MIXED HEMATOPOIETIC CHIMERISM IN AN ANIMAL MODEL

初步研究表明，通过在犬白细胞抗原（DLA）相同骨髓移植前给予200 cGy亚致死剂量的全身照射（TBI）和在犬白细胞抗原（DLA）相同骨髓移植后进行免疫抑制治疗，可以在随机繁殖的犬中实现稳定的同种异体混合造血嵌合。霉酚酸酯（MMF）和环孢素（CSP）给予4-5周的新型免疫抑制具有协同特性，可以控制宿主抗移植物（HVG）和移植物抗宿主（GVH）反应，并建立稳定的移植物-宿主耐受状态。采用这种方法，同种异体移植变得安全，没有严重的毒性和传统高剂量调节方案所特有的骨髓消融。基于额外的初步数据。我们假设移植前低剂量脑外伤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可以替代TBI。因此，我们建议在非清髓条件作用后使用这种犬混合供体-宿主造血嵌合模型来实现三个广泛的具体目标。首先，我们建议确认TBI通过免疫抑制而不是通过“骨髓空间的创造”起作用。其次，我们将确定是否可以减少TBI，甚至完全取代免疫抑制剂，预期毒性比辐照小。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细胞表面抗原单克隆抗体、CTLA4Ig（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cd40配体，在混合嵌合模型中具有免疫抑制特性。有前途的药剂应与现有药剂联合使用，评价其对HVG和GVH反应的控制作用。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体-宿主造血转化为全供体造血。

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.