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 5

Reduced autoaggressive CD8+ T cell responses after combination treatment.

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Reduced autoaggressive CD8+ T cell ...
(A) The percentage of NP118 tetramer–positive CD8+ T cells in nondiabetic LCMV-infected RIP-NP mice (5 weeks after infection) or after treatment (anti-CD3 alone or combination therapy). Numbers above the gated cells correspond to the percentage of tetramer-positive CD8+ T cells found in the individual mice represented in the figure. Histograms, shown as insets, represent the average of n = 6–9 mice per group. As control, BALB/c mice were used. *P = 0.0036 compared with mice that have been infected but are in the memory phase of viral clearance (memory mice) and **P = 0.0057 compared with mice treated with NM-anti-CD3 alone. (B) The percentage of NRP-V7 tetramer–positive CD8+ T cells is shown for prediabetic NOD mice (10-week-old mice), for diabetic NOD mice, and for cured NOD mice after treatment (anti-CD3 alone or combination therapy). Numbers in the upper-right corner correspond to the percentage of tetramer-positive CD8+ T cells found in the individual mice shown in the figure. Histograms, shown as insets, represent the average of n = 5 mice per group. (C) The percentage of IFN-γ– and TNF-α–expressing CD8+ T cells was measured by intracellular staining in nondiabetic LCMV-infected RIP-NP mice, either nontreated (memory) or treated (anti-CD3 or combination therapy). Rows correspond to 3 different in vitro stimulations. Splenocytes and PLN cells were pooled and stimulated with either PMA/ionomycin or NP118 peptide or remained unstimulated (None). Histograms, shown as insets, correspond to the mean ± SD of IFN-γ– or TNF-α–positive CD8+ T cells (n = 3–5 mice per group). *P < 0.05 compared with the LCMV memory control.