Mayumi GP & Cardiology Clinic, Saitama City, Japan.
Front Immunol. 2021 Sep 29;12:744430. doi: 10.3389/fimmu.2021.744430. eCollection 2021.
The bone marrow transplantation (BMT) between haplo-identical combinations (haploBMT) could cause unacceptable bone marrow graft rejection and graft-versus-host disease (GVHD). To cross such barriers, Johns Hopkins platform consisting of haploBMT followed by post-transplantation (PT) cyclophosphamide (Cy) has been used. Although the central mechanism of the Johns Hopkins regimen is Cy-induced tolerance with bone marrow cells (BMC) followed by Cy on days 3 and 4, the mechanisms of Cy-induced tolerance may not be well understood. Here, I review our studies in pursuing skin-tolerance from minor histocompatibility (H) antigen disparity to xenogeneic antigen disparity through fully allogeneic antigen disparity. To overcome fully allogeneic antigen barriers or xenogeneic barriers for skin grafting, pretreatment of the recipients with monoclonal antibodies (mAb) against T cells before cell injection was required. In the cells-followed-by-Cy system providing successful skin tolerance, five mechanisms were identified using the correlation between super-antigens and T-cell receptor (TCR) Vβ segments mainly in the H-2-identical murine combinations. Those consist of: 1) clonal destruction of antigen-stimulated-thus-proliferating mature T cells with Cy; 2) peripheral clonal deletion associated with immediate peripheral chimerism; 3) intrathymic clonal deletion associated with intrathymic chimerism; 4) delayed generation of suppressor T (Ts) cells; and 5) delayed generation of clonal anergy. These five mechanisms are insufficient to induce tolerance when the donor-recipient combinations are disparate in MHC antigens plus minor H antigens as is seen in haploBMT. Clonal destruction is incomplete when the antigenic disparity is too strong to establish intrathymic mixed chimerism. Although this incomplete clonal destruction leaves the less-proliferative, antigen-stimulated T cells behind, these cells may confer graft-versus-leukemia (GVL) effects after haploBMT/PTCy.
骨髓移植（BMT）在半相合（haploBMT）组合中可能导致不可接受的骨髓移植物排斥和移植物抗宿主病（GVHD）。为了克服这些障碍，约翰霍普金斯平台包括haploBMT 后移植（PT）环磷酰胺（Cy）已被使用。尽管约翰霍普金斯方案的核心机制是 Cy 诱导的骨髓细胞（BMC）耐受，然后在第 3 和第 4 天用 Cy，但 Cy 诱导的耐受机制可能还没有得到很好的理解。在这里，我回顾了我们的研究，从次要组织相容性（H）抗原差异到异种抗原差异，通过完全同种抗原差异来追求皮肤耐受。为了克服皮肤移植的完全同种抗原或异种抗原障碍，在细胞注射前，需要用针对 T 细胞的单克隆抗体（mAb）预处理受者。在细胞-随后 Cy 系统中，在 H-2 相同的鼠组合中，主要通过超抗原和 T 细胞受体（TCR）Vβ 片段之间的相关性，确定了五种机制。这些机制包括：1）Cy 对抗原刺激-因此增殖的成熟 T 细胞进行克隆性破坏；2）与即刻外周嵌合相关的外周克隆性缺失；3）与胸腺内嵌合相关的胸腺内克隆性缺失；4）抑制性 T（Ts）细胞的延迟产生；5）克隆性无反应的延迟产生。当供体-受体组合在 MHC 抗原加次要 H 抗原上存在差异时，如 haploBMT 所见，这五种机制不足以诱导耐受。当抗原差异太强以至于不能建立胸腺内混合嵌合时，克隆性破坏是不完全的。尽管这种不完全的克隆性破坏留下了增殖能力较低的抗原刺激 T 细胞，但这些细胞在 haploBMT/PTCy 后可能赋予移植物抗白血病（GVL）效应。
