Sakamoto K, Sachs D H, Shimada S, Popitz-Bergez F A, Pennington L R, Pescovitz M D, McDonough M A, MacVittie T J, Katz S I, Gress R E
Immunology Branch, National Cancer Institute, Bethesda, MD 20892.
Transplantation. 1988 May;45(5):869-75.
Graft-versus-host disease (GVHD) has been evaluated in partially inbred miniature swine in order to study this complication of allogeneic bone marrow transplantation (BMT) in a major histocompatibility complex (MHC) genetically defined large animal model. Bone marrow from MHC homozygous ("parental") swine was injected into irradiated (900 rads total-body irradiation) MHC heterozygous ("F1") swine that shared one haplotype with the donor. All 18 animals successfully engrafted with donor bone marrow, and 17 of these developed skin rash of varying intensity depending on the extent of T cell depletion of infused marrow. Of 18 animals, 8 received undepleted bone marrow from exsanguinated donors and 2 also received additional peripheral blood lymphocytes (PBL) as a source of mature T cells. All 8 showed a moderate-to-severe rash, and the 2 pigs that received additional donor PBL developed the most severe rash. The cutaneous eruption seen in this model clinically, histologically, and immunologically resembled human GVHD. Two protocols of T cell depletion of donor bone marrow by antiporcine T cell monoclonal antibodies plus complement were tested for their effect on development of GVHD. The combination of two monoclonal antibodies, 74-12-4 (PT4) and 76-2-11 (PT8), had a marginal effect on the subsequent development of cutaneous manifestations of GVHD. However, treatment of the donor marrow by a combination of three monoclonal antibodies--PT4, PT8, and MSA4 (PT11)--effectively decreased the severity of the GVHD skin rash. These results indicate that (1) the GVHD associated with allogeneic bone marrow transplantation in swine is dependent on T cells in the marrow; (2) effective T cell depletion of donor marrow by monoclonal antibodies and complement does not prevent engraftment; and (3) this swine GVHD model, which allows study with F1 and homozygous parental combinations in an MHC genetically defined large animal, is particularly useful for the understanding of GVHD pathogenesis, prevention, and treatment.
为了在主要组织相容性复合体（MHC）基因定义的大型动物模型中研究异基因骨髓移植（BMT）的这种并发症，已经在部分近交小型猪中评估了移植物抗宿主病（GVHD）。将来自MHC纯合（“亲代”）猪的骨髓注射到接受了全身900拉德照射的MHC杂合（“F1”）猪体内，这些F1猪与供体共享一个单倍型。所有18只动物均成功植入供体骨髓，其中17只根据输注骨髓中T细胞的清除程度出现了不同强度的皮疹。18只动物中，8只接受了来自放血供体的未清除骨髓，2只还接受了额外的外周血淋巴细胞（PBL）作为成熟T细胞的来源。所有8只都出现了中度至重度皮疹，而接受额外供体PBL的2只猪出现了最严重的皮疹。该模型中观察到的皮肤疹在临床、组织学和免疫学上与人类GVHD相似。测试了两种通过抗猪T细胞单克隆抗体加补体对供体骨髓进行T细胞清除的方案对GVHD发生的影响。两种单克隆抗体74-12-4（PT4）和76-2-11（PT8）的组合对GVHD皮肤表现的后续发展有轻微影响。然而，用三种单克隆抗体PT4、PT8和MSA4（PT11）联合处理供体骨髓可有效降低GVHD皮疹的严重程度。这些结果表明：（1）猪中与异基因骨髓移植相关的GVHD依赖于骨髓中的T细胞；（2）通过单克隆抗体和补体对供体骨髓进行有效的T细胞清除并不能阻止植入；（3）这种猪GVHD模型允许在MHC基因定义的大型动物中进行F1和亲代纯合组合的研究，对于理解GVHD的发病机制、预防和治疗特别有用。
