NONMYELOABLATIVE HOST CONDITIONING PROTECTS AGAINST GVHD

Stanford University, Stanford CA

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Abstract

Graft versus host disease (GVHD) remains a major barrier to the widespread use of allogeneic bone marrow and progenitor cell transplantation in humans. We developed a non-myeloablative host conditioning regimen which permits engraftment of MHC-mismatched donor bone marrow and peripheral blood mononuclear cell transplants in mice and rats, and prevents GVHD. The regimen combines fractionated irradiation targeted to the lymphoid tissues (total lymphoid irradiation), and depletive anti-T cell antibodies. After conditioning, hosts are protected against GVHD by the predominance (>90%) of NK.1+ or DX5+TCRalpha-beta+ T cells amongst the residual host T cells. These host cells prevent injury of host tissues by their secretion of high levels of IL-4. The current proposal will determine whether the protective non- myeloablative regimen can be used to effectively treat the BCL1, B cell lymphoma, in BALB/c mice. Tumor bearing hosts will be treated with this protective regimen, and will receive combined bone marrow and peripheral blood mononuclear cell transplants from C57BL/6 donors. Hosts treated with conventional total body irradiation and given the transplant uniformly die of severe GVHD within a few weeks. We expect that the hosts treated with the protective regimen will not develop GVHD, and yet the transplant will eradicate the tumor cells. Hosts will be monitored for the development of chimerism, and the presence of BCL1-idiotype positive tumor cells over a period of at least six months. In similar experiments, tumor-bearing hosts will be treated with the protective regimen, and will receive G-CSF "mobilized" blood progenitor cell transplants from C57BL/6 donors. Hosts treated with conventional total body irradiation are expected to develop lethal GVHD after the "mobilized" blood transplant, and those treated with the protective regimen are expected to survive long-term without progressive tumor growth. In further studies, we will determine whether the NK1.1+ TCRalpha- beta+ T cells that protect against GVHD do not interfere with the capacity of CD8+ T cells to mediate graft versus leukemia activity and facilitation of hematopoietic progenitor cell engraftment. Finally, we will determine whether the source of NK1.1+ and DX5+TCRalpha- beta+ T cells in the spleen of TLI treated hosts is from rapidly dividing progenitors in the bone marrow rather than progenitors in the thymus. The proposed experiments have application to allogeneic "mobilized" blood progenitor cell transplantation in non-myeloablated MHC- matched or haploidentical human recipients with hematologic or lymphoid malignancies, especially those recipients over 55 years old. This proposal represents an animal model of the clinical trials proposed in Project 1.