of MADD or dephosphorylation of pMADD can significantly enhance spontaneous as well as TRAIL-induced apoptosis of cancer cells including papillary and follicular thyroid cancer cells. However, the role of MADD, nor how its function is affected by the genetic alterations that enhance Akt activity, in ATC are unknown. Currently, our VA Merit Review funded program involves studying MADD function in ATC. These studies could provide unique insights for developing MADD targeted therapies to enhance TRAIL sensitivity of ATC. For the past 5 years, I have served as Dr. Maker’s formal mentor on his KKO8 award. His growth as an independent investigator has been truly spectacular, and he has managed his program independently for the past two years. His novel proposal is a clear indicator of his growth as an independent investigator. His training as a physician scientist in tumor immunology and surgical oncology have complemented my own interest in molecular aspects of cancer biology and immunology/autoimmunity. This complementarity has served both of us very well. I am quite certain that while we each maintain our independent research programs, to ensure a robust scientific and intellectual environment, we will continue our collaboration on projects of mutual interest.