The goal of the proposed research is to effectively treat the BCL1, B cell lymphoma, in mice using an in allogeneic bone marrow transportation regimen that will not only eliminate tumor cells without graft versus host disease (GVHD), but also allow for satisfactory immune reconstitution of hosts lacking a thymus. Immune reconstitution of MHC-haplotype matched humans given bone marrow or hematopoietic progenitor transplants for treatment of malignancy remains a major problem. In order to facilitate immune reconstitution of CD4+ and CD8* T cells in lethally irradiated BALB/c x C57BL/6 hosts, we will add a newly identified committed T cell progenitor (CTP) to allogeneic C57BL/6 transplants that include purified hematopoietic stem cells (HSC) for hematopoietic reconstitution and purified marrow CD8' T cells for tumor cell killing without GVHD. Hosts will be euthymic or thymectomized. The CTP have been shown to rapidly reconstitute the CD4+ and CD8' T cells of irradiated athymic nude mice via an extrathymic pathway. Hosts will be monitored for survival, tumor cell elimination chimerism, GVHD, and reconstitution of mature CD4' and CD8' T cells. The function of the latter cells will be determined by assaying protection against murine cytomegalovirus infection, antibody responses to sheep red blood cells, and delayed type hypersensitivity responses to ovalbumin. In addition, donor-type chimeric cells will be studied for tolerance to host alloantigens. Purified populations of donor cells will be obtained by cytometry to identify and sort HSC, CTP, and CDS' T cells. Chimerism and presence of tumor cells will be measured by immunofluorescent staining and flow cytometric analysis such that chimeric cells derived from each of the three injected donor cells can be identified. GVHD will be monitored by clinical signs, survival, and histopathology.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Experimental Therapeutics Subcommittee 1 (ET)
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Yovandich, Jason L
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Stanford University
Internal Medicine/Medicine
Schools of Medicine
United States
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Ermann, Joerg; Hoffmann, Petra; Edinger, Matthias et al. (2005) Only the CD62L+ subpopulation of CD4+CD25+ regulatory T cells protects from lethal acute GVHD. Blood 105:2220-6
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Edinger, Matthias; Hoffmann, Petra; Ermann, Joerg et al. (2003) CD4+CD25+ regulatory T cells preserve graft-versus-tumor activity while inhibiting graft-versus-host disease after bone marrow transplantation. Nat Med 9:1144-50
Chatterjea-Matthes, Devavani; Garcia-Ojeda, Marcos E; Dejbakhsh-Jones, Sussan et al. (2003) Early defect prethymic in bone marrow T cell progenitors in athymic nu/nu mice. J Immunol 171:1207-15
Hoffmann, Petra; Ermann, Joerg; Edinger, Matthias et al. (2002) Donor-type CD4(+)CD25(+) regulatory T cells suppress lethal acute graft-versus-host disease after allogeneic bone marrow transplantation. J Exp Med 196:389-99