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  • Title: CD3 antibody treatment stimulates the functional capability of regulatory T cells.
    Author: Chatenoud L.
    Journal: Novartis Found Symp; 2003; 252():279-86; discussion 286-90. PubMed ID: 14609225.
    Abstract:
    Autoimmune diabetes progression in NOD mice is under the control of CD4+ regulatory T cells. In the thymus these regulatory cells are CD25+-like CD4+ cells shown to control physiologic organ-specific autoimmunity. In contrast, in the periphery, both CD4+CD25+ and CD4+CD25- cells exhibit regulatory capacities. We have accumulated evidence showing an important role of transforming growth factor beta (TGFbeta) in this T cell-mediated regulation in vivo. Additionally, onset of autoimmune diabetes was preceded by a functional abnormality of CD4+CD25+ regulatory T cells as assessed by their inability to suppress in vitro the proliferation of polyclonally activated CD25- T cells. Antibodies to CD3 are potent immunosuppressants now generally applied as non Fc-receptor (FcR) binding monoclonals (F(ab')2 fragments in mice and humanized Fc-mutated monoclonals in humans). They were shown to induce durable regression of overt diabetes in NOD mice by restoring self-tolerance. The data from our laboratory were the first to show that in NOD mice anti-CD3 antibodies could reverse recent onset of disease by restoring tolerance to beta cell antigens. Thus in NOD mice presenting full-blown diabetes, a five consecutive day treatment with low doses of the hamster anti-CD3 monoclonal antibody 145 2C11 induced complete and durable disease remission, within 2-4 weeks in the absence of insulin treatment. This result has led to clinical trials, presently ongoing, in recent onset type 1 diabetic patients using non FcR binding monoclonal 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. Concerning the mechanistic aspects, data from the NOD mouse model indicate 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. Our recent data show that in CD3-treated NOD mice, these immunoregulatory T cells concentrate in the CD4-CD62L+ compartment and part of the population shares the CD25 marker. Furthermore, we also obtained evidence in CD3-treated NOD for a significant increase (in the pancreatic and mesenteric lymph nodes but not in the spleen) in the proportion of CD4+CD25+CTLA4+ T cells which produce TGFbeta.
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