Graft-versus-leukemia (GVL) effect after allogeneic bone marrow transplantation (BMT) is a potent form immunotherapy with a potential for curing many hematological diseases. GVL is tightly linked to graft-versus- host disease (GVHD), the most frequent and severe complication of allogeneic BMT. Hence, improved understanding of the immunobiology in the efficacy (GVL) and the toxicity (GVHD) of allogeneic BMT will allow clinicians to better harness this powerful treatment modality. Several convergent lines of evidence have established a critical role for donor T cells in the induction of both GVHD and GVL. Recent data have demonstrated that direct allo-antigen presentation by host antigen presenting cells (APCs) is required for the induction of GVHD. Exciting preliminary data generated by us show that cross-presentation of tumor associated allo-antigens and / or tumor specific antigens by professional APCs is crucial for GVL responses. However, the nature of the antigen-specific responses induced by cross-presentation and whether these responses can be modulated to improve the anti-leukemic effect of allogeneic BMT is not known. In this proposal we will build on our exciting preliminary observations and test the central hypothesis that cross- presentation of antigens by host APCs can be modulated to enhance tumor specific responses of donor T cells and thus improve GVL. Specifically, we will systematically test the induction of allo-antigen and tumor specific antigen responses by APCs and determine whether strategies to enhance cross-presentation of tumor specific antigens will enhance GVL without exacerbating GVHD.
The specific aims of this proposal are:
Specific Aim 1 : To determine the role of direct and cross-presentation of antigens in the induction of antigen specific responses after allogeneic BMT.
Specific Aim 2 : To analyze the role of cross-presentation by host APCs in enhancing GVL responses without exacerbating GVHD after allogeneic BMT.PROJECT NARRATIVE Graft-versus-leukemia (GVL) effect after allogeneic bone marrow transplantation (BMT) is a potent form of immunotherapy with a potential for curing leukemia and other blood diseases. Unfortunately the beneficial GVL effect of allogeneic BMT is tightly linked to its severe complication, acute graft-versus-host disease (GVHD). Antigen presenting cells (APCs) are required for both GVHD and GVL. Our proposal aims to understand the role of APCs in these processes and if successful could pave way for separating GVL from GVHD.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL090775-05
Application #
8197524
Study Section
Transplantation, Tolerance, and Tumor Immunology (TTT)
Program Officer
Welniak, Lisbeth A
Project Start
2007-12-17
Project End
2013-06-05
Budget Start
2011-12-01
Budget End
2013-06-05
Support Year
5
Fiscal Year
2012
Total Cost
$371,626
Indirect Cost
$121,626
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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Choi, Sung Won; Braun, Thomas; Chang, Lawrence et al. (2014) Vorinostat plus tacrolimus and mycophenolate to prevent graft-versus-host disease after related-donor reduced-intensity conditioning allogeneic haemopoietic stem-cell transplantation: a phase 1/2 trial. Lancet Oncol 15:87-95
Toubai, Tomomi; Mathewson, Nathan; Reddy, Pavan (2014) The role of dendritic cells in graft-versus-tumor effect. Front Immunol 5:66
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Toubai, Tomomi; Sun, Yaping; Luker, Gary et al. (2013) Host-derived CD8+ dendritic cells are required for induction of optimal graft-versus-tumor responses after experimental allogeneic bone marrow transplantation. Blood 121:4231-41
Mathewson, Nathan; Toubai, Tomomi; Kapeles, Steven et al. (2013) Neddylation plays an important role in the regulation of murine and human dendritic cell function. Blood 122:2062-73
MacDonald, Kelli P; Shlomchik, Warren D; Reddy, Pavan (2013) Biology of graft-versus-host responses: recent insights. Biol Blood Marrow Transplant 19:S10-4
Sun, Yaping; Sun, John; Tomomi, Toubai et al. (2013) PU.1-dependent transcriptional regulation of miR-142 contributes to its hematopoietic cell-specific expression and modulation of IL-6. J Immunol 190:4005-13
Tawara, Isao; Sun, Yaping; Lewis, Eli C et al. (2012) Alpha-1-antitrypsin monotherapy reduces graft-versus-host disease after experimental allogeneic bone marrow transplantation. Proc Natl Acad Sci U S A 109:564-9
Reddy, Pavan (2012) Editorial: HDAC inhibition begets more MDSCs. J Leukoc Biol 91:679-81

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