Our laboratory has had a long-standing interest in the biology of alloengraftment and development of methods to overcome resistance to engraftment of allogeneic stem cells. We hypothesize that the induction of stable mixed chimerism in sensitized nonmyeloablated recipients will be more readily achieved by manipulation of the immune rather than the hematopoietic system. We will utilize our expertise in conditioning regimens to design simulations in mice that are nontoxic and are directly extrapolatable to the clinic and immune strategies to prevent graft rejection and GVHD. Preclinical expts will be performed in well-established mouse models.
Our specific aims are:
Aim 1 : To develop novel nontoxic conditioning regimens using pharmacological agents that are myelotoxic or lymphotoxic, an irradiation-based approach that is selectively lymphotoxic and keratinocyte growth factor to reduce regimen- related toxicity;
Aim 2 : To develop novel donor hematopoietic strategies using flt3 ligand alone or with G-CSF to increase donor HSC without increasing GVHD;
Aim 3 : To determine which immune-based approaches will facilitate alloengraftment without GVHD by using photochemical treatment of the donor lymphocytes, pharmacological agents that affect lymphokine production or responses, antibodies that affect T cell signalling or delayed donor lymphocytes infusion to treat low level chimeras;
Aim 4 : To determine whether our murine protocol can be applied to the treatment of hemoglobinopathies in mice and to ensure engraftment without toxicity when our proposed sickle cell anemia patient trial in matched sibling donors is applied to a setting of presentized recipients of unrelated donor grafts Reagents chosen for analysis are in clinical trials in humans or are soon to be studied in clinical trials in BMT patients. At the conclusion of our study, we will have gained the necessary experience and generated the required data to rapidly translate our studies into the clinic.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL063452-02
Application #
6183981
Study Section
Special Emphasis Panel (ZHL1-CSR-O (M2))
Program Officer
Badman, David G
Project Start
1999-08-16
Project End
2003-07-31
Budget Start
2000-08-01
Budget End
2001-07-31
Support Year
2
Fiscal Year
2000
Total Cost
$294,000
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Pediatrics
Type
Schools of Medicine
DUNS #
168559177
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
Tchorsh-Yutsis, Dalit; Hecht, Gil; Aronovich, Anna et al. (2009) Pig embryonic pancreatic tissue as a source for transplantation in diabetes: transient treatment with anti-LFA1, anti-CD48, and FTY720 enables long-term graft maintenance in mice with only mild ongoing immunosuppression. Diabetes 58:1585-94
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
Orchard, Paul J; Blazar, Bruce R; Wagner, John et al. (2007) Hematopoietic cell therapy for metabolic disease. J Pediatr 151:340-6
Taylor, Patricia A; Ehrhardt, Michael J; Roforth, Matthew M et al. (2007) Preformed antibody, not primed T cells, is the initial and major barrier to bone marrow engraftment in allosensitized recipients. Blood 109:1307-15

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