The laboratory has two areas of interest. One set of studies focuses on the pathogenesis of Systemic Lupus Erythematosus (SLE) a multisystem autoimmune disease characterized by the development of autoantibodies to a variety of cellular constituents. Our investigations are centered on the NZB mouse as a model for this disease. Although the B cells in these mice are polyclonally activated previous work suggests that T cell help is required for the development of the high affinity pathogenic antibodies that mediate disease. To determine whether this T cell help arises from a generalized defect in T cell tolerance induction or an abnormality in T-B collaboration we have examined antigen-specific tolerance in beef insulin (BI) transgenic NZB backcross mice or following administration of aqueous protein antigens. Our studies show that in control BALB/c mice both the BI transgene and administration of aqueous BI induce a state of partial tolerance manifested by relative preservation of a Th2-like response with production of IgG1 BI-specific antibody but a marked reduction in Th1-associated IgG2a and corresponding IL-2 production. In contrast, NZB mice produce both isotypes of antibodies despite appropriate reduction of antigen-induced IL-2 production in response to tolerization. Further studies will focus on this altered response to tolerization. In particular, we will examine events occuring during T-B collaboration using adoptive transfer experiments, administration of cytokines and/or anti-cytokine mAbs and additional transgenic mouse model systems.
The other area of interest in the laboratory is the structure of the T cell recognition complex. We have previously generated several panels of BI-specific Ad-restricted T cell hybridomas bearing TCR chains that demonstrate limited amino acid differences in their alpha- or beta-chain V regions. To study the nature of the interaction between these TCR and the antigen/MHC complex we have systematically mutated the Ad molecule and are examining the ability of transfectants to present BI to our T cell hybridomas.
Publications and Awards
- Wither, J., Pawling, J., Phillips, L., Delovitch, T., & Hozumi, N. J. Immunol. 146, 3513-3522 (1991).
- Wither, J., Poplonski, L., Delovitch, T., & Hozumi, N. Arthritis and Rheumatism 36, S93 (1993).
- Wither, J., Poplonski, L., & Vukusic, B. Arthritis and Rheumatism 37, R39 (1994).