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IFN-? receptor-deficient donor T cells mediate protection from graft-versus-host disease and preserve graft-versus-tumor responses after allogeneic bone marrow transplantation.

ABSTRACT: Graft-versus-host disease (GVHD) is a major complication of allogeneic bone marrow transplantation. It has been previously reported that lung GVHD severity directly correlates with the expansion of donor Th17 cells in the absence of IFN-?. However, the consequence of Th17-associated lung GVHD in the presence of IFN-? has not been well characterized. In the current study, T cells from IFN-? receptor knockout (IFN-?R(-/-)) mice, capable of producing IFN-? but unable to signal in response to IFN-?, have been used to elucidate further the role of IFN-? in GVHD. We found the transfer of donor T cells from either IFN-?R(-/-) or IFN-? knockout (IFN-?(-/-)) mice resulted in significant increases in donor Th17 cells in the lung. Marked increases in IL-4-producing Th2 cells infiltrating the lungs were also observed in the mice of donor IFN-?R(-/-) T cells. Notably, despite the presence of these cells, these mice did not show the severe immune-mediated histopathological lung injury observed in mice receiving donor IFN-?(-/-) T cells. Increases in lung GVHD did occur in mice with donor IFN-?R(-/-) T cells when treated in vivo with anti-IFN-? demonstrating that the cytokine has a protective role on host tissues in GVHD. A survival benefit from acute GVHD was also observed using donor cells from IFN-?R(-/-) T cells compared with control donors. Importantly, tumor-bearing mice receiving IFN-?R(-/-) T cells versus wild-type donor T cells displayed similar graft-versus-tumor (GVT) effects. These results demonstrate the critical role of IFN-? on host tissues and cell effector functions in GVHD/GVT.

SUBMITTER: Sun K

PROVIDER: S-EPMC3509544 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature

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IFN-γ receptor-deficient donor T cells mediate protection from graft-versus-host disease and preserve graft-versus-tumor responses after allogeneic bone marrow transplantation.

Sun Kai K Hsiao Hui-Hua HH Li Minghui M Ames Erik E Bouchlaka Myriam M Welniak Lisbeth A LA Hagino Takeshi T Jagdeo Jared J Pai Chien-Chun CC Chen Mingyi M Blazar Bruce R BR Abedi Mehrdad M Murphy William J WJ

Journal of immunology (Baltimore, Md. : 1950) 20120709 4

Graft-versus-host disease (GVHD) is a major complication of allogeneic bone marrow transplantation. It has been previously reported that lung GVHD severity directly correlates with the expansion of donor Th17 cells in the absence of IFN-γ. However, the consequence of Th17-associated lung GVHD in the presence of IFN-γ has not been well characterized. In the current study, T cells from IFN-γ receptor knockout (IFN-γR(-/-)) mice, capable of producing IFN-γ but unable to signal in response to IFN-γ, ...[more]

PMID: 22778394

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Project description:BackgroundAllogeneic bone marrow transplantation (allo-BMT) is a potentially curative therapy for a variety of hematologic diseases, but benefits, including graft-versus-tumor (GVT) activity are limited by graft-versus-host-disease (GVHD). Carcinoembryonic antigen related cell adhesion molecule 1 (Ceacam1) is a transmembrane glycoprotein found on epithelium, T cells, and many tumors. It regulates a variety of physiologic and pathological processes such as tumor biology, leukocyte activation, and energy homeostasis. Previous studies suggest that Ceacam1 negatively regulates inflammation in inflammatory bowel disease models.MethodsWe studied Ceacam1 as a regulator of GVHD and GVT after allogeneic bone marrow transplantation (allo-BMT) in mouse models. In vivo, Ceacam1(-/-) T cells caused increased GVHD mortality and GVHD of the colon, and greater numbers of donor T cells were positive for activation markers (CD25(hi), CD62L(lo)). Additionally, Ceacam1(-/-) CD8 T cells had greater expression of the gut-trafficking integrin ?(4)?(7), though both CD4 and CD8 T cells were found increased numbers in the gut post-transplant. Ceacam1(-/-) recipients also experienced increased GVHD mortality and GVHD of the colon, and alloreactive T cells displayed increased activation. Additionally, Ceacam1(-/-) mice had increased mortality and decreased numbers of regenerating small intestinal crypts upon radiation exposure. Conversely, Ceacam1-overexpressing T cells caused attenuated target-organ and systemic GVHD, which correlated with decreased donor T cell numbers in target tissues, and mortality. Finally, graft-versus-tumor survival in a Ceacam1(+) lymphoma model was improved in animals receiving Ceacam1(-/-) vs. control T cells.ConclusionsWe conclude that Ceacam1 regulates T cell activation, GVHD target organ damage, and numbers of donor T cells in lymphoid organs and GVHD target tissues. In recipients of allo-BMT, Ceacam1 may also regulate tissue radiosensitivity. Because of its expression on both the donor graft and host tissues, this suggests that targeting Ceacam1 may represent a potent strategy for the regulation of GVHD and GVT after allogeneic transplantation.

Project description:Some retrospective studies have suggested that long-term donor statin use may protect against graft-versus-host disease (GVHD) in patients receiving cyclosporine (CSP)-based immunosuppression after allogeneic hematopoietic cell transplantation (HCT), but prospective studies of short-term treatment of donors with statin have shown conflicting results. We conducted 2 consecutive prospective clinical trials to assess whether donor statin treatment was associated with protection against severe acute GVHD (aGVHD). In a single-arm phase II trial (study 1), we evaluated whether short-term statin treatment of HLA-matched related donors for 14 days before HCT prevented grade III-IV aGVHD. In a prospective observational cohort study (study 2), we evaluated whether longer-term (>14 days) donor statin use was required for GVHD-protective effects. Study 1 was terminated after 6 of the 35 recipients (17%) developed grade III-IV GVHD. For study 2, we identified 135 patients whose unrelated donors had received long-term treatment with statins up to the time of HCT and 4942 patients whose donors had not received long-term statin treatment. The adjusted odds ratio for grade III-IV aGVHD (statin versus no statin) was .83 (95% confidence interval [CI], .46 to 1.50; P = .54). Multivariable analysis showed no statistically significant differences between the 2 groups in the risk of grade II-IV aGVHD, chronic GVHD, nonrelapse mortality, recurrent malignancy, or overall mortality. Among patients receiving CSP-based immunosuppression, including 35 with donors receiving long-term statin treatment and 973 with donors who did not receive statins, the adjusted odds ratio of grade III-IV aGVHD was .30 (95% CI, .07 to 1.35; P = .12). In study 1, short-term statin treatment of donors was ineffective in preventing grade III-IV GVHD. In study 2, in the prespecified subgroup of recipients given CSP-based immunosuppression, nondefinitive evidence suggested that donor statin use was associated with a reduced risk of severe aGVHD.

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IFN-? receptor-deficient donor T cells mediate protection from graft-versus-host disease and preserve graft-versus-tumor responses after allogeneic bone marrow transplantation.

Publications

IFN-γ receptor-deficient donor T cells mediate protection from graft-versus-host disease and preserve graft-versus-tumor responses after allogeneic bone marrow transplantation.

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