MIXED HEMATOPOIETIC CHIMERISM IN AN ANIMAL MODEL

产品说明：初步研究表明，在随机繁殖的狗中，通过在白细胞抗原（DLA）相同的骨髓移植前给予亚致死剂量200 cGy的全身照射（TBI），并在移植后给予免疫抑制治疗，可以获得稳定的异基因混合造血嵌合体。 给予4-5周的霉酚酸酯（MMF）和环孢菌素（CSP）的新型免疫抑制剂具有协同特性，其可以控制宿主抗移植物（HVG）和移植物抗宿主（GVH）反应，并建立稳定状态的移植物-宿主耐受性。 通过这种方法，同种异体移植变得安全，没有传统的高剂量预处理程序的严重毒性和骨髓消融特征。 根据额外的初步数据。我们推测移植前低剂量TBI的主要作用是提供宿主免疫抑制。 如果这一假设被证明是正确的，毒性较小的免疫抑制剂可以取代TBI。 因此，我们建议在非清髓性条件处理后使用这种混合供者-宿主造血嵌合体的犬模型来实现三个广泛的具体目标。 首先，我们建议确认创伤性脑损伤是通过免疫抑制而不是通过“创造骨髓空间”发挥作用。“第二，我们将确定TBI是否可以减少，甚至完全取代免疫抑制剂，预计毒性低于辐射。 我们假设，在癌症治疗中，治疗药物的组合可能比单一药物更好。 我们将研究药物和生物试剂，如雷帕霉素，T细胞表面抗原的单克隆抗体，CTLA 4 Ig（细胞毒性T细胞淋巴细胞抗原4 -免疫球蛋白融合蛋白）。 和抗CD 40配体，因为它们在混合嵌合体模型中具有免疫抑制特性。 有前途的药物应与目前使用的药物相结合，并对HVG和GVH反应的控制进行评价。 第三，我们将确定供体淋巴细胞输注是否以及以何种方式可以安全地将混合供者-宿主造血转化为全供者型造血。

DESCRIPTION: (Applicant's Description) Preliminary studies hae shown that stable allogeneic mixed hematopoietic chimerism can be accomplished in randombred dogs by administering a sublethal dose of 200 cGy total body irradiation (TBI) before and immunosuppressive therapy after dog leukocyte antigen (DLA) - identical marrow transplants. The novel immunosuppression of mycophenolate mofetil (MMF) and cyclosporine (CSP) given for 4-5 weeks has synergistic properties that can control both host- versus-graft (HVG) and graft-versus-host (GVH) reactions,and establish a stable state of graft-host tolerance. With this approach, allogeneic transplants have become safe without severe toxicities and myeloablation characteristic of traditional high- dose conditioning programs. Based on additional preliminary data. We hypothesize that the major role of low-dose TBI before transplant has been to provide host immunosuppression. If this hypothesis proves correct, less toxic immunosuppression could be substituted for TBI. Accordingly, we propose to use this canine model of mixed donor - host hematopoietic chimerism after nonmyeloablative conditioning to achieve three broad specific aims. First, we propose to confirm that TBI works through immunosuppresion and not through "creation of marrow space." Second, we will determine whether TBI can be reduced or even completely replaced by immunosuppressive agents that are expected to have less toxicity than irradiation. We hypothesize that, as in cancer therapy, combinations of therapeutic agents may be better than single agents. We will study pharmaceutical and biological reagents, such as rapamycin, monoclonal antibodies to T-cell surface antigens, CTLA4Ig (cytotoxic T-cell lymphocyte antigen 4 - immunoglobulin fusion protein). And anti-CD40 ligand, for their immunosuppressive properties in the mixed chimerism model. Promising agent should be combined with currently used ones and evaluated for control of HVG and GVH reactions. Third, we will determine whether, and in what manner, donor lymphocyte infusions can be used to safely convert mixed donor-host to all-donor type hematopoiesis.