Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, CO.
Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, CO.
Am J Transplant. 2017 Jul;17(7):1742-1753. doi: 10.1111/ajt.14194. Epub 2017 Feb 21.
Several approaches successfully achieve allograft tolerance in preclinical models but are challenging to translate into clinical practice. Many clinically relevant factors can attenuate allograft tolerance induction, including intrinsic genetic resistance, peritransplant infection, inflammation, and preexisting antidonor immunity. The prevailing view for immune memory as a tolerance barrier is that the host harbors memory cells that spontaneously cross-react to donor MHC antigens. Such preexisting "heterologous" memory cells have direct reactivity to donor cells and resist most tolerance regimens. In this study, we developed a model system to determine if an alternative form of immune memory could also block tolerance. We posited that host memory T cells could potentially respond to donor-derived non-MHC antigens, such as latent viral antigens or autoantigens, to which the host is immune. Results show that immunity to a model nonself antigen, ovalbumin (OVA), can dramatically disrupt tolerance despite undetectable initial reactivity to donor MHC antigens. Importantly, this blockade of tolerance was CD8 T cell-dependent and required linked antigen presentation of alloantigens with the test OVA antigen. As such, this pathway represents an unapparent, or "incognito," form of immunity that is sufficient to prevent tolerance and that can be an unforeseen additional immune barrier to clinical transplant tolerance.
几种方法在临床前模型中成功地实现了同种异体移植物耐受，但将其转化为临床实践具有挑战性。许多与临床相关的因素会削弱同种异体移植物耐受的诱导，包括内在的遗传抗性、移植前感染、炎症和预先存在的抗供体免疫。免疫记忆作为耐受障碍的主流观点是，宿主存在自发与供体 MHC 抗原交叉反应的记忆细胞。这种预先存在的“异源”记忆细胞对供体细胞具有直接反应性，并抵抗大多数耐受方案。在这项研究中，我们开发了一种模型系统来确定另一种形式的免疫记忆是否也可以阻断耐受。我们假设宿主记忆 T 细胞可能对供体来源的非 MHC 抗原（如潜伏病毒抗原或自身抗原）产生反应，宿主对这些抗原具有免疫力。结果表明，尽管对供体 MHC 抗原最初没有反应性，但对模型非自身抗原卵清蛋白（OVA）的免疫可以显著破坏耐受。重要的是，这种耐受的阻断依赖于 CD8 T 细胞，并需要同种抗原与测试 OVA 抗原的连接抗原呈递。因此，该途径代表一种未被察觉的或“隐匿的”免疫形式，足以阻止耐受，并且可能是临床移植耐受的一个意外的额外免疫障碍。
