Mekala Divya J, Geiger Terrence L
Department of Pathology, St Jude Children's Research Hospital, 332 N Lauderdale St, D-4047, Memphis, TN 38105, USA.
Blood. 2005 Mar 1;105(5):2090-2. doi: 10.1182/blood-2004-09-3579. Epub 2004 Nov 4.
We developed an approach that increases CD4+CD25+ regulatory T-cell potency by antigen-specifically redirecting them against pathologic T lymphocytes. The regulatory cells are transgenically modified with chimeric receptors that link antigen-major histocompatibility complex (MHC) extracellular and transmembrane domains with the cytoplasmic signaling tail of T-cell receptor zeta (TCR-zeta). The receptors' antigen-MHC recognizes the TCR of cognate T lymphocytes. Receptor engagement stimulates the receptor-modified T cell (RMTC) through the linked zeta chain. CD4+CD25+ RMTCs expressing a myelin basic protein (MBP) 89-101-IAs-zeta receptor, unlike unmodified CD4+CD25+ T cells or CD4+CD25- RMTCs, prevented and treated experimental allergic encephalomyelitis (EAE) induced with MBP89-101. The RMTCs were effective even after the autoreactive T-cell repertoire had diversified to include specificities not directly targeted by the chimeric receptor. Remissions were sustained and mortality was decreased from more than 50% to 0%. These results provide proof of principal for a novel approach to enforce the interaction of regulatory and pathologic T lymphocytes, thereby facilitating the treatment of autoimmune disease.
我们开发了一种方法，通过将 CD4+CD25+ 调节性 T 细胞抗原特异性地重定向到病理性 T 淋巴细胞上，来增强其效力。这些调节性细胞通过嵌合受体进行转基因修饰，该嵌合受体将抗原 - 主要组织相容性复合体（MHC）的细胞外和跨膜结构域与 T 细胞受体 ζ（TCR-ζ）的细胞质信号尾部连接起来。受体的抗原 - MHC 识别同源 T 淋巴细胞的 TCR。受体结合通过连接的 ζ 链刺激受体修饰的 T 细胞（RMTC）。与未修饰的 CD4+CD25+ T 细胞或 CD4+CD25- RMTC 不同，表达髓鞘碱性蛋白（MBP）89-101-IAs-ζ 受体的 CD4+CD25+ RMTC 预防并治疗了由 MBP89-101 诱导的实验性自身免疫性脑脊髓炎（EAE）。即使自身反应性 T 细胞库已经多样化，包括嵌合受体未直接靶向的特异性，RMTC 仍然有效。缓解得以持续，死亡率从超过 50%降至 0%。这些结果为一种新方法提供了原理证明，该方法可加强调节性和病理性 T 淋巴细胞之间的相互作用，从而促进自身免疫性疾病的治疗。
