Cellular therapy of autoimmunity using antigen-expressing B cells

描述（由申请人提供）：控制针对疾病相关抗原的致病性T细胞的活性是旨在治疗自身免疫性疾病的实验方法的期望目标，并且正在不断寻求免疫调节的新的和改进的方法。大多数常规的免疫调节方法在预防自身免疫中是有效的，但不能控制正在进行的疾病。在我们使用自身免疫实验模型的初步研究中，我们探索了一种创新的基于B细胞的细胞治疗方法，该方法不仅在预防方面而且在治疗正在进行的疾病方面都是成功的。在刘易斯（RT. 1 l）大鼠中，通过皮下注射热灭活M.结核病H37 Ra（Mtb），关节炎大鼠的致病性T细胞应答针对分枝杆菌热休克蛋白-65（Bhsp 65）。我们在注射Mt B之前或之后用表达Bhsp 65-IgG重链构建体的逆转录病毒转导的B细胞腹膜内处理刘易斯大鼠。对照组大鼠接受卵清蛋白（Ova）-IgG表达B细胞或可溶性Bhsp 65/Ova。其中，只有表达Bhsp 65的B细胞方案可以下调正在进行的（已建立的）AA。在这项研究中，我们建议检查的机制，Bhsp 65表达B细胞控制的致病过程，以诱导对AA的保护。部分支持我们的初步研究结果，我们提出，这种调节AA涉及激活的CD 4 + CD 25 + Foxp 3+调节性T细胞，触发疾病抑制抗Bhsp 65抗体介导的机制，和下调致病性T细胞活性。我们研究的具体目标如下：目标1。a）根据转导的B细胞呈递给T细胞的表位，确定转导的B细胞对天然Bhsp 65的加工和呈递，和B）确定B细胞疗法对CD 4 + CD 25 + Foxp 3 + T细胞的频率和抑制功能的影响。目标2. a）检测抗Bhsp 65抗体诱导抗AA保护的机制，和B）体内测试表达Bhsp 65的B细胞对致病性T细胞活性的控制模式。本研究的结果对于阐明自身免疫性疾病发病机制中的重要途径以及开发这些衰弱性疾病的新治疗方法具有重要意义。免疫系统失调会导致自身免疫性疾病，如关节炎、糖尿病、多发性硬化症和狼疮。使用关节炎的动物模型，我们已经应用了一种创新的方法（使用抗原表达B细胞的细胞疗法）来抑制自身免疫的起始以及进展。在这项研究中，我们建议检查免疫学机制，其中B细胞治疗诱导对自身免疫的保护。这项研究的结果将有助于开发新的治疗方案，关节炎和其他自身免疫性疾病。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE 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.