Williams W V, Fang Q, Von Feldt J M, Boyer J D, Luchi M, Wang B, Weiner D B
Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia 19104, USA.
Immunol Res. 1994;13(2-3):145-53. doi: 10.1007/BF02918275.
Immunotherapy against autoreactive T-cell receptors (TCRs) has been reported to have promise in several animal models of autoimmune diseases. Facilitated DNA inoculation has many potential advantages as a modality for development of specific immune responses. Specifically, this technology is able to deliver exogenous antigens for processing via both the endogenous pathway, with subsequent presentation by class-I major histocompatibility (MHC) antigens, and the exogenous pathway, with subsequent presentation by class-II MHC antigens. This allows for induction of both arms of the cellular immune system. These cellular immune responses may be particularly important in targeting and controlling pathogenic cell populations. The application of this technology to the treatment of human autoimmune diseases depends on the availability of readily manipulated systems for the evaluation of specific interventions. Here we report the full length cloning and expression of TCRs from rheumatoid arthritis synovial tissue. These were developed by recombinant polymerase chain reaction, cloning and retroviral transduction into a TCR-alpha/beta-negative murine T-cell hybridoma. Reconstitution of CD3 expression was confirmed by flow cytometry. Similar constructs have been developed for TCR-based immunotherapy by facilitated inoculation of DNA intramuscularly. Preliminary analysis of immune responses in mice indicates that these constructs elicit anti-TCR responses. These studies indicate the ability to reconstitute expression of potentially autoreactive human TCRs in a model system wherein specific immune responses elicited against these TCRs by various immunogens can be evaluated.
据报道，针对自身反应性T细胞受体（TCR）的免疫疗法在几种自身免疫性疾病的动物模型中具有前景。作为一种产生特异性免疫反应的方式，简便的DNA接种具有许多潜在优势。具体而言，该技术能够通过内源性途径传递外源性抗原进行加工，随后由I类主要组织相容性复合体（MHC）抗原呈递，以及通过外源性途径传递，随后由II类MHC抗原呈递。这能够诱导细胞免疫系统的两个分支。这些细胞免疫反应在靶向和控制致病细胞群体方面可能特别重要。该技术在人类自身免疫性疾病治疗中的应用取决于是否有易于操作的系统来评估特定干预措施。在此，我们报道了类风湿性关节炎滑膜组织中TCR的全长克隆和表达。这些是通过重组聚合酶链反应、克隆并逆转录病毒转导至TCR-α/β阴性小鼠T细胞杂交瘤中而获得的。通过流式细胞术确认了CD3表达的重建。通过肌肉内简便接种DNA，已开发出类似的基于TCR的免疫疗法构建体。对小鼠免疫反应的初步分析表明，这些构建体引发了抗TCR反应。这些研究表明，能够在一个模型系统中重建潜在自身反应性人类TCR的表达，在该系统中可以评估各种免疫原针对这些TCR引发的特异性免疫反应。
