Abstract
Autoantigen-specific methods to prevent and treat Type 1 Diabetes (T1D) carry high hopes to permanently cure this disease, but have largely failed in clinical trials. One suggested approach to increase the efficacy of islet antigen-specific vaccination is to combine it with a modulator of the T cell response, with the goal of reducing effector differentiation and promoting regulatory T cells (Tregs). Here we asked if addition of antibodies that block the IL-7/IL-7Rα pathway altered the T cell response to islet antigen vaccination and prevented T1D in non-obese diabetic (NOD) mice. Anti-IL-7Rα monoclonal antibodies (mAbs) reduced the numbers of islet antigen-specific T cells generated after vaccination with islet peptides and alum. However, addition of anti-IL-7Rα antibodies to peptide/alum vaccination unexpectedly increased non-specific IFN-γ, IL-2 and IL-10 cytokine production and did not result in improved prevention of T1D onset. In a second approach, we used a conjugate vaccine to deliver islet autoantigens, using Keyhole Limpet Hemocyanin (KLH) as a carrier. Islet antigen-KLH vaccination led to a significant expansion of antigen-specific Tregs and delayed diabetes onset in NOD mice. These outcomes were not further improved by addition of anti-IL-7Rα antibodies. To the contrary, blocking IL-7Rα during vaccination led to non-specific cytokine production and reduced the efficacy of a KLH-conjugated vaccine to prevent T1D. Our study thus revealed that adding anti-IL-7Rα antibodies during autoantigen immunization did not improve the efficacy of such vaccinations to prevent T1D, despite altering some aspects of the T cell response in a potentially advantageous way. Further refinement of this approach will be required to separate the beneficial from the adverse effects of anti-IL-7Rα antibodies to treat autoimmune disease.
Highlights
Anti-IL-7Rα monoclonal antibodies (mAbs) have shown efficacy to prevent and reverse autoimmune diabetes in non-obese diabetic (NOD) mice [1, 2], a widely used model of spontaneous Type 1 Diabetes (T1D) that possesses many features of the human disease [3]
To analyze the impact of anti-IL-7Rα blockade on the Ag-specific T cells responding to vaccination in vivo, lymph nodes and spleen were harvested on day 7 after immunization, and magnetic enrichment with a BDC2.5 Class II tetramer was used to detect and enumerate endogenous BDC2.5-specific T cells directly ex vivo
Our study explored the feasibility of using anti-IL-7Rα mAbs in combination with an islet antigen vaccination method to modulate an autoantigen-specific T cell response and prevent T1D
Summary
Anti-IL-7Rα mAbs have shown efficacy to prevent and reverse autoimmune diabetes in NOD mice [1, 2], a widely used model of spontaneous T1D that possesses many features of the human disease [3]. Blocking IL-7Rα altered the balance of Foxp3-negative naïve/effector/memory CD4+ T cells (designated hereafter as “conventional” T cells (Tconv)) and Foxp3+ regulatory CD4+ T cells (Tregs) in favor of the latter in the lymphoid organs. These changes likely contribute to the therapeutic effect of anti-IL-7Rα mAbs in preventing and reversing islet pathology. Broadly immunosuppressive agents may be better suited for short-term administration in combination with other interventions to increase their efficacy in T1D [4]
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