Abstract
Genetically modified B cells are excellent tolerogenic antigen-presenting cells (APCs) in multiple models of autoimmunity. However, the mechanisms of action are still not completely understood. In our models, we generate antigen-specific tolerogenic B cells by transducing naïve or primed B cells with an antigen–immunoglobulin G (peptide–IgG) construct. In order to be transduced, B cells require activation with mitogens such as LPS. We and others have found that LPS stimulation of B cells upregulates the production of IL-10, a key cytokine for maintaining immune tolerance. In the current study, we defined the role of B-cell produced IL-10 in tolerance induction by using IL-10 deficient B cells as donor APCs. We found that peptide–IgG transduced IL-10 KO B cells have the same effects as wt B cells in tolerance induction in an experimental autoimmune encephalomyelitis model. Moreover, we demonstrated that the tolerogenic effect of peptide–IgG B cells was completely abrogated in anti-IL-10 receptor antibody treated recipients. Taken together, our results suggest that tolerance induced by peptide–IgG B-cell gene therapy requires IL-10 from the host but not donor B cells. These data shed important insights into the mechanisms of tolerance induction mediated by B-cell gene therapy.
Highlights
Immune tolerance to self-antigens must be maintained or autoimmunity occurs
This suggests that IL-10 KO B cells have normal antigen-presenting function and more importantly, that IL-10 produced by donor B cells is not required for tolerance induction
We demonstrated that antigen-specific tolerance does not need IL-10 generated by peptide–IgG transduced tolerogenic B cells
Summary
Based on the excellent tolerogenicity of IgG (Aldo-Benson and Borel, 1976; Borel et al, 1976) and the capacity of B cells to be tolerogenic antigen-presenting cells (APCs; Eynon and Parker, 1992; Fuchs and Matzinger, 1992; Gilbert and Weigle, 1994), our laboratory has developed a B-cell based gene therapy approach for actively inducing tolerance in animal models of autoimmune diseases and hemophilia (Skupsky et al, 2007). Achievement of antigen-specific tolerance in these models indicates the promise of this method as therapy for patients with autoimmune diseases or hemophiliacs with fVIII inhibitor formation. Similar results were reported by several other groups where B cells were utilized for tolerance induction in EAE (Chen et al, 2001, 2004) and in a mouse model of asthma (Ahangarani et al, 2009)
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