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; Nishikii, Hidekazu; Baker, Jeanette et al. (2017) Foxp3+ regulatory T cells maintain the bone marrow microenvironment for B cell lymphopoiesis. Nat Commun 8:15068
Hongo, David; Tang, Xiaobin; Zhang, Xiangyue et al. (2017) Tolerogenic interactions between CD8+ dendritic cells and NKT cells prevent rejection of bone marrow and organ grafts. Blood 129:1718-1728
Du, Jing; Paz, Katelyn; Thangavelu, Govindarajan et al. (2017) Invariant natural killer T cells ameliorate murine chronic GVHD by expanding donor regulatory T cells. Blood 129:3121-3125
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
Nishikii, Hidekazu; Kim, Byung-Su; Yokoyama, Yasuhisa et al. (2016) DR3 signaling modulates the function of Foxp3+ regulatory T cells and the severity of acute graft-versus-host disease. Blood 128:2846-2858
Penny, Hweixian Leong; Prestwood, Tyler R; Bhattacharya, Nupur et al. (2016) Restoring Retinoic Acid Attenuates Intestinal Inflammation and Tumorigenesis in APCMin/+ Mice. Cancer Immunol Res 4:917-926
Strober, Samuel (2016) Use of hematopoietic cell transplants to achieve tolerance in patients with solid organ transplants. Blood 127:1539-43
Erickson, K F; Winkelmayer, W C; Busque, S et al. (2016) A Cost Analysis of Tolerance Induction for Two-Haplotype Match Kidney Transplant Recipients. Am J Transplant 16:371-3
Pierini, Antonio; Strober, William; Moffett, Caitlin et al. (2016) TNF-? priming enhances CD4+FoxP3+ regulatory T-cell suppressive function in murine GVHD prevention and treatment. Blood 128:866-71
Müller, Antonia M S; Florek, Mareike; Kohrt, Holbrook E K et al. (2016) Blood Stem Cell Activity Is Arrested by Th1-Mediated Injury Preventing Engraftment following Nonmyeloablative Conditioning. J Immunol 197:4151-4162

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