Abstract
A recent type 1 diabetes (T1D) clinical trial of rituximab (a B cell-depleting anti-CD20 antibody) achieved some therapeutic benefit in preserving C-peptide for a period of approximately nine months in patients with recently diagnosed diabetes. Our previous data in the NOD mouse demonstrated that co-administration of antigen (insulin) with anti-CD3 antibody (a T cell-directed immunomodulator) offers better protection than either entity alone, indicating that novel combination therapies that include a T1D-related autoantigen are possible. To accelerate the identification and development of novel combination therapies that can be advanced into the clinic, we have evaluated the combination of a mouse anti-CD20 antibody with either oral insulin or a proinsulin-expressing DNA vaccine. Anti-CD20 alone, given once or on 4 consecutive days, produced transient B cell depletion but did not prevent or reverse T1D in the NOD mouse. Oral insulin alone (twice weekly for 6 weeks) was also ineffective, while proinsulin DNA (weekly for up to 12 weeks) showed a trend toward modest efficacy. Combination of anti-CD20 with oral insulin was ineffective in reversing diabetes in NOD mice whose glycemia was controlled with SC insulin pellets; these experiments were performed in three independent labs. Combination of anti-CD20 with proinsulin DNA was also ineffective in diabetes reversal, but did show modest efficacy in diabetes prevention (p = 0.04). In the prevention studies, anti-CD20 plus proinsulin resulted in modest increases in Tregs in pancreatic lymph nodes and elevated levels of proinsulin-specific CD4+ T-cells that produced IL-4. Thus, combination therapy with anti-CD20 and either oral insulin or proinsulin does not protect hyperglycemic NOD mice, but the combination with proinsulin offers limited efficacy in T1D prevention, potentially by augmentation of proinsulin-specific IL-4 production.
Highlights
In type 1 diabetes (T1D) antigen-specific immunotherapy (ASI) is a desirable goal because it offers the prospect of inducing immune tolerance with a good safety profile [1]
We investigated the efficacy of a novel anti-CD20 antibody, clone 5D2, in preventing or reversing diabetes in NOD mice, in combination with a proinsulinexpressing plasmid DNA vaccine or oral insulin
We combined the administration of a Bcell depleting anti-CD20 antibody with either proinsulin plasmid or oral insulin to determine the efficacy of these combinations in protecting hyperglycemic NOD mice
Summary
In type 1 diabetes (T1D) antigen-specific immunotherapy (ASI) is a desirable goal because it offers the prospect of inducing immune tolerance with a good safety profile [1]. It is possible that in human T1D, ASI alone is not sufficient to induce tolerance but requires combination with an appropriate immune modulator that can enhance regulatory T cell (Treg) function and reduce the load of effector cells This approach was recently validated in the NOD mouse, in which combination of non-Fc receptor binding anti-CD3 Mab with nasal proinsulin was more effective in reversing diabetes than either agent alone [3]. This has prompted strong interest in combination therapies, those in which the individual components have already shown safety or efficacy in human trials [4]. Based on these considerations we explored the combination of an insulin-based antigen with anti-CD20 Mab in the NOD mouse
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