The non-obese diabetic (NOD) mouse spontaneously develops insulin- dependent diabetes mellitus, a polygenic disease caused by autoimmune destruction of the insulin-producing beta-cells. Development of diabetes in the NOD mouse clearly depends on T-cell function; immunosuppressive agents which suppress T-cell function (cyclosporin, antithymocyte globulin, azathioprine and prednisone) or which deplete mature T cells (anti-CD3, anti-CD4 and anti-CD8 monoclonal antibodies) prevent the development of autoimmune diabetes when they are given at an early age. Anti-lymphocyte serum (ALS), another potent T cell immunosuppressive agent, also induces a long-term abrogation of autoimmunity when administered early after the onset of diabetes. We have recently found that the administration of interleukin-3 (lL-3) starting at 15-40 days of age prevents or delays the onset of diabetes in NOD mice. Moreover, bone marrow cells of lL-3 treated mice appear to delay the onset of diabetes when they are adoptively transferred together with diabetic NOD mouse splenocytes. Because the lack (or deficiency) of immune regulatory cells has been postulated as a possible mechanism underlying the development of autoimmune diabetes, we hypothesize that administration of lL-3 at an early age in NOD mice prevents development of diabetes through stimulation of autoimmune regulatory cells in the bone marrow which interfere with auto reactive immune responses. The proposed studies will test this hypothesis.
Four specific aims are: 1) to determine an optimal protocol for lL-3 administration, 2) to determine the immunoregulatory activity of bone marrow cells obtained from lL-3 administered NOD mice, 3) to characterize immunoregulatory cells induced by lL-3 administration, and 4) to determine immunoregulatory activity of bone marrow cells stimulated in vitro by lL-3. We believe that these studies will provide important information concerning the mechanism(s) underlying the development of diabetes in NOD mice and insight into a possible new therapeutic modality which would prevent autoimmune diabetes without generalized immunosuppression or the adverse effects associated with most of the current immunotherapeutic regimens.
| Kimura, T; Ito, A; Hancock, W W et al. (1999) Islet mass plays a critical role in initiation, but not progression, of the diabetogenic process in NOD mice. J Autoimmun 12:243-9 |
| Itoh, A; Maki, T (1996) Protection of nonobese diabetic mice from autoimmune diabetes by reduction of islet mass before insulitis. Proc Natl Acad Sci U S A 93:11053-6 |
