Autoimmunity:

Dr. Bellur Prabhakar’s laboratory has been working on autoimmune diseases for over 30 years. A major focus of our research effort has been to identify, clone and characterize autoantigens implicated in different autoimmune diseases. More recently, our work is focused on understanding the role of dendritic cells in modulating immune responses with a particular emphasis on regulatory T cell induction and maintenance.

One of the methods of Treg induction involves treating mice with experimental autoimmune diseases with low doses of GM-CSF which causes selective expansion of CD8a- myeloid dendritic cells and retains them in a semi-matured status (tolerogenic BMDCs). Antigen presentation by these tolerogenic DCs results in selective expansion of Tregs that produce higher amounts of IL-10, which suppresses the pathogenic T cell response and consequently the disease. This modality of treatment has been successfully used to prevent and suppress ongoing, experimental autoimmune thyroiditis in CBA mice and myasthenia gravis in C57/Bl mice; and to prevent type-1 diabetes in NOD mice.

More recently, characterization of tolerogenic BMDCs revealed that they 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. Using BMDCs from MHC class II-/- mice, we have shown that G-BMDCs induced Treg expansion occurred in the absence of canonical TCR engagement, but required exogenous IL-2.

At the present time our NIH funded program involves elucidating the underlying mechanism of action of OX40 and Notch3 mediated co-signaling in the TCR-independent Treg expansion. We are optimizing expansion of Tregs to test their efficacy in the NOD model of Type 1 diabetes.

Cancer Biology:

The incidence of thyroid cancer is rapidly rising in USA. Patients with differentiated thyroid cancer are successfully treated with thyroidectomy and radioiodine (¹³¹I). However, in a proportion of these patients the tumor becomes poorly differentiated (PDTC) and loses its ability to take up radioiodine leading to disease recurrence and death. Additionally, 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 such as ATC cells is highly desired.

Map kinase Activating Death Domain containing protein (MADD) is a splice variant (SV) of the IG20 gene which can encode 6 different isoforms. MADD 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 several different types of cancer cells. Thyroid cancers have genetic alterations that result in constitutive activation of PI3K/Akt signaling pathways that contribute to tumor formation and progression. These mutations can result in increased phosphorylation of MADD, which could oppose apoptosis in thyroid cancer.

Depletion or dephosphorylation of MADD can significantly enhance TRAIL-induced apoptosis of 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. Interestingly, the pro-apoptotic effects of TRAIL and/or down modulation of MADD function are primarily seen in cancer cells, and not in normal cells; therefore, they can be used in combination to selectively target cancer cells.

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.

These and other funded projects in the laboratory will provide ample opportunities for the trainees, who will work in a harmonious laboratory environment in which the team of investigators has been together for over the years and has a wealth of knowledge and extensive technical expertise. We have significant insights that we have gained over the years and a solid momentum from which the trainees can benefit.

PhD, The John Hopkins University