The application of allogeneic bone marrow transplantation (BMT) has been impeded by the development of its severe complication, acute graft-versus-host disease (GVHD). Alloreactive donor T cells are critical for causing GVHD. Naturally occurring thymic derived donor CD4+CD25+Foxp3+ regulatory T cells (Tregs) suppress experimental GVHD. However the mechanism of GVHD suppression by the donor Tregs is not well understood. Several recent observations have also brought in a renewed focus on the role of host professional antigen presenting cells (APCs) in the induction and maintenance of GVHD. But the role of APCs in modulating the responses of Tregs after allogeneic BMT is not known. The central premise of this proposal is that host APCs are critical for the induction, function and regulation of Treg mediated suppression of GVHD. In this proposal we will build on our exciting preliminary observations that demonstrate a requirement of APCs in Treg mediated reduction of GVHD.
The specific aims of this proposal are:
Specific Aim 1 : To determine the requirement of APCs in induction of donor type natural CD4+CD25+Foxp3+ regulatory T cells (Tregs) mediated regulation of GVHD.
Specific Aim 2 : To analyze the role of APCs in modulating the function of Tregs as determined by the suppression of GVHD.
Specific Aim 3 : To elucidate the critical cellular and molecular mechanisms for the positive and negative regulation of Treg mediated reduction in GVHD by the APCs. Allogeneic bone marrow transplantation (BMT) is a curative therapy for a number of blood diseases. However, the application of this effective therapy has been impeded by the development of its most severe complication, graft-versus-host disease (GVHD). Our proposal aims to understand the underlying mechanisms of interaction between various immune cells that are critical for GVHD. If successful, this could reduce GVHD and make allogeneic BMT safer.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI075284-05
Application #
8287166
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Nabavi, Nasrin N
Project Start
2008-07-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2014-06-30
Support Year
5
Fiscal Year
2012
Total Cost
$364,230
Indirect Cost
$119,205
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
Tawara, Isao; Liu, Chen; Tamaki, Hiroya et al. (2013) Influence of donor microbiota on the severity of experimental graft-versus-host-disease. Biol Blood Marrow Transplant 19:164-8
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
Tawara, Isao; Sun, Yaping; Liu, Chen et al. (2012) Donor- but not host-derived interleukin-10 contributes to the regulation of experimental graft-versus-host disease. J Leukoc Biol 91:667-75
Toubai, Tomomi; Tawara, Isao; Sun, Yaping et al. (2012) Induction of acute GVHD by sex-mismatched H-Y antigens in the absence of functional radiosensitive host hematopoietic-derived antigen-presenting cells. Blood 119:3844-53
Reddy, Pavan; Socie, Gerard; Cutler, Corey et al. (2012) GVHD prevention: an ounce is better than a pound. Biol Blood Marrow Transplant 18:S17-26

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