Controlling the activity of pathogenic T cells directed against a disease-related antigen is a desired goal of experimental approaches aimed at the treatment of autoimmune diseases, and novel and improved methods of immunoregulation are continuously being sought. Most of the conventional methods of immune modulation are effective in the prevention of autoimmunity, but fail to control the ongoing disease. In our preliminary studies using an experimental model of autoimmunity, we explored an innovative B cell-based cellular therapy approach that was successful not only in the prevention but also in the treatment of ongoing disease. Adjuvant arthritis (AA) can be induced in the Lewis (RT.1l) rat by injecting s.c. heat-killed M. tuberculosis H37Ra (Mtb), and the pathogenic T cell response of arthritic rats is directed to mycobacterial heat-shock protein-65 (Bhsp65). We treated Lewis rats i.p. with retrovirally-transduced B cells expressing Bhsp65-IgG heavy chain construct either before or after injection of Mtb. Control rats received ovalbumin (Ova)-IgG-expressing B cells or soluble Bhsp65/Ova. Of these, only the Bhsp65-expressing B cell regimen could downregulate the ongoing (established) AA. In this study, we propose to examine the mechanisms by which Bhsp65-expressing B cells control the pathogenic processes to induce protection against AA. Supported in part by our preliminary results, we propose that this regulation of AA involves the activation of CD4+CD25+Foxp3+ regulatory T cells, the triggering of disease-suppressing anti-Bhsp65 antibody-mediated mechanisms, and the downmodulation of pathogenic T cell activity.
The specific aims of our study are as follows- Aim 1. a) To define the processing and presentation of native Bhsp65 by transduced B cells in terms of the epitopes presented to the T cells by these B cells, and b) To determine the influence of B cell therapy on the frequency and suppressive function of CD4+CD25+Foxp3+ T cells.
Aim 2. a) To examine the mechanisms by which antibodies against Bhsp65 induce protection against AA, and b) To test in vivo the mode of control of the pathogenic T cell activity by the Bhsp65-expressing B cells. The results of this study would be of significance in elaborating important pathways involved in the pathogenesis of autoimmune diseases as well as developing novel therapeutic approaches for these debilitating disorders.
Dysregulation of the immune system leads to autoimmune diseases like arthritis, diabetes, multiple sclerosis, and lupus. Using an animal model of arthritis, we have applied an innovative method (cellular therapy using antigen-expressing B cells) to suppress the initiation as well as the progression of autoimmunity. In this study, we propose to examine the immunological mechanisms by which the B cell therapy induces protection against autoimmunity. The results of this study would help develop novel treatment regimens for arthritis and other autoimmune diseases.
