Graft-vs.-lymphoma effect in an allogeneic hematopoietic stem cell transplantation model.
It is known that an important curative benefit of allogeneic bone marrow transplantation (BAMT) in the treatment of hematolymphoid malignancies is a graft-vs.-tumor (GVT) effect. GVT activity has been attributed to mature immune cells contained within the graft because T-cell depletion of bone marrow results in increased rates of disease relapse post-transplantation. We previously demonstrated successful engraftment of highly purified hematopoietic stem cells (HSCs) transplanted across major histocompatibility complex (MHC) barriers in mice. In the present study, we have developed a preclinical model of allogeneic HSC transplantation into lymphoma-inoculated mice, allowing us to directly test whether purified HSCs have measurable GVT activity. We then performed cotransfer studies of HSCs with purified immune cells to identify which population(s) confers tumor protection and the mechanism by which such cells suppress tumor growth. MHC-mismatched donor-recipient combinations were studied. All of the GVT activity was contained in the CD8+ cell fraction and, at the doses of CD8+ cells tested, tumor protection was separable from acute graft-vs.-host disease (aGVHD). Although there appears to be no functional difference between BM- and splenic-derived CDS8+ cells with regard to GVT activity without aGVHD, this was not the case for purified CD3+ cells. CD3+ cells derived from BM were tumor protective, whereas transplantation of equivalent doses of CD3+ cells purified from spleen resulted in lethal GVHD. The mechanism by which the GVT-conferring cells protect recipient mice from tumors was studied using immune defective mice as donors. We found that an intact pathway of perforin-dependent cytolysis, as well as an intact Fas-ligand pathway, is required in order to exert maximal anti-tumor activity.
Ito
M
M
Department of Medicine, Stanford University School of Medicine, California 94305, USA.
Shizuru
J A
JA
D000818:Animals; D016026:Bone Marrow Transplantation / Q000401:mortality; D017252:CD3 Complex; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D006086:Graft vs Host Disease / Q000276:immunology / Q000473:pathology; D020350:Graft vs Tumor Effect; D018380:Hematopoietic Stem Cell Transplantation / Q000401:mortality; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D007376:Interleukin-2 / Q000235:genetics / Q000276:immunology; D016393:Lymphoma, B-Cell / Q000276:immunology / Q000401:mortality / Q000628:therapy; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009368:Neoplasm Transplantation; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D013154:Spleen / Q000166:cytology / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D014184:Transplantation, Homologous / Q000276:immunology* / Q000401:mortality; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000235:genetics / Q000276:immunology
D017252:CD3 Complex; D007376:Interleukin-2; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D019014:fas Receptor; D054353:Perforin; D007371:Interferon-gamma