STEM CELL TRANSPLANTATION WITH S-59 PHOTOCHEMICALLY TREA

骨髓移植有可能完全治愈血红蛋白病的疾病症状。对镰状细胞病或地中海贫血患者成功应用错配（相关-单倍体相同）骨髓移植，需要在骨髓中实现同种异体嵌合并稳定，且发病率和死亡率低于现有的错配骨髓移植（BMT）方案。这一目标需要使用更少的全身辐射和更少的药物骨髓消融来支持移植。通过使用补骨脂素光化学处理供体白细胞，混合嵌合骨髓状态已在小鼠中实现并稳定，这些白细胞的增殖能力被阻断，但仍保留其免疫活性。在完全MHC错配的环境下，本文提出了模型小鼠骨髓移植实验，该实验将证明，在低剂量清髓辐射条件下，在没有清髓和免疫抑制药物的情况下，S-59（一种补骨脂素）光化学处理（S-59 PCT）的t细胞添加物促进和稳定同种异体嵌合，大大降低移植物抗宿主病（GVHD）的风险。第一年，小鼠实验将在威斯康辛医学院进行。mhc错配模型由C57BL/6 （H-2b）供体和亚致死辐照的AKR/J （H-2k）受体组成。GVH反应性主要针对MHC I类和II类差异。在第二年和第三年，将与儿童医院奥克兰研究所合作，移植相同小鼠品系的地中海贫血小鼠模型，并评估BMT在改善贫血方面的治疗价值。遗传背景不明确的小鼠镰状细胞模型也将被研究，因为它将最准确地模拟人类的移植情况。

Bone marrow transplantation has the potential of providing a complete cure of the disease symptoms of hemoglobinopathies. Successful application of mismatched (related-haploidentical) bone marrow transplantation to patients with sickle cell disease or a thalassemia requires that allochimerism be achieved and stabilized in the bone marrow with less morbidity and mortality than are being experienced in existing mismatched bone marrow transplantation (BMT) protocols. This goal requires use of less total body radiation and less drug myeloablation in support of the transplantation. Mixed chimeric bone marrow states have been achieved and stabilized in mice through the use of psoralen photochemically treated donor leukocytes which are blocked in their proliferative capabilities, but which retain their immunological activities. Model mouse bone marrow transplantation experiments, in a complete MHC mismatch setting, are proposed here which will prove, under low dose myeloablative radiation conditions and in the absence of myeloablative and immunosuppressive drugs, that S-59 (a psoralen) photochemically treated (S-59 PCT) T-cell add-backs promote and stabilize allochimerism with greatly reduced risk of graft versus host disease (GVHD). In the first year, the mouse experiments will be performed at the Medical College of Wisconsin. The MHC-mismatched model consists of C57BL/6 (H-2b) donors and sub-lethally irradiated AKR/J (H-2k) as recipients. GVH reactivity is primarily directed against MHC class I and class II disparities. In the second and third years, in collaboration with the Children's Hospital Oakland Research Institute, thalassemia mouse models involving the same mouse strains will be transplanted and the therapeutic value of BMT in improving the anemias will be evaluated. A mouse sickle cell model with a poorly defined genetic background will also be studied, because it will most accurately mimic the transplantion situation with humans.