Characterization of graft-versus-host disease in SCID mice and prevention by physicochemical stressors.
BACKGROUND
Graft versus host disease (GVHD) prevents potentially curative allogeneic stem cell transplantation from being offered to cancer patients who lack a suitably matched donor. New methods to prevent GVHD are required to allow successful transplants across major histocompatibility complex barriers.


METHODS
A model of GVHD in C.B-17 SCID mice was developed to allow the study of allo-activated donor T cells without confounding effects of host lymphocytes. The abilities of cyclosporin-A, anticytokine antibodies, and oxidative stress to prevent GVHD in this model was studied.


RESULTS
T cells from major histocompatibility-mismatched donor mice caused severe GVHD in sublethally irradiated SCID hosts that could be ameliorated by coadministration of donor bone marrow but not by cyclosporine-A or anticytokine antibodies. In contrast, three-log more T cells could be injected without clinical consequences if they had been pretreated with a combination of heat, ultraviolet light, and oxygenation. The effect was not the trivial result of donor T cell destruction because T cell reconstitution, although delayed, recovered to normal levels within 2 weeks. Protection from GVHD required oxygenation and was associated with normalization of the CD4/CD8 donor T cell ratio, recovery of host hematopoiesis, and decreased inflammatory cytokine production.


CONCLUSIONS
Pretreatment of donor T cells with a combination of physicochemical stressors effectively prevents GVHD caused by major major histocompatibility disparities and may facilitate the safe transplantation of patients without HLA-identical donors.
Sheng-Tanner
X
X
Division of Cancer Biology Research, Sunnybrook and Women's College Health Sciences Centre, Toronto, Ontario, Canada.
McKerlie
C
C
Spaner
D
D
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D016026:Bone Marrow Transplantation / Q000009:adverse effects / Q000276:immunology; D016572:Cyclosporine / Q000494:pharmacology; D016207:Cytokines / Q000276:immunology; D004195:Disease Models, Animal; D006086:Graft vs Host Disease / Q000209:etiology* / Q000276:immunology / Q000517:prevention & control*; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008285:Major Histocompatibility Complex; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D018384:Oxidative Stress; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000637:transplantation; D014019:Tissue Donors; D014184:Transplantation, Homologous
D000906:Antibodies; D016207:Cytokines; D007166:Immunosuppressive Agents; D016572:Cyclosporine