Biographical Sketch:

Dr. Syamal Datta received bachelor's degree in Physiology from Presidency College, University of Calcutta, India, in 1960, and medical degree from Medical College, University of Calcutta in 1966. Despite much adversity and grinding poverty, those institutions have interesting history. For example, J.C. Bose over there had discovered the key to wireless radio transmitter in 1895; yes, even before Marconi (Science 279:476, January 23, 1998). In 1924, S.N. Bose, revolutionized quantum theory for elementary particles (Bose-Einstein statisitics), and conceived a new form of matter, called the Bose-Einstein Condensate which became a reality >70 years later (Science 270:1902, 1995). Another scientist there, M. Saha, formulated the foundations of one branch of astrophysics relating stars to atoms, and C.V. Raman, in a dilapidated lab., discovered the molecular scattering of light, called of course, Raman Spectra. Ronald Ross worked out the life cycle of malaria parasite and years of work in Medical College, Calcutta also helped Robert Koch discover the typhoid bacillus. Dr. Datta came from Calcutta to USA in 1968 and completed clinical training at Cook County Hospital and University of Illinois, Chicago, and then went on to do full time laboratory research beginning in 1972. After completing research training in Immunology with Dr. Robert Schwartz at Tufts University in Boston, Dr. Datta rose through the ranks to become full professor in 1985 and a leading investigator in autoimmunity. Incidentally, the field of autoimmunity was firmly established with the first description of a spontaneous autoimmune disease by Dameshek and Schwartz at Tufts, and Schwartz's work on immunosuppression had made organ transplantation in humans a reality.

Short Research Description:

Determining the molecular, cellular and genetic basis of the prototypic autoimmune disease, called systemic lupus; in mouse models and in humans. Develop specific immunotherapy for the disease. Determine basic mechanisms regulating lymphocyte activation threshold.

Research Abstract:

Our goal is to define the fundamental mechanism of Systemic Lupus Erythematosus (SLE) and design specific immunotherapy. Our laboratory was the first to identify the primary immunogen that initiates and drives the pathogenic autoimmune response in lupus. To this end, we cloned the unique T helper (Th) cells that drive the production of pathogenic anti-DNA autoantibodies in SLE, and found that their receptor (TCR) genes encoded negatively charged residues in their antigen-binding (CDR) regions. This led to our discovery that the pathogenic Th cells of lupus recognize positively charged nucleosomal antigens that are processed and presented by the anti-DNA B cells, which they help. We have identified the critical peptide epitopes for the Th cells in the core histones of the nucleosome particle. Remarkably, the nucleosomal peptide epitopes do not obey the rules of MHC-restriction; they can be promiscuously presented and recognized in the context of diverse MHC alleles, and this property is conferred by the lupus TCR ˆ chains. High affinity interactions between the lupus TCRs and MHC/nucleosomal peptide complex caused by reciprocally charged residues probably overcomes the requirement for MHC restriciton. Thus, our studies open up the possibility of developing universally tolerogenic epitopes for therapy of lupus in humans despite their diversity HLA alleles. These results also have profound implications regarding the selection of autoimmune T cells in the lupus-prone thymus and their expansion in the periphery. We are developing transgenic mice bearing TCR genes of the nucleosome-specific Th cells of lupus, to determine how the high-affinity, autoimmune TCRs escape censorship in the lupus-prone thymus despite the presence of nucleosomes, the ubiquitous products of apoptosis. The transgenic mice are also being studied to determine how regulatory controls in the periphery of the lupus-prone immune system break down to permit expansion of such pathogenic T cells.

In addition, we have found that the Th cells, as well as B cells of lupus, have a regulatory defect in the expression of CD40 ligand (CD40L), which mediates abnormal costimulatory signals to autoimmune B cells, sustaining the production of pathogenic autoantibodies. These results suggested a new paradigm for B cell hyperactivity in lupus and provided alternative targets for immunotherapy. We found that only three injections of anti-CD40L antibody given in one week period to mice with manifest lupus selectively blocks the pathogenic autoimmune response and delays the development of lupus nephritis by one year (equivalent to three decades in humans). We are currently studying the immunologic mechanism for this long-term beneficial effect of anti-CD40L therapy in lupus. We are also studying the abnormal regulation of expression of CD40L gene and protein in lupus, which could reveal the basic mechanism of T and B cell hyperactivity in this disease and would be of diagnostic and prognostic value as well.

Finally, we have discovered, and are in the process of characterizing several new genes that might be important for lymphocyte activation.

Publications:

1. Desai-Mehta, A., Mao, C., Rajagopalan, S., Robinson, T. and Datta, S.K.: Structure and specificity of T-cell receptors expressed by pathogenic anti-DNA autoantibody-inducing T cells in human lupus. J. Clin. Invest. 95: 531-541, 1995.

2. Desai-Mehta, A., Lu, L., Ramsey-Goldman, R. and Datta, S.K.: Hyperexpression of CD40 ligand by B and T cells in human lupus and its role in pathogenic autoantibody production. J. Clin. Invest. 97: 2063-2073, 1996.

3. Kaliyaperumal, A., Mohan, C., Wu, W. and Datta, S.K. : Nucleosomal peptide epitopes for nephritis-inducing T helper cells of murine lupus. J. Exp. Med. 183:2459-2469, 1996.

4. Kalled, S.L., Cutler, A.H., Datta, S.K. and Thomas, D. : Anti-CD40 ligand antibody treatment of SNF1 mice with established nephritis: Preservation of kidney function. J. Immunol. 160: March 1, 1998 (in press).