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Elevated Expression of Interferon-Induced Genes and Damage Associated Molecular Pattern Receptor Genes in Chronic Graft Versus Host Disease

Track: Poster Abstracts
Saturday, March 1, 2014, 6:45 PM-7:45 PM
Longhorn Hall E (Exhibit Level 1) (Gaylord Texan)
Fran Hakim, PhD , Experimental Transplantation and Immunology Branch, NCI, Bethesda, MD
Ping Jin, MD , Department of Transfusion Medicine, Clinical Center, NIH, Bethesda, MD
Sarfraz Memon, MD , Experimental Transplantation and Immunology Branch, National Cancer Institute, NIH, Bethesda, MD
Xiao-Yi Yan, MD , Experimental Transplantation and Immunology Branch, National Cancer Institute, NIH, Bethesda, MD
Matin Imanguli, MD, DDS , Experimental Transplantation and Immunology Branch, National Cancer Institute, NIH, Bethesda, MD
Kristin Baird, MD , Pediatric Oncology Branch, National Cancer Institute, NIH, Bethesda, MD
Edward W Cowen, MD , Dermatology Branch, National Cancer Institute, NIH, Bethesda, MD
David F. Stroncek, MD , Department of Transfusion Medicine, Clinical Center, NIH, Bethesda, MD
Ronald Gress, MD , Experimental Transplantation and Immunology Branch, NCI, Bethesda, MD
Steven Z. Pavletic, MD , Experimental Transplantation and Immunology Branch, National Cancer Institute, Bethesda, MD
Chronic Graft versus Host Disease (CGVHD) is an autoimmune-like disorder that remains the main cause of nonrelapse morbidity and mortality following allogeneic hematopoietic stem cell transplantation (alloHSCT), yet its pathogenic mechanisms remain poorly understood. To identify the systemic cytokine pathways supporting the development and persistence of CGVHD, we performed microarray analysis on sorted monocytes from normal controls (NC) and patients with severe cutaneous involvement, including both lichenoid and sclerotic CGVHD. Monocytes were chosen as in vivo reporter cells, capable of upregulating distinct patterns of gene expression in response to different cytokines. Two main pathways were determined to be significantly upregulated. (1) Interferon (IFN)-inducible genes including those involved in signaling, anti-viral function, lymphocyte homeostasis and trafficking, apoptosis and antigen uptake and presentation (STAT1, GBP1, IL15, TNFSF13B, CXCL10, TNFSF10, FCGR1A, MSR1, TAP1). (2) Upregulation of innate immune TLR/RIG1/CLR receptors that can respond to pathogens or cell damage by triggering IFN production and inflammasome formation (TLR2, TLR4, AIM2, DDX58, IFIH1, CLEC4E). Based on the microarray profile, we designed a multiplex RNA analysis probe set to test gene expression in monocytes from (1) CGVHD patients with a broad range of organ involvement, (2) alloHSCT patients without clinical signs of CGVHD (NP) and (3) normal controls (NC). The genes involved in IFN induced and innate immune pathways that were identified by microarray analysis were verified in this more quantitative analysis in 75 CGVHD, 14 NP and 20 NC; comparable upregulation of these pathways was found in patients with extensive lichenoid or sclerotic CGVHD. Furthermore, these pathways were substantiated in ELISA assays by elevated levels of IFN induced chemokines (CXCL9, CXCL10) and cytokines (BAFF) in CGVHD patient plasma, and were consistent with increased levels of Type I Interferon producing cells and IFN-induced factors (MXA, CXCL9) in inflammatory infiltrates in CGVHD targeted tissues. These results suggest that IFN induced by the innate immune system’s response to damage associated molecular patterns (DAMP) could initiate and contribute to a sustained inflammatory process in CGVHD.
Disclosures:
Nothing To Disclose
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