Stable mixed hematopoietic chimerism in DLA-identical littermate dogs given sublethal total body irradiation before and pharmacological immunosuppression after marrow transplantation
Stable mixed hematopoietic chimerism in DLA-identical littermate dogs given sublethal total body irradiation before and pharmacological immunosuppression after marrow transplantation
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DOI：
10.1182/blood.v89.8.3048
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发表时间：
1997-04-15
期刊：
影响因子：
20.3
通讯作者：
Shulman, H
中科院分区：
文献类型：
--
作者：
Storb, R;Yu, C;Shulman, H
移植后给予环孢素（CSP）35天，导致建立稳定的骨髓移植物从DLA相同的犬同窝出生后，否则次优，但尽管如此，致命的条件与450 cGy的全身照射（TBI）。我们现在要问的是，在亚致死性TBI或无TBI的情况下，是否可以实现持续的同种异体移植。研究了五组受体。第1组犬在移植后第-1至35天口服200 cGy TBI和移植后CSP，15 mg/kg，每日两次。第2组中的狗在第1、3、6和11天沿着CSP静脉内（IV）给予200 cGy TBI和0.4 mg/ kg甲氨蝶呤（MTX）。第3组中的狗在移植后第0至27天接受200 cGy TBI和CSP，同时沿着麦考酚酸酯（MMF），10 mg/kg，每天两次皮下（SC）给药，这是一种新型免疫抑制组合。第4组给予100 cGy TBI和MMF/CSP。第5组中的狗不给予TBI，并且它们在移植后接受MMF/CSP。通过对外周血、淋巴结和骨髓细胞进行（Ca）（n）二核苷酸重复序列聚合研究来评估同种异体移植物。组1中的狗具有不超过4周的暂时性混合供体-宿主造血嵌合体。第2组6只犬中有3只在3 ~ 11周内出现短暂的混合嵌合体，3只在60周内保持稳定的混合嵌合体，第3组5只犬中有4只在54 ~ 57周内保持稳定的混合嵌合体，而1只在12周后失去同种异体移植物，第4组和第5组的所有犬在2 ~ 12周后均发生排斥反应。总之，在非骨髓抑制和无毒的预处理方案后建立稳定的混合造血嵌合体仍然是一个困难的目标。在这里，我们提出的证据，在一个大的随机繁殖的动物物种，这一目标可能是实现与移植后的药理学免疫抑制，能够抑制浴宿主抗移植物（HVG）和移植物抗宿主（GVH）反应，在设置DLA相同的移植物。(C)1997年，美国血液学会。
Postgrafting cyclosporine (CSP) given for 35 days resulted in establishment of stable marrow grafts from DLA-identical canine littermates after otherwise suboptimal, but nevertheless, lethal conditioning with 450 cGy of total body irradiation (TBI). We now asked whether sustained allografts could be achieved after sublethal TBI or without TBI. Five groups of recipients were studied. Dogs in group 1 were given 200 cGy TBI and postgrafting CSP, 15 mg/kg twice daily by mouth on days -1 to 35 posttransplant. Dogs in group 2 were given 200 cGy TBI and methotrexate (MTX), 0.4 mg/ kg intravenously (IV) on days 1, 3, 6, and 11 along with CSP. Dogs in group 3 were given 200 cGy TBI and CSP along with mycophenolate mofetil (MMF), 10mg/kg twice daily subcutaneously (SC) on days 0 to 27 after transplant, a novel immunosuppressive combination. Dogs in group 4 were given 100 cGy TBI and MMF/CSP. Dogs in group 5 were not given TBI and they received MMF/CSP posttransplant. Allografts were assessed by (Ca)(n) dinucleotide repeat polymerphism studies in cells from peripheral blood, lymph nodes, and marrow. Dogs in group 1 had transient mixed donor-host hematopoietic chimerism for no more than 4 weeks. Three of six dogs in group 2 had transient mixed chimerism for 3 to 11 weeks, and three have remained stable mixed chimeras for up to 60 weeks now, Four of five dogs in group 3 have remained stable mixed chimeras for 54 to 57 weeks now, while one lost the allograft after 12 weeks, All dogs in groups 4 and 5 rejected their allografts after 2 to 12 weeks. In summary, the establishment of stable mixed hematopoietic chimerism following nonmyelosuppressive and nontoxic conditioning programs has remained a difficult goal. Here we present evidence in a large random-bred animal species that this goal may be achievable with pharmacological immunosuppression postgrafting, capable of inhibiting bath host-versus-graft (HVG) and graft-versus-host (GVH) reactions in the setting of DLA-identical grafts. (C) 1997 by The American Society of Hematology.