Cellular Immunology: Role of dendritic cells in B cell tolerance - Elimination of self-reactive B cells is important to prevent autoimmune disease in the host. This takes place in the bone marrow for most mammals and to some extent in the spleen. Soluble self- protein antigens generally induce anergy while membrane-bound self-antigens induce clonal deletion in self-reactive B cells. We found that immature dendritic cells from the bone marrow can present self-antigens to induced clonal deletion in B cells. Present studies are to understand the nature of dendritic cells and the negative signal provided by the dendritic cells to induced clonal deletion of self-reactive B cells.

B- cell Lymphoma and B-cell chronic lymphocytic leukemia (B-CLL): Non-Hodgkin’s lymphoma (NHL) is the fifth most common cancer for both males and females in the United States. The age-adjusted incidence of non-Hodgkin lymphoma rose by 84% during the period 1975-2004, one of the very few cancers to show an increase in incidence. About 90% NHLs are of B-cell origin, with diffuse large B-cell lymphoma (30-40%) and follicular lymphoma (20%) being the two most common NHLs.   Almost 90% of lymphomas are B-cell in origin. We have demonstrated that tonic B cell receptor (BCR) signaling is important for survival of B lymphoma cells and that interfering with BCR signaling at the stage of spleen tyrosine kinase with synthetic small molecules or natural products such as curcumin and withaferin A can inhibit growth of B lymphoma cells. Current efforts are to determine the specific proximal protein tyrosine kinases, especially of the Src family that are important for B lymphoma survival. B-CLL is a leukemia primarily seen in adults. CLL cells are unlike most cancers in that they exhibit very little proliferation but survive for long time in vitro and in vivo. We are determining if the tonic BCR signaling is also important for B-CLL using murine and human models.

Myeloid Dysplastic Syndrome (MDS) and the role of early growth response -1 (Egr-1): MDS is a disease that appears at late stages of life either as de novo or secondary to treatment of cancer patients with radiation and chemotherapy. The latter group is called therapy related MDS (t-MDS) and is associated with a deletion of small segment of chromosome 5q. This region contains genes for Egr-1 and the micro-RNA, MiR-146 both of which have distinct roles in differentiation of hematopoietic stem cells and progenitor cells. Our goals are to develop animal models to determine the impact of these two genes and other genes present in the 5q deletion on the development of MDS with a long-term goal to identify early biomarkers of the disease and drug targets.