Transplants for myelodysplasia and myelofribrosis

本项目的目标是，首先，开发毒性较小的免疫抑制调节程序，异基因造血干细胞移植（HSCT）在犬模型，可应用于患者谁没有HLA相同的同胞供体，第二，完善现有的方案，主要组织相容性复合体匹配的收件人。在最后一次授权期间，我们描述了DLA相同匹配的犬同窝仔中的方案，该方案包括在HSCT之前的200 cGy全身照射（TBI）的非骨髓消融剂量以及在HSCT之后的霉酚酸酯（MMF）和环孢霉素（CSP），我们成功地将其转化为患有恶性和非恶性疾病的人类患者。新的移植方法的基本原理是使用移植后免疫抑制与MMF/CSP，不仅更好地控制移植物抗宿主病（GVHD），而且抑制宿主抗移植物反应。这样，调节程序的强度就可以降低。结合新的原则与以前发表的观察，我们已经表明，DLA-单倍体相合HSCT可以几乎均匀地建立后，只有450 cGy的TBI时，给予药物，此外，抗CD 44单克隆抗体（单克隆抗体，S5）移植前。我们计划将TBI剂量降低到200 cGy的亚致死范围，并通过评估三种明显不同的方法在该模型中获得更好的GVHD控制：（1）将移植后MMF/CSP分别从先前使用的28天和35天延长至100天;（2）评估LFA 1的拮抗剂，（白细胞功能性抗原-1）移植物周围;和（3）向该方案中加入CTLA 4 Ig +/-针对CD 154的Mab（CD 40配体）的T细胞共刺激阻断。在DLA相同的同窝仔，我们将检查是否有针对性的照射公司的短寿命的α-发射放射性核素，铋213（Bi-213），通过适当的单克隆抗体提供可以取代200 cGy的外部束TBI在提供必要的移植免疫抑制。我们将首先用泛造血抗CD 45抗体靶向宿主细胞，然后用抗T细胞受体抗体测试T细胞特异性消融。成功的策略将与用毒性较小的免疫抑制方案完全取代TBI的目标相结合。

The objectives of this project are, first, to develop less toxic immunosuppressive conditioning programs for allogeneic hematopoietic stem cell transplants (HSCT) in a canine model that can be applied to patients who do not have HLA-identical sibling donors and, second, to refine existing regimens for major histocompatibility complex matched recipients. In the last grant period, we described a regimen in DLA- identical matched canine littermates consisting of a non-marrow ablative dose of 200 cGy total body irradiation (TBI) before, and mycophenolate mofetil (MMF) and cyclosporine (CSP) after HSCT, which we successfully translated to human patients with malignant and non- malignant diseases. The principal underlying the new transplant approach was to use post-grafting immunosuppression with MMF/CSP, not only for better control of graft-versus-host disease (GVHD), but also to suppress host-versus-graft reactions. This way, the intensity of the conditioning programs could be reduced. Combing the new principal with previously published observations, we have shown that DLA- haploidentical HSCT could be almost uniformly established after only 450 cGy TBI when drugs were given, in addition, an anti-CD44 monoclonal antibody (Mab, S5) before transplant. We plan to lower the TBI dose to the sublethal range of 200 cGy and to obtain better control of GVHD in this model by evaluating three distinctly different approaches: (1) extending post-grafting MMF/CSP from the previously used 28 and 35 days, respectively to 100 days; (2) evaluating an antagonist to LFA1 (leukocyte functional antigen-1) peritransplant; and (3) adding T cell co- stimulatory blockade with CTLA4lg+/- an Mab to CD154 (CD40 ligand) to the regimen. In DLA-identical littermates, we will examine whether targeted irradiation firm a short-lived alpha-emitting radionuclide, Bismuth 213 (Bi-213), delivered through appropriate MAbs can be substituted for 200 cGy external beam TBI in providing immunosuppression necessary for engraftment. We will first target host cells with a pan-hematopoietic anti-CD45 antibody, and then test T cell- specific ablation with an anti-T cell receptor antibody. Successful strategies will be used in combination with the goal of completely replacing TBI with less toxic immunosuppression regimens.