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方法