Allogeneic stem cell transplantation (alloSCT) can cure hematologic malignancies and nonmalignant disorders of hematopoiesis. Allograft T cells are critical for T cell reconstitution and mediate a potent anti- leukemia/lymphoma effect. Unfortunately donor T cells can broadly attack the recipient causing graft-vs-host disease (GVHD). Methods of promoting the positive effects of donor T cells while minimizing GVHD have been elusive. Much GVHD research has focused on how antigen presenting cells (APCs) initially prime donor T cells in secondary lymphoid tissues (SLTs). However, APCs are not limited to SLTs. Tissue infiltrative APCs (t-APCs) that are resident and are recruited during inflammation play important roles in anti-pathogen and autoimmune responses. t-APCs are heterogeneous in function and ontogeny, differ from organ to organ, and with inflammation. They interact with T cells in situ and can traffic to draining lymph nodes where they can prime T cells or transfer antigen to other APCs. While T cells are required for GVHD, cellular infiltrates in organs with GVHD have abundant MHCII+ t-APCs. Consistent with a role for t-APCs in GVHD, CD4 cells can mediate GVHD indirectly, without making TCR:MHCII contacts with target tissues;histology in these mice reveal CD4 cells adjacent to MHCII+ hematopoietic cells. We hypothesize that T cells in GVHD lesions are activated locally by t-APCs and that conversely t-APCs are activated by donor T cells. In support of this hypothesis we have employed multiphoton intravital microscopy (MPIM) of GVHD tissues in living mice to demonstrate that donor CD4+ and CD8+ T cells make stable interactions with donor-derived CD11c+ or LysM+ cells. A detailed understanding of the interactions between T cells and t-APCs should identify new targets for suppressing GVHD. We propose to investigate t-APCs in GVHD using novel fluorescent protein-transgenic mice, bone marrow from mice in which t-APC subsets can be inducibly deleted and MPIM. Specifically we will: 1) define the identities of t-APCs in GVHD and determine how those cells are recruited;2) test the hypothesis that T cells make antigen-specific stable interactions with t-APCs in skin and bowel affected by GVHD;and 3) determine whether these interactions contribute to GVHD.

Public Health Relevance

Blood stem cell transplantation from a sibling or unrelated donor is often the only curative option for patients with cancers of blood cells and inherited disorders of blood cells such as sickle cell anemia. Much of the anticancer effect is mediated by immune cells from the donor;however they can also attack normal tissues in the patient, such as the skin and intestines. The goal of this work is to better understand how immune cells cause damage in tissues, so that this attack can be mitigated, while preserving the anti-cancer effect.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL083072-07
Application #
8293033
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Welniak, Lisbeth A
Project Start
2005-12-01
Project End
2016-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
7
Fiscal Year
2012
Total Cost
$415,000
Indirect Cost
$165,000
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
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Li, Hongmei; Matte-Martone, Catherine; Tan, Hung Sheng et al. (2011) Graft-versus-host disease is independent of innate signaling pathways triggered by pathogens in host hematopoietic cells. J Immunol 186:230-41
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