Kinetics of Gene Expression in Murine Cutaneous Graft-versus-Host Disease

Memorial Sloan-Kettering Cancer Center, New York, New York, United States
American Journal Of Pathology (Impact Factor: 4.59). 07/2004; 164(6):2189-202. DOI: 10.1016/S0002-9440(10)63776-5
Source: PubMed


The kinetics of gene expression associated with the development of cutaneous graft-versus-host disease (GVHD) were examined in a mouse model of MHC-matched allogeneic hematopoietic stem cell transplantation. Ear skin was obtained from recipient mice with or without GVHD between 7 and 40 days after transplantation for histopathological analysis and gene expression profiling. Gene expression patterns were consistent with early infiltration and activation of CD8(+) T and mast cells, followed by CD4(+) T, natural killer, and myeloid cells. The sequential infiltration and activation of effector cells correlated with the histopathological development of cutaneous GVHD and was accompanied by up-regulated expression of many chemokines and their receptors (CXCL-1, -2, -9, and -10; CCL-2, -5, -6, -7, -8, -9, -11, and -19; CCR-1 and CCR-5), adhesion molecules (ICAM-1, CD18, Ly69, PSGL-1, VCAM-1), molecules involved in antigen processing and presentation (TAP1 and TAP2, MHC class I and II, CD80), regulators of apoptosis (granzyme B, caspase 7, Bak1, Bax, and BclII), interferon-inducible genes (STAT1, IRF-1, IIGP, GTPI, IGTP, Ifi202A), stimulators of fibroblast proliferation and matrix synthesis (interleukin-1beta, transforming growth factor-beta1), and markers of keratinocyte proliferation (keratins 5 and 6), and differentiation (small proline-rich proteins 2E and 1B). Many acute-phase proteins were up-regulated early in murine cutaneous GVHD including serum amyloid A2 (SAA2), SAA3, serpins a3g and a3n, secretory leukocyte protease inhibitor, and metallothioneins 1 and 2. The kinetics of gene expression were consistent with the evolution of cutaneous pathology as well as with current models of disease progression during cutaneous GVHD.

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Available from: Aleksandra Petrovic, May 15, 2014
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    • "In this context, irradiation has been demonstrated to induce up-regulation of E-selectin and intercellular adhesion molecule 1 on endothelial cells in vitro (53). Similarly, experiments involving the transfer of syngeneic T cells to freshly irradiated recipients indicate that irradiation can induce the early and transient up-regulation of certain inflammatory chemokines and adhesion molecules (32, 54, 55) in nonlymphoid tissues. In contrast, up-regulated expression of these molecules by peripheral tissues is greater and sustained for longer periods after the transfer of allogeneic T cells to freshly irradiated recipients (32, 54, 55). "
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    ABSTRACT: Transfer of T cells to freshly irradiated allogeneic recipients leads to their rapid recruitment to nonlymphoid tissues, where they induce graft-versus-host disease (GVHD). In contrast, when donor T cells are transferred to established mixed chimeras (MCs), GVHD is not induced despite a robust graft-versus-host (GVH) reaction that eliminates normal and malignant host hematopoietic cells. We demonstrate here that donor GVH-reactive T cells transferred to MCs or freshly irradiated mice undergo similar expansion and activation, with similar up-regulation of homing molecules required for entry to nonlymphoid tissues. Using dynamic two-photon in vivo microscopy, we show that these activated T cells do not enter GVHD target tissues in established MCs, contrary to the dogma that activated T cells inevitably traffic to nonlymphoid tissues. Instead, we show that the presence of inflammation within a nonlymphoid tissue is a prerequisite for the trafficking of activated T cells to that site. Our studies help to explain the paradox whereby GVH-reactive T cells can mediate graft-versus-leukemia responses without inducing GVHD in established MCs.
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    • "Our finding – that this is also true for GvHD skin lesions, is in keeping with the fact that CCL27/CTACK has been shown to be induced by IL-1 and TNF-a and, to a lesser extent, by IFN-c (Homey et al, 2000), all cytokines associated with the initial inflammatory response in acute GvHD. In addition to the presence of inflammatory cytokines, CCL17/TARC (the ligand for CCR4), was reported to be significantly upregulated during the first week post-transplant in a murine model of GvHD (Sugerman et al, 2004). "
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