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.
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.
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|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|
|Simonetta, Federico; Alvarez, Maite; Negrin, Robert S (2017) Natural Killer Cells in Graft-versus-Host-Disease after Allogeneic Hematopoietic Cell Transplantation. Front Immunol 8:465|
|Zhang, Hong; Gregorio, Josh D; Iwahori, Toru et al. (2017) A distinct subset of plasmacytoid dendritic cells induces activation and differentiation of B and T lymphocytes. Proc Natl Acad Sci U S A 114:1988-1993|
|Chen, Yi-Bin; Efebera, Yvonne A; Johnston, Laura et al. (2017) Increased Foxp3+Helios+Regulatory T Cells and Decreased Acute Graft-versus-Host Disease after Allogeneic Bone Marrow Transplantation in Patients Receiving Sirolimus and RGI-2001, an Activator of Invariant Natural Killer T Cells. Biol Blood Marrow Transplant 23:625-634|
|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|
|Mavers, Melissa; Maas-Bauer, Kristina; Negrin, Robert S (2017) Invariant Natural Killer T Cells As Suppressors of Graft-versus-Host Disease in Allogeneic Hematopoietic Stem Cell Transplantation. Front Immunol 8:900|
|Revelo, Xavier S; Ghazarian, Magar; Chng, Melissa Hui Yen et al. (2016) Nucleic Acid-Targeting Pathways Promote Inflammation in Obesity-Related Insulin Resistance. Cell Rep 16:717-30|
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