Nonmyeloablative transplants for nonmalignant disorders

我们建议开发成功的非清髓性造血干细胞移植（HSCT）的策略，使用相关和无关的捐助者在严重再生障碍性贫血，范可尼贫血，其他遗传性和获得性疾病，T细胞缺乏症和自身免疫性疾病的患者的治疗。策略将根据HSCT所针对的基础疾病而有所不同。统一的原则是将预处理方案的强度降低到与常规预处理方案的显著全血细胞减少症和其他常见的短期和长期毒性无关的水平，降低到与常规预处理方案的显著全血细胞减少症和其他常见的短期和长期毒性无关的水平。非清髓性HSCT的一个新方面是使用抗代谢物吗替麦考酚酯和T细胞活化阻断剂环孢菌素进行移植后免疫抑制。在犬模型中的临床前研究表明，药物组合不仅控制移植物抗宿主病，而且抑制宿主抗移植物反应。后一项发现消除了大部分高剂量抑制的宿主抗移植物反应。后一个发现允许消除大部分高剂量细胞毒性移植前预处理治疗，否则需要稳定的同种异体移植。进一步的犬研究表明，通过细胞毒性预处理方案“创造骨髓空间”对于稳定的同种异体移植是不必要的。我们已经成功地应用了从犬研究中得出的原则来治疗患有血液恶性肿瘤的老年和医学上虚弱的患者。在这里，我们建议扩大非清髓性预处理的研究，包括非恶性疾病的患者。对于本项目中涉及的大多数获得性和遗传性疾病，一些宿主免疫或造血细胞（混合供体/宿主造血嵌合体）的持续存在是可以接受的，而不会损害移植物治愈患者潜在疾病表现的能力。对于其他患者，包括患有自身免疫性疾病的患者，混合嵌合体可能不够，并且造血可能必须通过使用供体淋巴细胞输注转化为全供体嵌合体。

We propose to develop successful non-myeloablative hematopoietic stem cell transplant (HSCT) strategies using both related and unrelated donors in the treatment of patients with severe aplastic anemia, Fanconi anemia, other genetic and acquired disease, T-cell deficiency diseases, and autoimmune diseases. The strategies will vary depending on the underlying diseases for which HSCT is carried out. The unifying principle is to reduce the intensity of the conditioning regimens to levels which are not associated with pronounced pancytopenias and other common sort- and long-term toxicities of conventional conditioning regimens to levels which are not associated with pronounced pancytopenias and other common short- and long-term toxicities of conventional conditioning regimens. A novel aspect of the non- myeloablative HSCT is the use of post-grafting immunosuppression with the anti-metabolite mycophenolate mofetil and the T-cell activation blocker cyclosporine. Preclinical studies in a canine model have shown that the drug combination not only controlled graft-versus-host disease but also suppressed host-versus-graft reactions. The latter finding allowed the elimination of much of the high-dose suppressed host-versus-graft reactions. The latter finding allowed the elimination of much of the high dose-cytotoxic pre-transplant conditioning therapy, otherwise needed for stable allogeneic engraftment. Further canine studies have indicate that "creation of marrow space" by cytotoxic conditioning regimens is unnecessary for stable allogeneic engraftment. We have successfully applied the principles derived from the canine studies to treat elderly and medically infirm patients with hematological malignancies. Here we propose to extend the studies on non-myeloablative conditioning to include patients with non-malignant diseases. For most of the acquired and genetic diseases addressed in this project, persistence of some host immune or hematopoietic cells (mixed donor/host hematopoietic chimerism) would be acceptable without impairing the transplants' ability to cure the patients' underlying disease manifestations. For other patients, including those with autoimmune diseases, mixed chimerism may not suffice, and hematopoiesis may have to be converted to all-donor chimerism with the use of donor lymphocyte infusions.