We previously demonstrated that SHIP expression is necessary for rejection of allogeneic BM grafts(1) and the GvHD that limits the utility of such transplants.(1,2) We have recently shown that induction of SHIP-deficiency for a one week period prior to allogeneic BMT is sufficient to protect a recipient from acute GvHD.(3) Host antigen presenting cells (APC) are responsible for triggering allogeneic T cell responses(4) that mediate GVHD.(5) A profound expansion of Myeloid Suppressor Cells (MySC) in the peripheral lymphoid organs of SHIP-/- mice antagonizes APC priming of allgeneic T cell responses (2,3). We have recently shown that purified SHIP-/- MySC have greater suppressive capacity than WT MySC.(3) In addition, we have shown that Treg cell numbers and function are increased in germline SHIP-deficient mice and mice with induced SHIP- deficiency. We hypothesize then that increased MySC and/or Treg cell function in SHIP-deficient transplant recipients protects them from GvHD and may also reduce solid organ allograft rejection. We have recently established lineage-specific SHIP deletion models for both myeloid cells and T cells. We will now determine whether myeloid- or T cell-restricted ablation of SHIP expression in transplant recipients is sufficient to abrogate acute GvHD (Aim 1). Having recently established an inducible flox/flox SHIP deletion model (MxCreSHIP ) and demonstrated that this is an effective system in which we can protect adult recipients from GvHD in a myeloablative transplant, we will now determine whether induced SHIP-deficiency is also protective from GvHD with other allogeneic BMT procedures (Aim 2).
In Aim 3, we will use the MX-CreSHIP model and RNAi targeting of SHIP to determine whether induced SHIP deficiency can enhance the success of allogeneic organ transplantation. We have also developed RNAi approaches to reversibly inhibit SHIP expression in vivo. RNAi targeting of SHIP expression will also be tested in Aim 2 for its ability to protect recipients from GvHD and in Aim 3 to determine if it can facilitate engraftment of solid organ allografts.
The Specific Aims are:
Aim 1 : Define the SHIP-deficient cell lineages required for host protection from GvHD.
Aim 2 : Define the manner in which SHIP-deficiency can be used to enhance allogeneic BM transplantation.
Aim 3 : Determine whether SHIP-deficiency can facilitate the transplantation of allogeneic organ grafts.

Public Health Relevance

We believe these studies will demonstrate that turning off one specific gene can prevent the rejection of transplanted bone marrow and organs that are not matched to the recipient. In addition, these studies will identify the types of immune cell types required for acceptance of these unmatched transplants.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL085580-04
Application #
8136047
Study Section
Hematopoiesis Study Section (HP)
Program Officer
Di Fronzo, Nancy L
Project Start
2008-09-24
Project End
2013-08-31
Budget Start
2011-09-01
Budget End
2013-08-31
Support Year
4
Fiscal Year
2011
Total Cost
$355,750
Indirect Cost
Name
Upstate Medical University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
058889106
City
Syracuse
State
NY
Country
United States
Zip Code
13210
Somasundaram, Rajesh; Fernandes, Sandra; Deuring, Jasper J et al. (2017) Analysis of SHIP1 expression and activity in Crohn's disease patients. PLoS One 12:e0182308
Park, Mi Young; Sudan, Raki; Srivastava, Neetu et al. (2016) LRBA is Essential for Allogeneic Responses in Bone Marrow Transplantation. Sci Rep 6:36568
Srivastava, Neetu; Iyer, Sonia; Sudan, Raki et al. (2016) A small-molecule inhibitor of SHIP1 reverses age- and diet-associated obesity and metabolic syndrome. JCI Insight 1:
Iyer, Sonia; Brooks, Robert; Gumbleton, Matthew et al. (2015) SHIP1-expressing mesenchymal stem cells regulate hematopoietic stem cell homeostasis and lineage commitment during aging. Stem Cells Dev 24:1073-81
Anderson, Courtney K; Salter, Alexander I; Toussaint, Leon E et al. (2015) Role of SHIP1 in Invariant NKT Cell Development and Functions. J Immunol 195:2149-2156
Lind, Evan F; Millar, Douglas G; Dissanayake, Dilan et al. (2015) miR-155 Upregulation in Dendritic Cells Is Sufficient To Break Tolerance In Vivo by Negatively Regulating SHIP1. J Immunol 195:4632-40
Blanco-Menéndez, Noelia; Del Fresno, Carlos; Fernandes, Sandra et al. (2015) SHIP-1 Couples to the Dectin-1 hemITAM and Selectively Modulates Reactive Oxygen Species Production in Dendritic Cells in Response to Candida albicans. J Immunol 195:4466-4478
Brooks, R; Iyer, S; Akada, H et al. (2015) Coordinate expansion of murine hematopoietic and mesenchymal stem cell compartments by SHIPi. Stem Cells 33:848-58
Fernandes, Sandra; Brooks, Robert; Gumbleton, Matthew et al. (2015) SHIPi Enhances Autologous and Allogeneic Hematolymphoid Stem Cell Transplantation. EBioMedicine 2:205-213
Russo, Christopher M; Adhikari, Arijit A; Wallach, Daniel R et al. (2015) Synthesis and initial evaluation of quinoline-based inhibitors of the SH2-containing inositol 5'-phosphatase (SHIP). Bioorg Med Chem Lett 25:5344-8

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