Submitted November 5, 2008
Accepted February 19, 2009
Bone marrow deficient in gamma interferon signaling selectively reverses GVHD-associated immunosuppression and enhances a tumor-specific GVT effect
Christian M. Capitini*, Sarah Herby, Matthew Milliron, Miriam R. Anver, Crystal L. Mackall, and Terry J. Fry
Immunology Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
Pathology/Histotechnology Laboratory, SAIC-Frederick, National Cancer Institute, National Institutes of Health, Frederick, MD, United States
Center for Cancer and Blood Disorders, Children's National Medical Center, Washington, DC, United States
* Corresponding author; email: capitinic{at}mail.nih.gov.
Vaccine-based expansion of T cells is one approach to enhance the graft-versus-tumor (GVT) effect of allogeneic bone marrow transplant (BMT), but the complex immunobiology of the allogeneic environment on responses to tumor vaccines have not been well characterized. We hypothesized that subclinical graft-versus-host-disease (GVHD) impairs immunity but modulation of gamma interferon (IFN
) signaling could reverse this effect. Dendritic cell vaccines and donor lymphocyte infusions (DLI) 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 receptor 1-deficient (IFNR1-/-) T cells cannot cause GVHD but also have diminished vaccine responses. Remarkably, IFNR1 -/- 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 GVT if GVHD is avoided, and that prevention of IFN signaling on donor bone marrow is an effective approach to preventing GVHD while preserving immunocompetence.
