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，并且不断寻求新的和改进的免疫调节方法。大多数传统的免疫调节方法在预防自身免疫方面是有效的，但不能控制正在发生的疾病。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取得了成功，而且在治疗正在进行的疾病方面也取得了成功。通过注射s.c.热灭活结核分枝杆菌H37Ra （Mtb）可诱导Lewis （rt . 11）大鼠佐剂性关节炎（AA），其致病性T细胞反应指向分枝杆菌热休克蛋白-65 （Bhsp65）。我们在注射Mtb之前或之后用表达Bhsp65-IgG重链结构的逆转录病毒转导的B细胞对Lewis大鼠进行i.p.处理。对照大鼠接受表达卵清蛋白(Ova)- igg的B细胞或可溶性Bhsp65/Ova。其中，只有表达bhsp65的B细胞方案可以下调正在进行的（已建立的）AA。在本研究中，我们拟探讨表达bhsp65的B细胞控制致病过程以诱导对AA的保护的机制。在我们的初步结果的部分支持下，我们提出AA的这种调节涉及CD4+CD25+Foxp3+调节性T细胞的激活，触发抗bhsp65抗体介导的疾病抑制机制，以及致病性T细胞活性的下调。我们研究的具体目的如下-目的1。a)根据B细胞向T细胞呈递的表位来定义转导的B细胞对天然Bhsp65的加工和呈递；B)确定B细胞治疗对CD4+CD25+Foxp3+ T细胞频率和抑制功能的影响。目标2。a)探讨抗Bhsp65抗体诱导抗AA的机制；b)在体内检测表达Bhsp65的b细胞对致病性T细胞活性的控制模式。本研究结果将对阐明自身免疫性疾病发病机制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。在关节炎动物模型中，我们采用了一种创新的方法（使用表达抗原的B细胞进行细胞治疗）来抑制自身免疫的发生和发展。在本研究中，我们拟探讨B细胞治疗诱导自身免疫保护的免疫学机制。这项研究的结果将有助于开发关节炎和其他自身免疫性疾病的新治疗方案。

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.