Bone marrow deficient in IFN-{gamma} signaling selectively reverses GVHD-associated immunosuppression and enhances a tumor-specific GVT effect.
Vaccine-based expansion of T cells is one approach to enhance the graft-versus-tumor effect of allogeneic bone marrow transplantation (BMT), but the complex immunobiology of the allogeneic environment on responses to tumor vaccines has not been well characterized. We hypothesized that subclinical graft-versus-host disease (GVHD) impairs immunity, but modulation of gamma interferon (IFN-gamma) signaling could reverse this effect. Dendritic cell vaccines and donor lymphocyte infusions (DLIs) were incorporated into a minor histocompatibility antigen-mismatched, T cell-depleted, allogeneic BMT mouse model. Animals were then challenged with H-Y expressing tumors. CD4(+) and CD8(+) responses to H-Y were diminished in vaccinated allogeneic versus syngeneic BMT recipients with DLI doses below the threshold for clinical GVHD, especially in thymectomized hosts. IFN-gamma receptor 1-deficient (IFN-gammaR1(-/-)) T cells cannot cause GVHD but also have diminished vaccine responses. Remarkably, IFN-gammaR1(-/-) bone marrow abrogates GVHD, allowing higher DLI doses to be tolerated, but improves vaccine responses and tumor protection. We conclude that tumor vaccines administered after allogeneic BMT can augment graft-versus-tumor if GVHD is avoided and that prevention of IFN-gamma signaling on donor bone marrow is an effective approach to preventing GVHD while preserving immunocompetence.
Capitini
Christian M
CM
Immunology Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. capitinic@mail.nih.gov
Herby
Sarah
S
Milliron
Matthew
M
Anver
Miriam R
MR
Mackall
Crystal L
CL
Fry
Terry J
TJ
D000818:Animals; D016026:Bone Marrow Transplantation / Q000379:methods / Q000502:physiology*; D005260:Female; D006086:Graft vs Host Disease / Q000150:complications / Q000235:genetics / Q000517:prevention & control*; D020350:Graft vs Tumor Effect / Q000235:genetics* / Q000276:immunology; D007165:Immunosuppression Therapy / Q000009:adverse effects; D007371:Interferon-gamma / Q000378:metabolism* / Q000502:physiology; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D017471:Receptors, Interferon / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D013379:Substrate Specificity / Q000235:genetics / Q000276:immunology; D019172:Transplantation Conditioning / Q000379:methods; D014407:Tumor Cells, Cultured; D019139:Tumor Escape / Q000235:genetics / Q000276:immunology; D000096743:Interferon gamma Receptor
D007371:Interferon-gamma; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor