ENGRAFTING SENSITIZED HOSTS WITH NONABLATIVE REGIMENS

在非致敏的主要组织相容性复合体（MHC）匹配的受者中，采用非清髓性预处理方案已经建立了植入。 先前输注血液制品的受体对供体次要组织相容性抗原变得敏感，增加了移植物排斥的风险。 患有遗传性红细胞疾病的患者需要输血，并且有更高的移植排斥概率。 在该提案中，将为致敏受者开发非清髓性预处理方案，这些方案1）缺乏清髓性方案的毒性特征，2）可以在门诊环境中安全给药。 针对致敏患者的非清髓性方案的开发将基于两个假设：1）致敏受体的宿主抗移植物（HVG）反应可以用免疫抑制剂而不是高剂量放化疗来抑制; 2）来自移植物的T细胞可以抑制宿主免疫系统，包括致敏免疫效应细胞。 将对这些假设进行检验，并在输血诱导致敏的临床前犬模型中开发非清髓性方案。在移植前通过输血致敏受者导致常规高剂量预处理的一致移植物排斥反应。 在目标1中，将确定在TBI的剂量递减研究中，除了CSP之外，进一步逐步加强移植前免疫抑制是否会成功促进植入。 将单独评估移植后免疫抑制（MMF/CSP），以确定其是否能预防TBI 920 cGy致敏受者的移植物排斥反应。 如果有效，则在完成目标1A时发生移植物排斥的最大TBI剂量下进行移植后免疫抑制的强化。 在目标2中，将确定促进GVH是否将通过抑制致敏的宿主T细胞和在骨髓中“创造空间”来实现植入。 如果这些研究是成功的，那么供体T细胞将离体扩增并转导“自杀（HSVtk）基因”以预防严重的GVHD。 在目标3中，最佳免疫抑制方案将与GVH增强方案组合。 该提案的最终目标是从预处理方案中消除细胞毒性剂。 通过减少与常规调节相关的发病率和死亡率，这些研究可以显着改变选定的遗传性红细胞疾病的管理。

Engraftment has been established in nonsensitized major histocompatibility complex (MHC)-matched recipients with nonmyeloablative conditioning regimens. Recipients previously transfused with blood products become sensitized to donor minor histocompatibility antigens, increasing the risk of graft rejection. Patients with inherited red blood cell diseases require blood transfusions and have a higher probability of graft rejection. In this proposal, nonmyeloablative conditioning regimens will be developed for sensitized recipients which 1) lack the toxicities characteristic of myeloablative regimens, and 2) could be safely administered in an outpatient setting. The development of the nonmyeloablative regimen for sensitized patients will be based on two hypotheses: 1) host-versus-graft (HVG) reactions of sensitized recipients can be suppressed with immunosuppressive agents other than high-dose chemoradiotherapy; 2) T cells from the graft can suppress the host immune system including sensitized immune effector cells. These hypotheses will be tested and nonmyeloablative regimens will be developed in a preclinical canine model of transfusion-induced sensitization. Sensitizing recipients with blood transfusions prior to transplant results in uniform graft rejection with conventional high-dose conditioning. In Aim 1, it will be determined if further stepwise intensification of pretransplant immunosuppression in addition to CSP will successfully promote engraftment in a dose de-escalation study of TBI. Posttransplant immunosuppression (MMF/CSP) will be assessed separately to determine if it prevents graft rejection in sensitized recipients at TBI 920 cGy. If effective, intensification of posttransplant immunosuppression will be done at the maximal TBI dose at which graft rejection occurs at the completion of Aim 1A. In Aim 2, it will be determined if promoting GVH will achieve engraftment by suppressing sensitized host T cells and "creating space" in the marrow. If these studies are successful, then donor T cells will be ex vivo expanded and transduced with a "suicide (HSVtk) gene" for prevention of severe GVHD. In Aim 3, the optimal immunosuppressive regimen will be combined with a GVH enhancing regimen. The ultimate goal of this proposal is the elimination of cytotoxic agents from the conditioning regimen. By lessening the morbidity and mortality associated with conventional conditioning, these studies could significantly change the management of selected inherited red blood cell diseases.