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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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Heart, Lung, and Blood Initial Review Group (HLBP)
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Stanford University
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Pierini, Antonio; Strober, William; Moffett, Caitlin et al. (2016) TNF-α priming enhances CD4+FoxP3+ regulatory T-cell suppressive function in murine GVHD prevention and treatment. Blood 128:866-71
Strober, Samuel (2016) Use of hematopoietic cell transplants to achieve tolerance in patients with solid organ transplants. Blood 127:1539-43
Pierini, Antonio; Alvarez, Maite; Negrin, Robert S (2016) NK Cell and CD4+FoxP3+ Regulatory T Cell Based Therapies for Hematopoietic Stem Cell Engraftment. Stem Cells Int 2016:9025835
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Pierini, Antonio; Colonna, Lucrezia; Alvarez, Maite et al. (2015) Donor Requirements for Regulatory T Cell Suppression of Murine Graft-versus-Host Disease. J Immunol 195:347-55
Pan, Yuqiong; Leveson-Gower, Dennis B; de Almeida, Patricia E et al. (2015) Engraftment of embryonic stem cells and differentiated progeny by host conditioning with total lymphoid irradiation and regulatory T cells. Cell Rep 10:1793-802
Kim, Byung-Su; Nishikii, Hidekazu; Baker, Jeanette et al. (2015) Treatment with agonistic DR3 antibody results in expansion of donor Tregs and reduced graft-versus-host disease. Blood 126:546-57
Pierini, Antonio; Schneidawind, Dominik; Nishikii, Hidekazu et al. (2015) Regulatory T Cell Immunotherapy in Immune-Mediated Diseases. Curr Stem Cell Rep 1:177-186
Schneidawind, Dominik; Baker, Jeanette; Pierini, Antonio et al. (2015) Third-party CD4+ invariant natural killer T cells protect from murine GVHD lethality. Blood 125:3491-500

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