We propose to develop non-toxic preclinical approaches for improving alloengraftment in patients sensitized by transfusion therapy using non-myeloablative conditioning regimen and conventional marrow cell dose. We noted that 2 Gy TBI permits uniform engraftment in rodents if anti CD154 mAb is infused. A major challenge continues to be engraftment of sensitized recipients given unrelated rather than matched sibling donor transplants. We have two basic hypotheses to explain why sensitized recipients are more likely to reject donor BM grafts: 1. T cell clonal size of host anti-donor T cells is substantially larger; 2. Costimulatory pathway dependency and requirements for memory host anti-donor alloreactive T cell expansion and function differ from those required for naive T cells. To overcome sensitization, we will need distinct types of approaches. The first will seek to reduce host anti-donor clonal T cell size by administering fludarabine or rapamycin. Because sufficient numbers of T cells may escape these pharmacological approaches, we will test cellular therapies to eliminate (veto) or suppress (CD4+25+) host anti-donor alloreactive T cell expansion. Although these approaches will reduce the graft rejection pool size, both effector/memory and newly generated naive T cells with alloreactive capacities will be able to respond to new antigenic challenge in the form of donor BM cells. Therefore, we will explore strategies to target T cell costimulatory pathways that may affect T cell expansion and/or function. We have developed new models to simultaneously track naive and effector/memory cell responses and alloantigen-specific CD4+ and CD8+ T cells capable of BM rejection. These studies will provide new insights into the immunobiology of graft rejection in sensitized recipients and led to innovative strategies to inhibit graft rejection that ultimately can be translated into the clinic.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL063452-06
Application #
6831196
Study Section
Special Emphasis Panel (ZRG1-ET-1 (02))
Program Officer
Di Fronzo, Nancy L
Project Start
1999-08-16
Project End
2007-11-30
Budget Start
2004-12-01
Budget End
2005-11-30
Support Year
6
Fiscal Year
2005
Total Cost
$371,250
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Pediatrics
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Blazar, B R; Flynn, R; Lee, R et al. (2015) Strategies to inhibit alloantibody production in alloprimed murine recipients of hematopoietic stem cell grafts. Am J Transplant 15:931-41
Taylor, Patricia A; Kelly, Ryan M; Bade, Nick D et al. (2012) FTY720 markedly increases alloengraftment but does not eliminate host anti-donor T cells that cause graft rejection on its withdrawal. Biol Blood Marrow Transplant 18:1341-52
Urbieta, Maite; Barao, Isabel; Jones, Monica et al. (2010) Hematopoietic progenitor cell regulation by CD4+CD25+ T cells. Blood 115:4934-43
Miller, Weston P; Srinivasan, Swetha; Panoskaltsis-Mortari, Angela et al. (2010) GVHD after haploidentical transplantation: a novel, MHC-defined rhesus macaque model identifies CD28- CD8+ T cells as a reservoir of breakthrough T-cell proliferation during costimulation blockade and sirolimus-based immunosuppression. Blood 116:5403-18
Sarantopoulos, Stefanie; Stevenson, Kristen E; Kim, Haesook T et al. (2009) Altered B-cell homeostasis and excess BAFF in human chronic graft-versus-host disease. Blood 113:3865-74
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Taylor, Patricia A; Ehrhardt, Michael J; Lees, Christopher J et al. (2008) TLR agonists regulate alloresponses and uncover a critical role for donor APCs in allogeneic bone marrow rejection. Blood 112:3508-16
Tian, Chaorui; Yuan, Xueli; Bagley, Jessamyn et al. (2008) Induction of transplantation tolerance by combining non-myeloablative conditioning with delivery of alloantigen by T cells. Clin Immunol 127:130-7
Tanaka, Katsunori; Albin, Monica J; Yuan, Xueli et al. (2007) PDL1 is required for peripheral transplantation tolerance and protection from chronic allograft rejection. J Immunol 179:5204-10
Serafini, Marta; Dylla, Scott J; Oki, Masayuki et al. (2007) Hematopoietic reconstitution by multipotent adult progenitor cells: precursors to long-term hematopoietic stem cells. J Exp Med 204:129-39

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