concanavalin-a and Prediabetic-State

In studies of immune cell defects in autoimmune diabetes mellitus, we observed that complete Freund's adjuvant (CFA) prevented the onset of diabetes when injected into 8- to 10-wk-old prediabetic nonobese diabetic (NOD) mice. The prevalence of the onset of diabetes in the CFA-injected versus uninjected NOD mice was 2 of 81 (2.5%) vs. 231 of 379 (61%) among females and 2 of 44 (4.5%) vs. 83 of 336 (25%) among males, respectively. The incidence of histologically identifiable insulitis was significantly reduced in CFA-treated prediabetic female NOD mice (18%) compared with the incidence in female age-matched controls (70%). Splenocytes or Mac-(1+)-enriched splenocytes from CFA-treated NOD mice, when cotransferred with splenocytes from diabetic mice, reduced the incidence of diabetes provoked by diabetic splenocytes in vivo. In the spleen, CFA injection induced sustained increases in cell proliferation and an associated major increase in the numbers of an immature cell type that expressed the Mac-1 surface antigen. In CFA-treated NOD mice, lymphocytes derived from the spleen failed to respond in vitro to stimulation by the mitogen concanavalin A or by anti-CD3. When cocultured, Mac-1+ cells, enriched from the splenocytes of CFA-treated mice, suppressed concanavalin A- or anti-CD3-induced proliferation of T lymphocytes derived from either the spleen or thymus of untreated NOD mice. Therefore, treatment with CFA prevents the development of diabetes, and concomitantly, insulitis while stimulating the generation of splenic suppressor cells that are capable of suppressing diabetogenic T-lymphocyte function in vivo and in vitro.

Topics: Animals; Cells, Cultured; Concanavalin A; Diabetes Mellitus, Experimental; Freund's Adjuvant; Islets of Langerhans; Lymphocyte Activation; Mice; Mice, Mutant Strains; Pancreatic Diseases; Phenotype; Prediabetic State; Spleen; T-Lymphocytes

To investigate the pathological role of suppressor T-cells in non-obese diabetic (NOD) mice, we stimulated splenic T-lymphocytes from diabetes-prone NOD mice with concanavalin A (ConA) and then evaluated their ability to suppress the lymphocyte-proliferative responses to mitogen and allogenic cells. Lymphocytes from NOD mice showed significantly less suppressor ability than did those from BALB/c mice and non-obese non-diabetic (NON) mice, the corresponding non-diabetic sister strain of the NOD mouse, both in the mitogen response and in the mixed lymphocyte reaction (MLR). We used monoclonal antibodies and flow cytometry to analyze the lymphocytic surface phenotypes, and found markedly fewer Lyt2+ T-lymphocytes (suppressor/cytotoxic T-lymphocyte) in the NOD mice than in both controls after exposure to ConA. These results suggest that suppressor T-cell activity is already depressed in NOD mice before diabetes begins and that a substantial decrease in the number of suppressor T-cells induced by ConA may explain this depressed suppressor activity. This impairment may contribute to the pathogenesis of type 1 diabetes in NOD mice.

Topics: Animals; Cells, Cultured; Concanavalin A; Diabetes Mellitus, Experimental; DNA Replication; Lymphocyte Activation; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Mice, Mutant Strains; Prediabetic State; Reference Values; T-Lymphocytes; T-Lymphocytes, Regulatory