translation of curative therapy concepts with t cell and cytokine antibody combinations for type 1 diabetes reversal in the iddm rat

Proinflammatory cytokines released from the pancreatic islet immune cell infiltrate in type 1 diabetes (t1d) cause insulinopenia as a result of severe beta cell loss due to apoptosis. diabetes prevention strategies targeting different cytokines with antibodies in combination with a t cell antibody, anti-tcr, have been assessed for therapy success in the lew.1ar1-iddm (iddm) rat, an animal model of human t1d. immediately after diabetes manifestation, antibody combination therapies were initiated over 5 days with anti-tnf-α (tumour necrosis factor), anti-il-1β (interleukin), or anti-ifn-γ (interferon) together with anti-tcr for the reversal of the diabetic metabolic state in the iddm rat. anti-tcr alone showed only a very limited therapy success with respect to a reduction of immune cell infiltration and beta cell mass regeneration. anti-tcr combinations with anti-il-1β or anti-ifn-γ were also not able to abolish the increased beta cell apoptosis rate and the activated immune cell infiltrate leading to a permanent beta cell loss. in contrast, all anti-tcr combinations with anti-tnf-α provided sustained therapy success over 60 to 360 days. the triple combination of anti-tcr with anti-tnf-α plus anti-il-1β was most effective in regaining sustained normoglycaemia with an intact islet structure in a completely infiltration-free pancreas and with a normal beta cell mass. besides the triple combination, the double antibody combination of anti-tcr with anti-tnf-α proved to be the most suited therapy for reversal of the t1d metabolic state due to effective beta cell regeneration in an infiltration free pancreas.