Nondepleting Antibody Therapy Reverses Diabetes Symptoms in Mouse Model

A mouse diabetes model was treated by an immunotherapeutic approach based on novel nondepleting antibodies specific for the T-cell receptors CD4 and CD8.

Residual beta cells found at the time of the clinical onset of type I diabetes are sufficient to control hyperglycemia, if they can be rescued from ongoing autoimmune destruction. To achieve this end, investigators at the University of North Carolina (Chapel Hill, NC, USA) developed an immunotherapeutic approach based on antibodies specific for the CD4 and CD8 receptors found on "autoreactive" T-cells. They then used these antibodies to treat members of a population of the mouse NOD diabetes model.

They reported in the June 29, 2012, online edition of the journal Diabetes that a short course of treatment with nondepleting antibodies specific for the CD4 and CD8 coreceptors rapidly reversed clinical disease in recent-onset diabetic NOD mice. Blood sugar levels returned to normal within 48 hours of treatment. Within five days, about 80% percent of the treated animals had entered diabetes remission with reversal of clinical symptoms.

Once established, remission was maintained indefinitely while immunity to foreign antigens was unimpaired. Induction of remission involved selective T-cell purging of the pancreas and draining pancreatic lymph nodes and upregulation of transforming growth factor (TGF)-beta1 by pancreas-resident antigen-presenting cells. Neutralization of TGF-beta1 blocked the induction of the remission process. In contrast, maintenance of remission was associated with tissue-specific immunoregulatory T cells.

"The protective effect is very rapid, and once established, is long-term," said senior author Dr. Roland Tisch, professor of microbiology and immunology at the University of North Carolina. "We followed the animals in excess of 400 days after the two antibody treatments, and the majority remained free of diabetes. And although the antibodies are cleared from within the animals in two to three weeks after treatment, the protective effect persists."

"We have demonstrated that the use of nondepleting antibodies is very robust," said Dr. Tisch. "We are now generating and plan to test antibodies that are specific for the human version of the CD4 and CD8 molecules."

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