Abstract

This project is based on a recent observation that osteoblasts are a regulatory component of thehematopoietic stem cell niche and can be targeted as a means to increase stem cell numbers. Activation ofthe parathyroid hormone (PTH)/parathyroid related hormone receptor (PPR) resulted in Notch pathwayactivation and thereby expansion of hematopoietic stem cells in a mouse model. This was accompanied by amarked improvement in animal survival following bone marrow transplantation with limiting numbers ofhematopoietic stem cells. This project will assess the potential for extending this model to a clinical contextby pursuing the following specific aims:
Aim 1 : Define whether stimulation of the stem cell niche with PTH can result in improved donor stem cellharvests.
Aim 2 : Determine if manipulation of the graft or niche can affect the kinetics of immune recovery.
Aim 3 : Determine if ex vivo manipulation of the graft and the niche can synergistically increase stem cellengraftment efficiency.Accomplishment of these aims depends upon the clinical and large animal components of this ProgramProject and would not be achievable without the PO1 mechanism. Successful completion of this project willprovide critical information about the value of using PTH specifically and targeting the stem cell niche moregenerally in stem cell based therapies for human disease.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
1P01CA111519-01A2
Application #
7158102
Study Section
Subcommittee G - Education (NCI)
Project Start
2006-07-01
Project End
2011-06-30
Budget Start
2006-09-12
Budget End
2007-07-31
Support Year
1
Fiscal Year
2006
Total Cost
$59,030
Indirect Cost

  Institution

Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199

  Publications

Sykes, Megan (2018) Immune monitoring of transplant patients in transient mixed chimerism tolerance trials. Hum Immunol 79:334-342
Buchan, Sarah; Manzo, Teresa; Flutter, Barry et al. (2015) OX40- and CD27-mediated costimulation synergizes with anti-PD-L1 blockade by forcing exhausted CD8+ T cells to exit quiescence. J Immunol 194:125-133
La Muraglia 2nd, G M; O'Neil, M J; Madariaga, M L et al. (2015) A novel approach to measuring cell-mediated lympholysis using quantitative flow and imaging cytometry. J Immunol Methods 427:85-93
Li, Hao Wei; Andreola, Giovanna; Carlson, Alicia L et al. (2015) Rapid Functional Decline of Activated and Memory Graft-versus-Host-Reactive T Cells Encountering Host Antigens in the Absence of Inflammation. J Immunol 195:1282-92
Matar, Abraham J; Patil, Aarti R; Al-Musa, Ahmad et al. (2015) Effect of Irradiation on Incidence of Post-Transplant Lymphoproliferative Disorder after Hematopoietic Cell Transplantation in Miniature Swine. Biol Blood Marrow Transplant 21:1732-8
Sykes, M (2015) Immune tolerance in recipients of combined haploidentical bone marrow and kidney transplantation. Bone Marrow Transplant 50 Suppl 2:S82-6
Duran-Struuck, Raimon; Huang, Christene A; Orf, Katherine et al. (2015) Miniature Swine as a Clinically Relevant Model of Graft-Versus-Host Disease. Comp Med 65:429-43
Wang, Hui; Yang, Yong-Guang (2014) The complex and central role of interferon-? in graft-versus-host disease and graft-versus-tumor activity. Immunol Rev 258:30-44
Leonard, D A; Kurtz, J M; Mallard, C et al. (2014) Vascularized composite allograft tolerance across MHC barriers in a large animal model. Am J Transplant 14:343-55
Wang, Yi; Wang, Hui; Xia, Jinxing et al. (2013) Activated CD8 T cells acquire NK1.1 expression and preferentially locate in the liver in mice after allogeneic hematopoietic cell transplantation. Immunol Lett 150:75-8

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