The hypothesis underlying the proposed project is that a beta granule associated protein (betaGAP) is the principal antigen for a panel of islet-reactive, diabetogenic T cell clones derived from the NOD mouse. Our primary objective, and the first aim, of the project continuation is to purify this protein antigen to homogeneity in order to obtain a sequence and definitive identification. Under the second aim, we plan to investigate whether antibodies with reactivity to beta granules are directed to the same antigens as T cells.
The third aim i s to analyze T cell receptor (TCR) sequences from the T cell clones to determine whether any distinct patterns of TCR gene usage can be detected. The significance of the proposed work lies in the fact that while a growing number of candidate antigens is being investigated for relevance to diabetes, no one antigen has been identified as the principal target of the autoreactive T cells that mediate disease. Our panel of well- characterized, diabetogenic T cell clones provides one of the best systems available to investigate this question. The value of these T cells as tools to probe disease-relevant beta cell antigens is indicated by two important features: (1) their ability to rapidly induce diabetes in two-week old mice, and (2) all of the diabetogenic clones tested react to a beta granule membrane associated protein, suggesting an immunodominant antigen.
|Bergman, B; McManaman, J L; Haskins, K (2000) Biochemical characterization of a beta cell membrane fraction antigenic for autoreactive T cell clones. J Autoimmun 14:343-51
|Piganelli, J D; Martin, T; Haskins, K (1998) Splenic macrophages from the NOD mouse are defective in the ability to present antigen. Diabetes 47:1212-8
|Dallas-Pedretti, A; McDuffie, M; Haskins, K (1995) A diabetes-associated T-cell autoantigen maps to a telomeric locus on mouse chromosome 6. Proc Natl Acad Sci U S A 92:1386-90
|Bergman, B; Haskins, K (1994) Islet-specific T-cell clones from the NOD mouse respond to beta-granule antigen. Diabetes 43:197-203