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 1

Purity and functionality of the anti-CD3 F(ab′)2 .

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Purity and functionality of the anti-CD3 F(ab′)2 ...
(A) The purity of anti-CD3 was assessed by staining with Coomassie blue brilliant. (B) ELISA experiment to compare the binding capacities of the purified nonmitogenic (NM) F(ab′)2 and full-length anti-CD3. (C) The half-life of the CD3 was evaluated in vivo. After i.v. injection of 200 μg into mice (n = 6), 50 μl blood was taken daily and the presence of anti-CD3 F(ab′)2 in the serum assessed by ELISA. NT, nontreated. (D) In vivo activity of the NM anti-CD3 F(ab′)2 was evaluated in RIP-LCMV mice (n = 6). Blood samples were analyzed days 1, 3, 8, and 15 after treatment with anti-CD3 alone and their contents in CD4+, CD8+, and CD25+ T cells compared with those of untreated and uninfected RIP-LCMV mice (control). (E) The efficacy of our commercial anti-CD3 F(ab′)2 was controlled by treating NOD mice after new-onset diabetes with 3 Ab doses (10, 50, and 100 μg/d, 5 consecutive days). The percentage of mice showing long-term remission was calculated and is shown in the figure.