PREVENTION OF AUTOIMMUNE DIABETES WITH NONACTIVATING ANTI-CD3 MONOCLONAL-ANTIBODY

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 < 0.01 and 235 +/- 16 mg/dl, P < 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 < 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. Despite the expression of this surface molecule, signaling by the TCR complex was blocked because T cells stimulated with anti-CD3 MoAb failed to produce lymphokines. We conclude that treatment with either whole anti-CD3 MoAb or F(ab')2 fragments suppresses the hyperglycemia and insulitis of MDSDM. The morbidity seen with whole MoAb does not occur with F(ab')2 fragments and is correlated with the failure of the latter to activate T cells in vivo. Nonactivating forms of anti-CD3 MoAbs may be a useful form of immunosuppressive treatment for incipient IDDM because they do not cause morbidity associated with activation of T cells, which occurs with whole MoAb.