Over the past five years, this group of investigators has made significant progress in establishing the tolerance induction regimen which utilizes allogeneic hematopoietic cell transplantation in patients conditioned with a non-myeloablative conditioning regimen of total lymphoid irradiation (TLI) and antithymocyte globulin (ATG). This regimen has proven safe and human leukocyte antigen (HLA)-matched allogeneic cells can engraft without the development of graft-versus-host disease (GVHD). Two interrelated issues emerge as a major challenge to applying this tolerance induction strategy to a broader group of patients. The first obstacle is the need to liberalize the genetic matching between donor and recipient pairs, and the second is resistance to engraftment of allogeneic hematopoietic stem cells. Concerns of GVHD can be set aside even in completely genetic mismatched pairs if rigorously depleted T cell grafts are used. However, resistance to hematopoietic cell engraftment increases as the T cell content within the graft is reduced. Furthermore, engraftment resistance increases with greater genetic differences between donor/recipient pairs. The overall goal of this project is to understand the barrier to hematopoietic cell engraftment in mice conditioned for transplantation with TLI/ATG, and develop strategies that can be translated to the clinical studies in Project I to achieve improved engraftment outcomes. It is notable that when compared to other standard conditioning regimens, a unique feature of the TLI/ATG conditioning is that there is a relative increase in the number of regulatory lymphoid populations, including both the natural killer- T (NK-T) and CD4[+] CD25[+] FoxP3[+] (Tregs) subsets. Preliminary data suggest that regulatory lymphoid cells are required to achieve successful engraftment in TLI/ATG conditioned hosts. Thus, this project has three specific aims.
Specific Aim 1 : To study the cellular barriers to engraftment of allogeneic hematopoietic cells in recipient mice conditioned with a non-myeloablative regimen of TLI/ATG.
Specific Aim #2 : To identify cells that can facilitate engraftment of purified HSC without eliciting GVHD in mice conditioned with a nonmyeloablative regimen of TLI/ATG.
Specific Aim 3 : To determine if homologous subsets of facilitating cells identified in Aim #2 exist in human mobilized peripheral blood.

Public Health Relevance

Project 2 will study the way transplanted blood stem cells are rejected by recipients that have been prepared to accept the blood cell grafts by a non-lethal conditioning regimen. The studies have relevance to all patients undergoing blood stem cell transplantation from a donor as graft rejection is a potential problem. Most importantly, these studies can lead to a safer way of performing blood stem cell trans- plantations and thereby expand the use of such transplantations to non-cancerous conditions such as autoimmune disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL075462-09
Application #
8470683
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
9
Fiscal Year
2013
Total Cost
$266,439
Indirect Cost
$99,915
Name
Stanford University
Department
Type
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
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Alonso, Michael N; Gregorio, Josh G; Davidson, Matthew G et al. (2014) Depletion of inflammatory dendritic cells with anti-CD209 conjugated to saporin toxin. Immunol Res 58:374-7
Strober, Samuel (2014) Path to clinical transplantation tolerance and prevention of graft-versus-host disease. Immunol Res 58:240-8
Medeiros, B C; Tian, L; Robenson, S et al. (2014) European LeukemiaNet classification intermediate risk-1 cohort is associated with poor outcomes in adults with acute myeloid leukemia undergoing allogeneic hematopoietic cell transplantation. Blood Cancer J 4:e216
Sega, Emanuela I; Leveson-Gower, Dennis B; Florek, Mareike et al. (2014) Role of lymphocyte activation gene-3 (Lag-3) in conventional and regulatory T cell function in allogeneic transplantation. PLoS One 9:e86551
Hongo, D; Tang, X; Baker, J et al. (2014) Requirement for interactions of natural killer T cells and myeloid-derived suppressor cells for transplantation tolerance. Am J Transplant 14:2467-77
Schneidawind, Dominik; Pierini, Antonio; Negrin, Robert S (2013) Regulatory T cells and natural killer T cells for modulation of GVHD following allogeneic hematopoietic cell transplantation. Blood 122:3116-21
Colonna, Lucrezia; Florek, Mareike; Leveson-Gower, Dennis B et al. (2013) IL-17 gene ablation does not impact Treg-mediated suppression of graft-versus-host disease after bone marrow transplantation. Biol Blood Marrow Transplant 19:1557-65
Davidson, Matthew G; Alonso, Michael N; Kenkel, Justin A et al. (2013) In vivo T cell activation induces the formation of CD209(+) PDL-2(+) dendritic cells. PLoS One 8:e76258
Kohrt, Holbrook E; Tian, Lu; Li, Li et al. (2013) Identification of gene microarray expression profiles in patients with chronic graft-versus-host disease following allogeneic hematopoietic cell transplantation. Clin Immunol 148:124-35

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