Graft-versus host disease (GVHD) is a major complication in recipients of allogeneic hematopoietic cell transplants (HCT). This procedure can be life saving for otherwise fatal disease, however GVHD is associated with significant morbidity and mortality. Fortunately, immunological tolerance occurs in a majority of patients despite the.development of acute and chronic GVHD. Immune suppression therapy (1ST) is administered to all patients at the time of transplantation, but the duration of therapy is variable. Some patients can be withdrawn from 1ST within 6 months of HCT, but most require 1ST for 2-3 years. Potential mechanisms for achieving peripheral tolerance include clonal deletion or exhaustion through activation-induced cell death, development of clonal anergy or non-responsiveness, and development of regulatory T cells (Treg) that suppress the immune response. Preliminary data shows that Treg expressing the CD4+CD25+CD12710 phenotype are decreased in the blood of patients with active chronic GVHD (cGVHD) on 1ST,and they tend to increase in patients with resolving cGVHD. Expression of the FoxpS gene, a functional marker for regulatory T cells, is also decreased in patients with active cGVHD, but expression levels tend to increase in tolerant patients. There are also other genes associated with immune regulation such as IL10 that are found variably expressed in cGVHD patients. There are also genes associated with T cell responder and effector functions such as IFNG and IL17 that are variably expressed in patients with active GVHD and patients receiving 1ST.These preliminary data lead us to test the hypothesis that multiple regulatory mechanisms are required for the control of GVHD. We will use micro array technology for the assessment of global gene expression and address the following questions: (i) identify the transcriptional profiles of T lymphocytes and selected subsets from HCT patients that are associated with the different stages of cGVHD and with 1ST,and identify the genes and pathways that distinguish patients with active cGVHD from patients achieving immunological tolerance;and (ii) determine the functional characteristics and regenerative capacity of regulatory T cells in patients with active and quiescent cGVHD and tolerant patients. Insight into the cellular changes occurring in patients with active and resolving cGVHD may lead to better methods for monitoring GVHD activity and guiding the use of 1ST,and suggest new strategies for facilitating the induction of tolerance.

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The number of patients receiving allogeneic hematopoietic cell transplants and surviving otherwise fatal disease continues to increase, however many of these patients continue to suffer from GVHD. The studies proposed here are aimed at understanding the factors responsible for ongoing GVHD and the mechanisms responsible for immunological tolerance. Understanding these processes may lead to more effective therapeutic interventions, and improve the quality of life and health of transplant survivors.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
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Special Emphasis Panel (ZAI1-SV-I)
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Fred Hutchinson Cancer Research Center
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Warren, E H; Deeg, H J (2013) Dissecting graft-versus-leukemia from graft-versus-host-disease using novel strategies. Tissue Antigens 81:183-93
Hansen, John A; Hanash, Samir M; Tabellini, Laura et al. (2013) A novel soluble form of Tim-3 associated with severe graft-versus-host disease. Biol Blood Marrow Transplant 19:1323-30
Warren, Edus H; Matsen 4th, Frederick A; Chou, Jeffrey (2013) High-throughput sequencing of B- and T-lymphocyte antigen receptors in hematology. Blood 122:19-22
Chien, Jason W; Zhang, Xinyi Cindy; Fan, Wenhong et al. (2012) Evaluation of published single nucleotide polymorphisms associated with acute GVHD. Blood 119:5311-9
Marcondes, A Mario; Li, Xiang; Tabellini, Laura et al. (2011) Inhibition of IL-32 activation by ?-1 antitrypsin suppresses alloreactivity and increases survival in an allogeneic murine marrow transplantation model. Blood 118:5031-9
Grogan, Bryan M; Tabellini, Laura; Storer, Barry et al. (2011) Activation and expansion of CD8(+) T effector cells in patients with chronic graft-versus-host disease. Biol Blood Marrow Transplant 17:1121-32
Turtle, Cameron J; Delrow, Jeff; Joslyn, Rochelle C et al. (2011) Innate signals overcome acquired TCR signaling pathway regulation and govern the fate of human CD161(hi) CD8?? semi-invariant T cells. Blood 118:2752-62
Chronic GVHD Consortium (2011) Rationale and design of the chronic GVHD cohort study: improving outcomes assessment in chronic GVHD. Biol Blood Marrow Transplant 17:1114-20
Abbasi, Nissa; Vadnais, Barbara; Knutson, Jennifer A et al. (2011) Pharmacogenetics of intravenous and oral busulfan in hematopoietic cell transplant recipients. J Clin Pharmacol 51:1429-38
Bhatia, Smita; Davies, Stella M; Scott Baker, K et al. (2011) NCI, NHLBI first international consensus conference on late effects after pediatric hematopoietic cell transplantation: etiology and pathogenesis of late effects after HCT performed in childhood--methodologic challenges. Biol Blood Marrow Transplant 17:1428-35

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