Many patients who could potentially be cured by bone marrow transplantation (BMT) do not have a suitable HLA-identical donor, and must therefore be denied this option. The major complication of BMT across HLA barriers is severe graft-vs-host disease (GVHD) caused by donor T cells. Utilization of T cell-depleted (TCD) bone marrow avoids GVHD), but has led to high rates of engraftment failure, immunoincompetence, and recurrence of leukemia. Recent findings in a murine model have demonstrated that the T cell subsets which cause GVHD may be distinguishable from those responsible for graft-versus-leukemia effects and from those required for engraftment. The overall objectives of this research proposal are to examine the effects of selective T cell subset depletion of donor marrow on immunologic reconstitution, alloengraftment and development of GVHD in a large animal preclinical model. We have previously developed partially inbred miniature swine in this laboratory as a preclinical model for studies of transplantation biology, and have demonstrated their similarity to man in m,any parameters related to BMT. In addition they represent the only large animal model in which transplantation across defined MHC barriers can be reproducibly performed.
Our specific aims are to: 1. Determine the pattern and thymic dependence of mature T cell development following ablative radiation and autologus BMT in miniature swine; 2. Determine the effect of depletion of selected T cell subsets on engraftment, GVHD, thymic function and immune reconstitution following BMT across minor antigen and defined single haplotype MHC antigen barriers; and 3. To attempt BMT across defined two haplotype MHC antigen barriers using bone marrow depleted of selected T cell subsets and to determine parameters of reconstitution and immune function of returning T cell subsets. These studies should provide data on the development of mature T cell subsets and on the role of these subsets in engraftment and GVHD following BMT, information which has previously been available only from rodent models. Since GVHD, failure of engraftment and immunoincompetence represent major limitations to clinical BMT across MHC barriers, these studies could have important clinical implications.
| Colby, C; Chang, Q; Fuchimoto, Y et al. (2000) Cytokine-mobilized peripheral blood progenitor cells for allogeneic reconstitution of miniature swine. Transplantation 69:135-40 |
| Kozlowski, T; Sablinski, T; Basker, M et al. (2000) Decreased graft-versus-host disease after haplotype mismatched bone marrow allografts in miniature swine following interleukin-2 treatment. Bone Marrow Transplant 25:47-52 |
| Huang, C A; Yamada, K; Murphy, M C et al. (1999) In vivo T cell depletion in miniature swine using the swine CD3 immunotoxin, pCD3-CRM9. Transplantation 68:855-60 |
