| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
* Immunology Program, H. Lee Moffitt Comprehensive Cancer Center and Research Institute, University of South Florida, Tampa, FL 33612;
Department of Pediatrics, Department of Pathology, and Department of Cell Biology, University of South Florida, Tampa, FL 33612; and
Interdisciplinary Oncology, University of South Florida, Tampa, FL 33612
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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported in part by grants from the National Institutes of Health (RO1 HL72523) and academic development funds from Moffitt Cancer Center and the University of South Florida. W.G.K. is the Newman Family Scholar of the Leukemia and Lymphoma Society.
2 Address correspondence and reprint requests to Dr. William G. Kerr, H. Lee Moffitt Comprehensive Cancer Center and Research Institute, University of South Florida, 12902 Magnolia Avenue, Tampa, FL 33612. E-mail address: kerrw{at}moffitt.org
3 Abbreviations used in this paper: GVHD, graft-vs-host disease; BM, bone marrow; BMT, BM transplantation; DC, dendritic cell; LN, lymph node; MySC, myeloid suppressor cell; poly(I:C), polyinosinic-polycytidylic acid; WT, wild type.
This article has been cited by other articles:
|
|
 |
|
  T. W. Poh, J. M. Bradley, P. Mukherjee, and S. J. Gendler Lack of Muc1-Regulated {beta}-Catenin Stability Results in Aberrant Expansion of CD11b+Gr1+ Myeloid-Derived Suppressor Cells from the Bone Marrow Cancer Res., April 15, 2009; 69(8): 3554 - 3562. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. L. Hazen, M. J. Smith, C. Desponts, O. Winter, K. Moser, and W. G. Kerr SHIP is required for a functional hematopoietic stem cell niche Blood, March 26, 2009; 113(13): 2924 - 2933. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. M. Collazo, D. Wood, K. H. T. Paraiso, E. Lund, R. W. Engelman, C.-T. Le, D. Stauch, K. Kotsch, and W. G. Kerr SHIP limits immunoregulatory capacity in the T-cell compartment Blood, March 26, 2009; 113(13): 2934 - 2944. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.-I. Youn, S. Nagaraj, M. Collazo, and D. I. Gabrilovich Subsets of Myeloid-Derived Suppressor Cells in Tumor-Bearing Mice J. Immunol., October 15, 2008; 181(8): 5791 - 5802. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Cheng, C. A. Corzo, N. Luetteke, B. Yu, S. Nagaraj, M. M. Bui, M. Ortiz, W. Nacken, C. Sorg, T. Vogl, et al. Inhibition of dendritic cell differentiation and accumulation of myeloid-derived suppressor cells in cancer is regulated by S100A9 protein J. Exp. Med., September 29, 2008; 205(10): 2235 - 2249. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. L. Bishop, L. M. Sly, G. Krystal, and B. B. Finlay The Inositol Phosphatase SHIP Controls Salmonella enterica Serovar Typhimurium Infection In Vivo Infect. Immun., July 1, 2008; 76(7): 2913 - 2922. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Kobayashi, T. Yoshida, D. Takeuchi, V. C. Jones, K. Shigematsu, D. N. Herndon, and F. Suzuki Gr-1+CD11b+ cells as an accelerator of sepsis stemming from Pseudomonas aeruginosa wound infection in thermally injured mice J. Leukoc. Biol., June 1, 2008; 83(6): 1354 - 1362. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
