Anti-CD3 and nasal proinsulin combination therapy enhances remission from recent-onset autoimmune diabetes by inducing Tregs
Damien Bresson, … , Kevan C. Herold, Matthias von Herrath
Damien Bresson, … , Kevan C. Herold, Matthias von Herrath
Published May 1, 2006
Citation Information: J Clin Invest. 2006;116(5):1371-1381. https://doi.org/10.1172/JCI27191.
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Research Article Metabolism

Anti-CD3 and nasal proinsulin combination therapy enhances remission from recent-onset autoimmune diabetes by inducing Tregs

Abstract

Safe induction of autoantigen-specific long-term tolerance is the “holy grail” for the treatment of autoimmune diseases. In animal models of type 1 diabetes, oral or i.n. immunization with islet antigens induces Tregs that are capable of bystander suppression. However, such interventions are only effective early in the prediabetic phase. Here, we demonstrate that a novel combination treatment with anti-CD3ε–specific antibody and i.n. proinsulin peptide can reverse recent-onset diabetes in 2 murine diabetes models with much higher efficacy than with monotherapy with anti-CD3 or antigen alone. In vivo, expansion of CD25+Foxp3+ and insulin-specific Tregs producing IL-10, TGF-β, and IL-4 was strongly enhanced. These cells could transfer dominant tolerance to immunocompetent recent-onset diabetic recipients and suppressed heterologous autoaggressive CD8 responses. Thus, combining a systemic immune modulator with antigen-specific Treg induction is more efficacious in reverting diabetes. Since Tregs act site-specifically, this strategy should also be expected to reduce the potential for systemic side effects.

Authors

Damien Bresson, Lisa Togher, Evelyn Rodrigo, Yali Chen, Jeffrey A. Bluestone, Kevan C. Herold, Matthias von Herrath

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Figure 6

CD4+ CD25+ T lymphocytes generated by combination therapy exert dominant tolerance and block autoimmune diabetes after adoptive transfer.

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CD4+ CD25+ T lymp...
(A) Adoptive transfer of 5 × 106 CD4+ T cells from nondiabetic donors, either nontreated RIP-LCMV mice (control, n = 5 mice) or mice treated with the anti-CD3 alone (n = 4 mice) or in combination with the proinsulin peptide (n = 6 mice). A 3-day antigenic stimulation of splenocytes derived from protected mice was performed for each group (treated as well as control) to expand the proinsulin-specific Treg population prior to adoptive transfers. The putative Tregs were transferred into nonimmunodeficient RIP-LCMV-NP recipient mice day 5 after LCMV infection. (B) CD4+CD25+ and CD4+CD25– T cells were purified from treated RIP-LCMV mice protected by the anti-CD3 alone (lower panel) or in combination with the proinsulin peptide (upper quadrant). Those cells (106) were transferred into nonimmunodeficient RIP-LCMV-NP recipient mice 5 days after LCMV infection (n = 6 mice per group). (C) Proliferation of CD4+CD25+ lymphocytes in the spleens and PLNs of RIP-LCMV recipient mice. CD4+CD25+ T lymphocytes were purified from treated RIP-LCMV mice protected by the anti-CD3 alone (left panels) or in combination with the hpIIp (right panels). These cells were CFSE labeled and transferred into wild-type RIP-LCMV recipient mice day 5 after infection. Spleens and PLNs were removed from recipients 2 days after transfer and stained with a CD4-specific antibody. The data are representative of 2 independent experiments. Numbers correspond to the mean ± SD of CFSE-diluted CD4+CD25+ lymphocytes (n = 2 mice per group).