Graft versus host disease (GVHD) is the major limitation to the widespread utilization of allogeneic stem cell transplantation in the treatment of patients with hematological malignancies, solid tumors, bone marrow failure syndromes and congenital diseases. GVHD is mediated by alloreactive donor T cells that recognize major or minor histocompatibility antigens presented by recipient antigen presenting cells. This process leads to a cascade of events that generate proinflammatory cytokines and causes the destruction of recipient cells. The expansion of alloreactive T cells is controlled both by homeostatic proliferation and regulatory T cells. CD4+/CD25+ Treg cells have been shown to be capable of inhibiting GVHD in multiple different murine models and the expansion of these cells for clinical use is feasible. However, little is known about the mechanism of activity of Treg cells in the prevention of GVHD. Whether Treg cells function to suppress alloreactive T cell proliferation in secondary lymphoid tissue or GVHD target organs is not known. The proteins responsible for the migration of Treg cells into secondary lymphoid tissue have not been demonstrated and the affect of blocking the function of the migration of Treg cells is not clear Our group has recently found that the administration of Treg cells that express L-selectin potently inhibited GVHD while Lselectinlo Treg cells had little effect. Additionally, we have recently shown that Treg cells express a different pattern of chemokine receptors after activation, that the chemokine receptor, CCR5, is markedly increased after activation, and that the absence of CCR5 on donor T cells markedly increased the severity of GVHD in irradiated recipient animals. In this proposal, we will investigate the migration of Treg cells in GVHD models. The following three specific aims will be evaluated:
Aim 1) : To evaluate the function of L-selectin, CCR5 and CCR7 in the migration of Treg cells into secondary lymphoid organs.
Aim 2) : To evaluate if Treg cells migrate to parenchymal organs in which GVHD occurs in vivo and if this migration is dependent on the expression of chemokine receptors such as CCR4, CCR5 or CCR8.
Aim 3) : (a) To determine if Treg cell function in GVHD models is dependent on migration to SLT. (b) To determine if the migration of Treg cells is dependent on the presence of Peyer's patches (PP) or the spleen. The overall goals of this work are to provide a better understanding of the mechanism of activity of Treg cells prior to a clinical trial evaluating their effects in blocking GVHD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI064363-02
Application #
7035261
Study Section
Transplantation, Tolerance, and Tumor Immunology (TTT)
Program Officer
Koh, Crystal Y
Project Start
2005-04-01
Project End
2009-12-31
Budget Start
2006-01-01
Budget End
2006-12-31
Support Year
2
Fiscal Year
2006
Total Cost
$383,411
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Lin, Kaifeng Lisa; Fulton, LeShara M; Berginski, Matthew et al. (2014) Intravital imaging of donor allogeneic effector and regulatory T cells with host dendritic cells during GVHD. Blood 123:1604-14
Fulton, LeShara M; Taylor, Nicholas A; Coghill, James M et al. (2014) Altered T-cell entry and egress in the absence of Coronin 1A attenuates murine acute graft versus host disease. Eur J Immunol 44:1662-71
Coghill, James M; Fowler, Kenneth A; West, Michelle L et al. (2013) CC chemokine receptor 8 potentiates donor Treg survival and is critical for the prevention of murine graft-versus-host disease. Blood 122:825-36
Fulton, LeShara M; Carlson, Michael J; Coghill, James M et al. (2012) Attenuation of acute graft-versus-host disease in the absence of the transcription factor ROR?t. J Immunol 189:1765-72
Coghill, James M; Sarantopoulos, Stefanie; Moran, Timothy P et al. (2011) Effector CD4+ T cells, the cytokines they generate, and GVHD: something old and something new. Blood 117:3268-76
Carlson, M J; Fulton, L M; Coghill, J M et al. (2010) L-selectin is dispensable for T regulatory cell function postallogeneic bone marrow transplantation. Am J Transplant 10:2596-603
Coghill, James M; Carlson, Michael J; Panoskaltsis-Mortari, Angela et al. (2010) Separation of graft-versus-host disease from graft-versus-leukemia responses by targeting CC-chemokine receptor 7 on donor T cells. Blood 115:4914-22
Carlson, Michael J; West, Michelle L; Coghill, James M et al. (2009) In vitro-differentiated TH17 cells mediate lethal acute graft-versus-host disease with severe cutaneous and pulmonary pathologic manifestations. Blood 113:1365-74
Wysocki, Christian A; Jiang, Qi; Panoskaltsis-Mortari, Angela et al. (2005) Critical role for CCR5 in the function of donor CD4+CD25+ regulatory T cells during acute graft-versus-host disease. Blood 106:3300-7