Kim Yong Chan, Zhang Ai-Hong, Su Yan, Rieder Sadiye Amcaoglu, Rossi Robert J, Ettinger Ruth A, Pratt Kathleen P, Shevach Ethan M, Scott David W
Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD;
Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD; and.
Blood. 2015 Feb 12;125(7):1107-15. doi: 10.1182/blood-2014-04-566786. Epub 2014 Dec 10.
Expansion of human regulatory T cells (Tregs) for clinical applications offers great promise for the treatment of undesirable immune responses in autoimmunity, transplantation, allergy, and antidrug antibody responses, including inhibitor responses in hemophilia A patients. However, polyclonal Tregs are nonspecific and therefore could potentially cause global immunosuppression. To avoid this undesirable outcome, the generation of antigen-specific Tregs would be advantageous. Herein, we report the production and properties of engineered antigen-specific Tregs, created by transduction of a recombinant T-cell receptor obtained from a hemophilia A subject's T-cell clone, into expanded human FoxP3(+) Tregs. Such engineered factor VIII (FVIII)-specific Tregs efficiently suppressed the proliferation and cytokine production of FVIII-specific T-effector cells. Moreover, studies with an HLA-transgenic, FVIII-deficient mouse model demonstrated that antibody production from FVIII-primed spleen cells in vitro were profoundly inhibited in the presence of these FVIII-specific Tregs, suggesting potential utility to treat anti-FVIII inhibitory antibody formation in hemophilia A patients.
扩增人类调节性T细胞（Tregs）用于临床应用，为治疗自身免疫、移植、过敏和抗药抗体反应（包括A型血友病患者的抑制剂反应）中的不良免疫反应带来了巨大希望。然而，多克隆Tregs是非特异性的，因此可能会导致全身性免疫抑制。为避免这种不良后果，产生抗原特异性Tregs将具有优势。在此，我们报告了通过将从一名A型血友病患者的T细胞克隆获得的重组T细胞受体转导到扩增的人类FoxP3(+) Tregs中而产生的工程化抗原特异性Tregs的制备及其特性。这种工程化的因子VIII（FVIII）特异性Tregs有效地抑制了FVIII特异性T效应细胞的增殖和细胞因子产生。此外，使用HLA转基因、FVIII缺陷小鼠模型进行的研究表明，在这些FVIII特异性Tregs存在的情况下，体外FVIII致敏的脾细胞产生抗体受到显著抑制，这表明其在治疗A型血友病患者抗FVIII抑制性抗体形成方面具有潜在用途。
