Truitt R L, Atasoylu A A
Department of Pediatrics, Medical College of Wisconsin, Milwaukee 53226.
Blood. 1991 Jun 1;77(11):2515-23.
Graft rejection, mixed chimerism, graft-versus-host disease (GVHD), leukemia relapse, and tolerance are interrelated manifestations of immunologic reactivity between donor and host cells that significantly affect survival after allogeneic bone marrow transplantation (BMT). In this report, a mouse model of BMT, in which the donor and host were compatible at the major histocompatibility complex (MHC), was used (1) to examine the interrelationship of pretransplant conditioning and T-cell content of donor BM with regard to lymphoid chimerism and GVHD and (2) to determine how these factors affected graft-versus-leukemia (GVL) reactivity and donor-host-tolerance. AKR (H-2k) host mice were administered optimal or suboptimal total body irradiation (TBI) as pretransplant conditioning followed by administration of BM cells from B10.BR (H-2k) donor mice with or without added spleen cells as a source of T lymphocytes. Transplanted mice were injected with a supralethal dose of AKR leukemia cells 20 and 45 days post-BMT to assess GVL reactivity in vivo. The pretransplant conditioning of the host and T-cell content of the donor marrow affected the extent of donor T-cell chimerism and the severity of GVH disease. GVL reactivity was dependent on transplantation of mature donor T cells and occurred only in complete chimeras. Transplantation of T-cell-deficient BM resulted in the persistence of host T cells, ie, incomplete donor T-cell chimerism, even when lethal TBI was used. Mixed chimerism was associated with a lack of GVL reactivity, despite the fact that similar numbers of donor T cells were present in the spleens of mixed and complete chimeras. In this model, moderate numbers of donor T cells facilitated complete donor T-cell engraftment, caused only mild GVHD, and provided a significant GVL effect without preventing the subsequent development of tolerance after conditioning with suboptimal TBI. In contrast, severe, often lethal, GVHD developed when the dose of TBI was increased, whereas tolerance and no GVH/GVL reactivity developed when the T-cell content of the marrow was decreased.
移植物排斥、混合嵌合体、移植物抗宿主病（GVHD）、白血病复发和免疫耐受是供体与宿主细胞之间免疫反应的相互关联的表现，这些表现显著影响异基因骨髓移植（BMT）后的生存率。在本报告中，使用了一种BMT小鼠模型，其中供体和宿主在主要组织相容性复合体（MHC）上相容，以（1）研究移植前预处理和供体骨髓T细胞含量与淋巴嵌合体和GVHD之间的相互关系，以及（2）确定这些因素如何影响移植物抗白血病（GVL）反应性和供体-宿主免疫耐受。AKR（H-2k）宿主小鼠在移植前接受最佳或次最佳全身照射（TBI）作为预处理，然后给予来自B10.BR（H-2k）供体小鼠的骨髓细胞，添加或不添加脾细胞作为T淋巴细胞来源。在BMT后20天和45天给移植小鼠注射超致死剂量的AKR白血病细胞，以评估体内GVL反应性。宿主的移植前预处理和供体骨髓的T细胞含量影响供体T细胞嵌合体的程度和GVH疾病的严重程度。GVL反应性取决于成熟供体T细胞的移植，并且仅发生在完全嵌合体中。即使使用致死性TBI，缺乏T细胞的骨髓移植也会导致宿主T细胞持续存在，即不完全的供体T细胞嵌合体。混合嵌合体与缺乏GVL反应性相关，尽管混合嵌合体和完全嵌合体的脾脏中存在数量相似的供体T细胞。在该模型中，适量的供体T细胞促进了供体T细胞的完全植入，仅引起轻度GVHD，并提供了显著的GVL效应，同时在次最佳TBI预处理后不阻止随后免疫耐受的发展。相比之下，当TBI剂量增加时会发生严重的、通常是致死性的GVHD，而当骨髓的T细胞含量减少时则会出现免疫耐受且没有GVH/GVL反应性。
