Transplants for myelodysplasia and myelofribrosis

该项目的目标是，首先，在犬模型中开发毒性较低的异基因造血干细胞移植(HSCT)免疫抑制调节方案，该方案可应用于没有HLA相合兄弟姐妹捐赠者的患者，其次，改进现有的主要组织相容性复合体匹配受者的治疗方案。在上一次资助期间，我们描述了一种在DLA相合的配对犬胎中使用的方案，该方案包括非骨髓切除剂量的全身照射(TBI)，以及在HSCT后给予霉酚酸酯(MMF)和环孢素(CSP)，我们成功地将其移植到人类恶性和非恶性疾病患者中。新的移植方法的基本原理是使用MMF/CSP的移植后免疫抑制，这不仅是为了更好地控制移植物抗宿主病(GVHD)，也是为了抑制宿主对移植物的反应。这样，条件反射程序的强度就可以降低。结合新的原理和以前发表的观察结果，我们发现，在给予药物的450cGyTBI后，再加上移植前抗CD44的单抗(Mab，S5)，DLA-单倍体相合的HSCT可以几乎均匀地建立。我们计划通过评估三种截然不同的方法，在这个模型中将TBI剂量降低到亚致死剂量200cGY，并获得更好的GVHD控制：(1)将移植后MMF/CSP的使用时间分别从以前的28天和35天延长到100天；(2)评估LFA1(白细胞功能抗原-1)的拮抗剂；以及(3)在方案中增加T细胞共刺激阻断与CD154(CD40配体)的CTLA4lg+/-单抗。在DLA相合的小鼠中，我们将研究靶向照射公司通过适当的单抗提供的短命阿尔法发射放射性核素Bimuth 213(Bi213)能否取代200cGy外照射在提供植入所需的免疫抑制方面的作用。我们将首先用泛造血抗CD45抗体来靶向宿主细胞，然后用抗T细胞受体抗体来测试T细胞特异性的消融。成功的策略将与用毒性较小的免疫抑制方案完全取代脑损伤的目标相结合。

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.