Autoreactive T cells mediate diabetes in animal models of insulin-dependent diabetes mellitus (IDDM) and are believed to cause the disease in humans. Therefore, immunotherapies directed against T cells are of particular interest for the treatment of IDDM. One candidate for such immunotherapy is anti-CD3 monoclonal antibodies (MoAbs), but clinical side effects are common with anti-CD3 treatment due to the ability of these MoAbs to activate T cells in vivo. However, F(ab')2 fragments of anti-CD3 are nonactivating and immunosuppressive. We evaluated the effects of whole anti-CD3 MoAb and F(ab')2 fragments in the setting of experimental autoimmune diabetes. Treatment with whole MoAb or F(ab')2 fragments significantly reduced the hyperglycemia induced with multiple low dosages of streptozocin (MDSDM; 232 +/- 23 mg/dl, P less than 0.01 and 235 +/- 16 mg/dl, P less than 0.01 vs. 325 +/- 25 mg/dl, respectively) in male CD1 mice. Both whole MoAb and F(ab')2 fragments suppressed the development of insulitis (P less than 0.001). Treatment with whole MoAb resulted in marked weight loss (10.4 +/- 1.5% of total body wt), and the mice appeared ill and listless, whereas, mice treated with F(ab')2 fragments gained weight (4.9 +/- 5.5% of total body wt) and appeared healthy. Treatment with whole MoAb caused activation of T cells in vivo as reflected by proliferation of freshly isolated spleen cells to recombinant interleukin-2. Depletion of T cells with whole MoAb was more pronounced than with F(ab')2 fragments, and T-cell receptor (TCR) reexpression on remaining cells occurred with F(ab')2 fragments within 48 h after F(ab')2 treatment.(ABSTRACT TRUNCATED AT 250 WORDS)