Induced SHIP Deficiency Expands Myeloid Regulatory Cells and Abrogates Graft-versus-Host Disease

Abstract

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.

SHIP Is Required for Dendritic Cell Maturation

“…However, the expansion of other immune cell types in vivo, such as myeloid-derived suppressor cells, likely also plays a role to suppress Th1 cell responses (37,46). Thus, as they become available, it will be very interesting to assess the DC phenotype and Th1/Th2 cell proclivity of DC-lineage specific SHIP knockout mice and to test the function of SHIP 2/2 DCs in vitro and in vivo in the absence of the influence of a pan-hematopoietic SHIP 2/2 milieu.…”

SHIP limits immunoregulatory capacity in the T-cell compartment

“…We previously found that donor and host allogeneic responses are compromised in SH2 domaincontaining inositol 5-phosphatase (SHIP)-deficient hosts, which exhibit significantly reduced acute rejection of MHC-mismatched bone marrow grafts and GVHD. 6,7 Thus, an immunosuppressive environment prevails in SHIP-deficient hosts. We consistently observe a profound expansion of myeloid suppressor cells (MySC) in SHIP-deficient mice.…”

“…We consistently observe a profound expansion of myeloid suppressor cells (MySC) in SHIP-deficient mice. [6][7][8][9] Because host and donor T regs limit GVHD 4,10 and Mac1 ϩ Gr1 ϩ cells, similar to SHIP Ϫ/Ϫ MySC, expand T regs in tumor and GVHD models 11,12 ; we considered that the T reg compartment in SHIP-deficient hosts may also be expanded. In addition, SHIP deficiency could intrinsically effect T reg homeostasis and function.…”

Subclinical GvHD in non-irradiated F1 hybrids: severe lymphoid-tissue GvHD causing prolonged immune dysfunction

“…The expansion of myeloid progenitor cells in these chimeras is reminiscent of the myeloid-derived suppressor cells described in association with myelosuppression, GvHD, tumors and chronic infections 21,29 where they have been implicated in tumor-specific and nonspecific T-cell dysfunction. [30][31][32] Our earlier data, 21 and more recently those of others, 33 suggest that these cells may have a role in controlling GvH reactivity. Whether they contribute in this model to confining GvH reactivity to the lymphohematopoietic system is the subject of ongoing investigations.…”