ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2008) 16 S26.3

Emerging therapeutic approaches to preserve beta cell function in type 1 DM

Lucienne Chatenoud

INSERM U580 Hôpital Necker Enfants Malades, Paris, France.

Antibodies to CD3 are potent immunosuppressants now applied as non Fc-receptor (FcR) binding monoclonals.

Data from our laboratory demonstrated that in NOD mice CD3 antibodies could reverse recent onset disease by restoring tolerance to beta cell antigens in a durable fashion. Thus in mice presenting full-blown diabetes, a five consecutive day treatment with low doses of the hamster anti-CD3 monoclonal antibody 145 2C11 or its F(ab)′2 fragments induced complete and durable disease remission, within 2–4 weeks in the absence of insulin treatment. Concerning their mode of action, data from the NOD mouse model indicated that CD3 antibodies promote 1) immediate clearance of insulitis followed by 2) ‘resetting’ of specialized subsets of immunoregulatory CD4+T cells mediating active tolerance similar to those that control the onset of spontaneous diabetes and 3) recovery of sensitivity of pathogenic T cells to immunoregulation. More recent results showed that the CD3-induced immunoregulatory T cells concentrate within both the CD4+CD25+ and CD4+CD62L+ compartments. We also obtained evidence in support of a key role for the cytokine TGF-beta in the anti-CD3-induced T cell-mediated immunoregulation.

These results have led to clinical trials in recent onset type 1 diabetic patients using non Fc-receptor (FcR) binding monoclonals antibodies to CD3 that are well tolerated since they are devoid of the mitogenic activity that was a hallmark of first generation CD3 antibodies such as OKT3. The results of these studies will be presented and discussed in the context of the current strategies aimed at inducing/restoring immune tolerance in the clinic to preserve over long term beta cell function in type 1 diabetes.

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