Saturday, March 2, 2013
Combination treatment with anti-CD20 and oral anti-CD3 prevents and reverses autoimmune diabetes
Abstract: Type 1 diabetes (T1D) is a T cell-mediated autoimmune disease, although B cells also play an important role in T1D development. Both T cell- and B cell-directed immunotherapies have shown efficacy in the prevention and reversal of T1D. However, whether the combined strategy of targeting both T and B cells could further improve the therapeutic efficacy remains to be explored. Herein we show that the combined treatment with intravenous anti-human CD20 (hCD20) and oral anti-CD3 significantly delayed diabetes development in pre-diabetic hCD20 transgenic NOD mice. More importantly, the combined treatment reversed diabetes in more than 60% of mice newly diagnosed with diabetes. Further mechanistic studies demonstrated that the addition of oral anti-CD3 to the B cell depletion therapy synergistically enhanced the suppressive function of Treg. Interestingly, the oral anti-CD3 treatment induced a fraction of IL-10-producing CD4 T cells in the small intestine through IL-10 and IL-27-producing dendritic cells. Thus, our findings demonstrated that combining anti-CD20 and oral anti-CD3 is superior to anti-CD20 monotherapy for restoring normoglycemia in diabetic NOD mice, providing important preclinical evidence for the optimization of B cell-directed therapy for type 1 diabetes.
Wednesday, January 9, 2013
By exposing female mice to the gut bacteria of a healthy adult male, researchers were able to prevent the females from developing type 1 diabetes, an autoimmune disorder. ... the treatment changed the levels of testosterone in female mice, which typically develop type 1 diabetes at a higher rate than their male counterparts.
Microbial exposures and sex hormones exert potent effects on autoimmune diseases, many of which are more prevalent in women. Here, we demonstrate a direct interaction between sex hormones and early life microbial exposures on the control of autoimmunity in the non-obese diabetic (NOD) mouse model of type 1 diabetes (T1D). Colonization by commensal microbes elevated serum testosterone and protected NOD males from T1D. Transfer of gut microbiota from adult males to immature females altered the recipient's microbiota, resulting in elevated testosterone and metabolomic changes, reduced islet inflammation and autoantibody production, and robust T1D protection. These effects were dependent on androgen receptor activity. Thus, the commensal microbial community alters sex hormone levels and regulates autoimmune disease fate in individuals with high genetic risk.