Allogeneic stem cell transplantation (Allo-SCT) remains the most active therapy for patients with high risk acute leukemia, low grade lymphoid malignancies, myelodysplastic syndromes and is increasingly used in patients with relapsed lymphoid malignancies. However, only 25-30% of patients who could benefit from allo-SCT receive this therapy due to the risk of graft-versus-host disease (GvHD) in patients undergoing transplantation across greater than a two antigen MHC barrier. The most common site of involvement for patients with acute GvHD is the skin. Similarly, the most common site of involvement in patients with chronic GvHD is the skin with fibrotic, sclerodermatous changes associated with significant long term morbidity. While donor T cells are critically required for th occurrence of GvHD, the exact role played by these cells in the effector processes during acute and chronic GvHD is not clear. Previous work had suggested that GvHD was mediated by Th1/Tc1 T cells, although conflicting data using mice unable to generate or respond to IFN-? has been published. Over the past decade, multiple new subsets of T cells have been described. Additionally, the previous notion that T cell lineages are fixed has been challenged by data from our group and others suggesting that epigenetic alterations of critical transcription factors (TFs) can modulate T cell lineages. Specifically, our group and others have found that Th17 cells in the presence of IL-12 become Th1 cells. These findings provide a new opportunity to reexamine the role of specific T cell subsets in the pathophysiology of acute and chronic GvHD. In this proposal, we will evaluate the hypothesis that the initial polarization of donor T cells in host lymphoid tissue is toward the Th17 lineage mediated by the elaboration of IL-6, IL-1? and TNF after receipt of conditioning therapy. Subsequently, the elaboration of IL-12 by host cells leads to a switch to Th1 polarization and the migration of these cells to GvHD target organs. Additionally, we will evaluate the phenotype of T cell responsible for inflammation in the skin during acute and chronic GvHD. We hypothesize that acute GvHD involving the skin is mediated by Th1/Th17 cells that recruit M1 macrophages while chronic GvHD is mediated by Th17/Th22 cells that recruit M2 macrophages and fibroblasts. We will focus on factors important for the recruitment of these cells to the skin. Furthermore, we will determine if blocking the function or migration of T cell subsets or particular populations of macrophages provides a new approach for the therapy of cutaneous acute and chronic GvHD.

Public Health Relevance

The transplantation of stem cells or bone marrow from one individual to another is a standard approach for the treatment of acute leukemia, bone marrow failure problems and lymphoid malignancies. However, this process is limited by the immune reactivity of donor cells against the host termed graft-versus-host disease (GvHD). The role that particular groups of T cells play in the occurrence of acute and chronic graft-versus-host disease (GvHD) is not clear. The focus of this proposal is to understand the role that T cell subsets play in the occurrence of acute and chronic GvHD with a particular focus on the pathophysiology of GvHD in the skin.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA166794-02
Application #
8468145
Study Section
Transplantation, Tolerance, and Tumor Immunology (TTT)
Program Officer
Mccarthy, Susan A
Project Start
2012-05-09
Project End
2017-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
2
Fiscal Year
2013
Total Cost
$290,781
Indirect Cost
$94,307
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
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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
Allen, Jessica L; Tata, Prasanthi V; Fore, Matthew S et al. (2014) Increased BCR responsiveness in B cells from patients with chronic GVHD. Blood 123:2108-15
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