Induced SHIP deficiency expands myeloid regulatory cells and abrogates graft-versus-host disease.
Graft-vs-host disease (GVHD) is the leading cause of treatment-related death in allogeneic bone marrow (BM) transplantation. Immunosuppressive strategies to control GVHD are only partially effective and often lead to life-threatening infections. We previously showed that engraftment of MHC-mismatched BM is enhanced and GVHD abrogated in recipients homozygous for a germline SHIP mutation. In this study, we report the development of a genetic model in which SHIP deficiency can be induced in adult mice. Using this model, we show that the induction of SHIP deficiency in adult mice leads to a rapid and significant expansion of myeloid suppressor cells in peripheral lymphoid tissues. Consistent with expansion of myeloid suppressor cells, splenocytes and lymph node cells from adult mice with induced SHIP deficiency are significantly compromised in their ability to prime allogeneic T cell responses. These results demonstrate that SHIP regulates homeostatic signals for these immunoregulatory cells in adult physiology. Consistent with these findings, induction of SHIP deficiency before receiving a T cell-replete BM graft abrogates acute GVHD. These findings indicate strategies that target SHIP could increase the efficacy and utility of allogeneic BM transplantation, and thereby provide a curative therapy for a wide spectrum of human diseases.
Paraiso
Kim H T
KH
Immunology Program, H. Lee Moffitt Comprehensive Cancer Center and Research Institute, University of South Florida, 12902 Magnolia Avenue, Tampa, FL 33612, USA.
Ghansah
Tomar
T
Costello
Amy
A
Engelman
Robert W
RW
Kerr
William G
WG
D000208:Acute Disease; D000818:Animals; D016026:Bone Marrow Transplantation / Q000276:immunology*; D004195:Disease Models, Animal; D006086:Graft vs Host Disease / Q000201:enzymology / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D006706:Homeostasis / Q000276:immunology*; D006801:Humans; D000072181:Inositol Polyphosphate 5-Phosphatases; D008198:Lymph Nodes / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D023461:Myeloid Progenitor Cells / Q000201:enzymology / Q000276:immunology*; D010744:Phosphoric Monoester Hydrolases / Q000172:deficiency* / Q000276:immunology / Q000378:metabolism; D013154:Spleen / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D013601:T-Lymphocytes / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D014184:Transplantation, Homologous
D010744:Phosphoric Monoester Hydrolases; D000072181:Inositol Polyphosphate 5-Phosphatases