Mixed chimerism induces donor-specific tolerance. However, graft-versus-host disease (GVHD) and failure of engraftment have limited the clinical application of this approach. Depletion of marrow T-cells, or transplantation of highly purified hematopoietic stem cells (HSC) into allogeneic recipients avoids GVHD, but the risk of graft failure is substantially increased. Non-HSC bone marrow populations increase engraftment. Bone marrow T cells eliminate alloreactive host cells and thus increase HSC engraftment in partially conditioned recipients. However, T-cell alloreactivity may also result in the death of the host through graft-versus-host disease (GVHD). We have discovered, and two independent labs have confirmed, a novel CD8+TCR- cell in bone marrow that facilitates engraftment of highly purified HSC in allogeneic recipients. A novel receptor consisting of the TCRbeta chain, CD3epsilon and an FC-specific """"""""p33-FC"""""""" protein was recently discovered, and hypothesized to mediate direct HSC recognition by FC. Our preliminary gene-array analyses of CD8+TCR- FC revealed transcripts in common between FC and T cells, but only FC had message for TNFalpha. Moreover, our recent data indicate that FC from TNFalpha-/- mice are not functional. Our central hypothesis is that CD8+TCR- FC. unlike T cells, maintain long-term renewal of HSC through a TNFalpha-dependent mechanism, and that FC are derived from a common lymphoid progenitor (CLP) and as such share functional molecules with conventional T or NK cells, but are distinct from them. To test our hypothesis we will evaluate the role of FC and bone-marrow gamma and alphabeta+T-cells, and CD8alpha and CD8beta molecules in the maintenance of HSC long-term renewal in allogeneic engraftment. Moreover, we will determine the role of TNFalpha in FC-mediated engraftment and HSC survival through the use of mice deleted for TNFalpha and its receptors as a source of FC, HSC or as recipients in allogeneic transplantation. We will directly test the role of the FC in survival of HSC by 1) providing HSC with a transgenic-BCL2 survival molecule to determine if they become independent of FC in allogeneic transplantation, and 2) examining the cobblestone-area-forming capacity (CAFC) of HSC in marrow from mice we determine to be defective in FC function. Finally, we will use mice mutant for CD3epsilon, CD3delta, and CD3zeta in combination with lineage tracking of transplanted GFP-transgenic tagged HSC and lymphoid-progenitor cells to investigate the ontogeny of the FC and the biologic role of the CD3 complex in facilitation.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
3R01HL063442-03S1
Application #
6890850
Study Section
Hematology Subcommittee 2 (HEM)
Program Officer
Henslee-Downey, Jean
Project Start
2001-12-01
Project End
2005-11-30
Budget Start
2004-03-01
Budget End
2004-11-30
Support Year
3
Fiscal Year
2004
Total Cost
$52,920
Indirect Cost
Name
University of Louisville
Department
Surgery
Type
Schools of Medicine
DUNS #
057588857
City
Louisville
State
KY
Country
United States
Zip Code
40292
Xu, Hong; Yan, Jun; Zhu, Ziqiang et al. (2013) A critical role for the TLR4/TRIF pathway in allogeneic hematopoietic cell rejection by innate immune cells. Cell Transplant 22:2367-80
Xu, Hong; Ramsey, Deborah M; Wu, Shengli et al. (2013) Simultaneous bone marrow and composite tissue transplantation in rats treated with nonmyeloablative conditioning promotes tolerance. Transplantation 95:301-8
Xu, Hong; Zhu, Ziqiang; Huang, Yiming et al. (2012) Innate and adaptive immune responses are tolerized in chimeras prepared with nonmyeloablative conditioning. Transplantation 93:469-76
Leventhal, Joseph; Huang, Yiming; Xu, Hong et al. (2012) Novel regulatory therapies for prevention of Graft-versus-host disease. BMC Med 10:48
Cardenas, Paul A; Huang, Yiming; Ildstad, Suzanne T (2011) The role of pDC, recipient T(reg) and donor T(reg) in HSC engraftment: Mechanisms of facilitation. Chimerism 2:65-70
Wu, Shengli; Xu, Hong; Chen, Bo et al. (2011) Sensitized recipients exhibit accelerated but not hyperacute rejection of vascularized composite tissue allografts. Transplantation 92:627-33
Huang, Yiming; Bozulic, Larry D; Miller, Thomas et al. (2011) CD8α+ plasmacytoid precursor DCs induce antigen-specific regulatory T cells that enhance HSC engraftment in vivo. Blood 117:2494-505
Xu, H; Huang, Y; Hussain, L R et al. (2010) Sensitization to minor antigens is a significant barrier in bone marrow transplantation and is prevented by CD154:CD40 blockade. Am J Transplant 10:1569-79
Huang, Yiming; Kucia, Magda; Hussain, Lala-Rukh et al. (2010) Bone marrow transplantation temporarily improves pancreatic function in streptozotocin-induced diabetes: potential involvement of very small embryonic-like cells. Transplantation 89:677-85
Enzmann, Volker; Yolcu, Esma; Kaplan, Henry J et al. (2009) Stem cells as tools in regenerative therapy for retinal degeneration. Arch Ophthalmol 127:563-71

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