Establishing Stable Mixed Hematopoietic Chimerism

建立稳定的混合造血嵌合体

• 批准号: 6989507
• 负责人: Rainer F. Storb
• 金额: $ 34.97万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-01 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6989507
• 关键词: T lymphocyte; artificial immunosuppression; bone marrow transplantation; dogs; laboratory mouse; methotrexate; monoclonal antibody; neoplasm /cancer immunotherapy; therapy design /development; tissue mosaicism; transplantation immunology; whole body irradiation dosage

We have established stable mixed donor/host hematopoietic chimerism in dogs by combining sublethal conditioning with 200 cGy total body irradiation (TBI) before and a short course of immunosuppression with mycophenolate mofetil (MMF) and cyclosporine after dog leukocyte antigen (DLA)-identical marrow transplantation. This has allowed transplantation without the severe organ toxicities and myeloablation characteristic of traditional high-dose conditioning regimens. The regimen has been translated successfully into the clinic to treat patients with malignant and nonmalignant diseases. During the last grant period, we showed that the major role of the 200 cGy TBI was to provide host immunosuppression since stable mixed chimerism could also be accomplished in dogs given irradiation limited to the cervical, thoracic, and upper abdominal lymph node chain. Further, we were able to decrease the TBI dose needed for conditioning to 100 cGy in recipient dogs primed with donor peripheral blood mononuclear cells (PBMC) and given the costimulatory blocker cytotoxic T lymphocyte antigen-4 immunoglobulin. Findings suggested that the historic concept of creation of marrow space for allografts by cytotoxic agents was no longer valid and grafts could be established solely with the help of immunosuppressive agents. Subsequent successful transplantation without conditioning in patients with impaired T-cell function lent further support to the new concept of engraftment through shifting of the immunological balance toward donor cells. Here, we seek to validate the new allograft concept and to determine whether specific immunosuppression without or with little toxicity can be substituted for both the broad immunosuppression and the short- and long-term toxicities associated with TBI. Two principal approaches will be taken to accomplish our goals. The first is to reduce host-versus-graft immune responses before marrow grafting by priming recipients with donor PBMC and then eliminating activated donor-reactive T cells by either an antibody against the T-cell activation antigen CD70, the antimetabolite methotrexate, or blockade of two costimulatory pathways, B7:CD28 and CD40:CD154. The second approach is to shift the immunological balance toward the graft using genetically-modified donor T cells which express resistance to MMF.

我们已经建立了稳定的混合供者/宿主造血嵌合体的狗相结合的亚致死预处理与200 cGy的全身照射（TBI）之前和短期的免疫抑制剂霉酚酸酯（MMF）和环孢素后，狗白细胞抗原（DLA）相同的骨髓移植。这使得移植没有严重的器官毒性和骨髓消融的特点，传统的高剂量预处理方案。该方案已成功地转化为临床治疗恶性和非恶性疾病的患者。在最后一次资助期间，我们发现200 cGy TBI的主要作用是提供宿主免疫抑制，因为在仅给予颈部、胸部和上部照射的狗中也可以实现稳定的混合嵌合体。 腹部淋巴结链此外，我们能够减少TBI剂量所需的条件，以100 cGy的受体犬与供体外周血单核细胞（PBMC），并给予共刺激阻断剂细胞毒性T淋巴细胞抗原-4免疫球蛋白。研究结果表明，通过细胞毒性药物为同种异体移植物创造骨髓空间的历史概念不再有效，移植物可以仅在免疫抑制剂的帮助下建立。随后在T细胞功能受损的患者中成功移植而不进行预处理，进一步支持了通过将免疫平衡向供体细胞转移来植入的新概念。在这里，我们寻求验证 新的同种异体移植概念，并确定是否有或很少有毒性的特异性免疫抑制可以取代广泛的免疫抑制和短期和长期毒性与TBI。为实现我们的目标，将采取两个主要办法。第一种方法是在骨髓移植前用供体PBMC预充受体，然后用抗T细胞活化抗原CD 70的抗体（抗代谢物甲氨蝶呤）或阻断两种共刺激途径（B7：CD 28和CD 40：CD 154）消除活化的供体反应性T细胞，从而降低宿主抗移植物免疫反应。第二种方法是使用表达对MMF抗性的遗传修饰的供体T细胞将免疫平衡向移植物转移。