Nonmyeloablative Allografts in DLA-haploidentical Dogs: Engraftment and GVHD

DLA 单倍体狗的非清髓性同种异体移植：移植和 GVHD

• 批准号: 7478449
• 负责人: BRENDA MARIE SANDMAIER
• 金额: $ 41.46万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7478449
• 关键词: Allogenic; Allografting; Antibodies; Antigens; Autologous; Biological; Bismuth; Blood Cells; Breeding; CD45 Antigens; Canis familiaris; Cell Adhesion Molecules; Cell Transplantation; Cells; Chimeric Proteins; Chimerism; Clinical; Clinical Trials; Condition; Cyclosporine/Mycophenolate Mofetil; Cytotoxic T-Lymphocyte-Associated Protein 4; Development; Dose; Drug resistance; Engraftment; Genes; Goals; Grant; Granulocyte Colony-Stimulating Factor; HLA Antigens; Hematopoietic; High Dose Chemotherapy; Host vs Graft Reaction; Human; Immunoglobulins; Immunologics; Immunosuppressive Agents; Label; Leukocytes; Lymphocyte; Marrow; Mediating; Methotrexate; Monoclonal Antibodies; Natural Killer Cells; Patients; Pre-Clinical Model; Prevention; Principal Investigator; Radioisotopes; Range; Rate; Recovery; Residual state; Sirolimus; Stem cells; T-Lymphocyte; TNFSF5 gene; Tin; Toxic effect; Translating; Translations; Transplantation; Treatment Protocols; Work; cellular transduction; chemotherapy; graft vs host disease; graft vs host reaction; killer T cell; mycophenolate mofetil; programs; response; temozolomide

The long-term objective of this project is to develop a safe and reliable nonmyeloablative approach at hematopoietic cell transplantation (HCT) from dog leukocyte antigen (DLA)-haploidentical donors, which can be translated into clinical trials. The studies will focus on the bi-directional immunologic barriers, host-versus-graft (HVG) and graft-versus-host (GVH) reactions, which must be overcome in order to achieve both uniform and sustained hematopoietic engraftment and graft-host tolerance. Two goals were pursued during the current grant period. One included extension of work in DLA-identical littermates in which we successfully substituted monoclonal antibodies (MAbs) directed at either TCRalpha-beta or the ubiquitous hematopoietic antigen, CD45, which were labeled with an alpha-emitting radionuclide Bismuth-213 (213Bi), for 2 Gy TBI. We also established successful DLA-haploidentical grafts when recipients were treated first with an anti-CD44 antibody combined with 4.5 Gy TBI and then given mycophenolate mofetil (MMF) and cyclosporine (CSP) after HCT for control of residual HVG reactions and for GVHD prevention. However, when the TBI dose was decreased to the sublethal range of 2 Gy, the engraftment rate declined to 50%, while the remainder of the dogs eventually rejected their grafts and survived with autologous marrow recovery. Also, GVHD control, which is largely T-cell mediated, has not been uniform. The current proposal seeks to continue the studies on DLA-haploidentical grafts since development of safe approaches will expand the choice of potential donors. Two principal experimental approaches will be taken. One involves combining low-dose TBI with relatively non-toxic biological and pharmacological immunosuppressive agents, including 213Bi-labeled antibodies to natural killer (NK) cells, all aimed at reducing both host NK and T cell responses and T cell responsiveness of the graft. The other is to administer chemotherapy early after transplant to not only control GVHD but also facilitate engraftment. After we have determined the optimal tinning and dosing of posttransplantation chemotherapy, we will evaluate the use of donor cells transduced with drug resistance genes which will allow using higher doses of posttransplantation chemotherapy for both induction of donor chimerism and control of GVHD. GVHD prevention will also include control of donor lymphocyte replication with certain immunosuppressive agents, e.g., MMF and sirolimus, combined with blockers of T-cell costimulation. Our ultimate aim is to develop allogeneic HCT strategies for patients with alternative donors with the least short- and long-term toxicities, which can be successfully applied to human patients.

该项目的长期目标是开发一种安全可靠的非清髓性方法 来自狗白细胞抗原(DLA)半相合供者的造血细胞移植(HCT)，可以 转化为临床试验。这些研究将集中在双向免疫屏障，宿主对移植物。 (HVG)和移植物抗宿主(GVH)反应，必须克服这些反应才能实现这两个目标 均匀持续的造血植入和移植物-宿主耐受性。在此期间，实现了两个目标 当前的授权期。其中一项包括在DLA完全相同的窝产仔中延长工作时间，在其中我们 针对TCRα-β或无处不在的 造血抗原CD45，用阿尔法发射放射性核素铋-213(213Bi)标记，用于 2GyTBI。我们还成功地建立了DLA-单倍体相合移植物，当受者首先接受 抗CD44抗体联合4.5GyTBI，然后给予霉酚酸酯(MMF)和 HCT后应用环孢素(CSP)控制残留的HVG反应和预防GVHD。然而， 当照射剂量降至2Gy亚致死剂量时，植入率降至50%。 而其余的狗最终拒绝了他们的移植，并用自体骨髓存活了下来 恢复。此外，GVHD的控制，主要是T细胞介导的，并不是一致的。 目前的建议寻求继续研究DLA-半相合移植物，因为 安全的做法将扩大潜在捐赠者的选择。两种主要的实验方法将是 有人了。一种是将低剂量的TBI与相对无毒的生物和药理结合起来 免疫抑制剂，包括针对自然杀伤(NK)细胞的~(213)Bi标记抗体，均针对 降低宿主NK和T细胞反应以及移植物的T细胞反应。另一种是管理 移植后早期化疗，既能控制移植物抗宿主病，又能促进植入。在我们有了 确定移植后化疗的最佳灌装和剂量，我们将评估 转导耐药基因的供体细胞将允许移植后使用更高剂量的药物 化疗既可诱导供者嵌合体，又可控制移植物抗宿主病。GVHD预防还将 包括用某些免疫抑制剂控制供者淋巴细胞复制，例如MMF和 西罗莫司与T细胞共刺激阻滞剂联合使用。 我们的最终目标是为有替代供者的患者开发异基因HCT策略 短期和长期毒性最小，可成功应用于人类患者。