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 2

Synergy between non–Fc-binding anti-CD3 and hpIIp in treating NOD and RIP-LCMV mice after overt diabetes.

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Synergy between non–Fc-binding anti-CD3 and hpIIp in treating NOD and RI...
Mice were treated with either the anti-CD3 or peptide alone [suboptimal dose of anti-CD3 F(ab′)2 i.v. or hpIIp i.n., both 40 μg/injection] or a combination of both (combination therapy [CT]). (A) In the H-2d RIP-LCMV model (upper panel), the efficacy of the combination treatment reached 50% (n = 34) compared with 20% with anti-CD3 alone (n = 26) or 0% with hpIIp alone (n = 6). In the NOD model (lower panel), the efficacy reached 55% with the combination treatment (n = 31), compared with 37% with anti-CD3 alone (n = 54) or 22% with the hpIIp alone (n = 9). At week 9 after treatment, the statistical significance was evaluated between the anti-CD3 alone and the combination therapy groups (*P < 0.05). (B) Pancreatic islets were scored for the presence of mononuclear infiltration (upper left panel). The average percentage shown was determined from at least 8 mice per group. Shown are histological stainings of pancreata from RIP-LCMV-NP mice (lower panels). At week 5 after treatment with anti-CD3 alone or in conjunction with the proinsulin peptide (CT), pancreata from protected animals were harvested. Six-micrometer tissue sections were cut and collected for immunochemistry. Sections were costained for insulin and NP expression (lower left panel). Sections were probed for cellular infiltration by CD4+ and CD8+ T cells (lower right panel). Representative sections are shown in each panel. Original magnification, ×20.