Contact hypersensitivity (CHS) is a simple in vivo assay of cell-mediated immune function in which exposure of epidermal and dermal cells to exogenous haptens results in a delayed-type hypersensitivity (DTH) reaction that can be measured and quantified. Epidermal Langerhans cells and dermal dendritic cells are the critical antigen-presenting cells in this reaction which initiate sensitization to haptens by presenting antigens to CD4- and CD8-bearing T lymphocytes which, in turn, secrete cytokines and recruit other cells to the site of the reaction. In the protocol described here, mice are shaved and the skin of their abdomens is exposed to a hapten.
View Article and Find Full Text PDFBackground: Broad-spectrum histone deacetylase (HDAC) inhibitors are useful in the treatment of allergic and autoimmune diseases and malignancy. However, use of more specific HDAC inhibitors might limit the toxicities caused by HDAC inhibition. HDAC6, a member of the HDAC family, is highly expressed on CD8 T cells and has been shown to regulate immune responses through interactions between T cells and antigen-presenting cells.
View Article and Find Full Text PDFProgrammed cell death 1 (PD-1) is an inhibitory molecule expressed by activated T cells. Its ligands (PD-L1 and -L2; PD-Ls) are expressed not only by a variety of leukocytes but also by stromal cells. To assess the role of PD-1 in CD8 T cell-mediated diseases, we used PD-1-knockout (KO) OVA-specific T cell-receptor transgenic (Tg) CD8 T cells (OT-I cells) in a murine model of mucocutaneous graft-versus-host disease (GVHD).
View Article and Find Full Text PDFThe pathomechanisms underlying the development of cutaneous graft-versus-host disease (GVHD) are incompletely defined. We previously reported that K14-mOVA mice expressing membrane ovalbumin (mOVA), driven by the keratin 14 (K14) promoter, developed GVHD-like mucocutaneous disease and weight loss following transfer of OVA-specific, CD8(+) OT-I T cells. In this study, we demonstrate that early in the course of disease, the kinetics of epidermal expression of C-X-C motif chemokine ligand 9 (CXCL9) and CXCL10, interferon-γ-inducible chemokines that bind the C-X-C motif chemokine receptor 3 (CXCR3) receptor, coincides with CXCR3 expression by OT-I cells in secondary lymphoid organs.
View Article and Find Full Text PDFThe utility of allogeneic hematopoietic stem cell transplantation is limited by graft-versus-host disease (GVHD), a significant cause of morbidity and mortality. Patients with GVHD exhibit cutaneous manifestations with histological features of interface dermatitis followed by scleroderma-like changes. JAK inhibitors represent a class of immunomodulatory drugs that inhibit signaling by multiple cytokines.
View Article and Find Full Text PDFWe have developed K14-mOVA transgenic (Tg) mice that express membrane-associated ovalbumin (mOVA) under the control of a K14 promoter, as well as double Tg mice, by crossing them with OT-I mice that have a TCR recognizing the OVA peptide. When injected with CD8(+) OT-I cells, K14-mOVA Tg mice develop graft-versus-host disease (GVHD), whereas double Tg mice are protected. This suggests that, in double Tg mice, regulatory mechanisms may prevent infused OT-I cells from inducing GVHD.
View Article and Find Full Text PDFWe recently demonstrated that differentiation of cytotoxic T cells requires cooperation between T-cell receptor (TCR)/costimulation and γc-cytokines. Here we demonstrate that the transcription factor IFN regulatory factor 8 (IRF8) is expressed in CD8 T cells by the combination of these two signals. More importantly, depletion of IRF8 in these cells abrogated the differentiation of naive CD8 T cells into effector cells in an experimental graft-vs.
View Article and Find Full Text PDFTransgenic (Tg) mouse models of autoimmunity have been used to express model antigens that can be recognized by T cells or by autoantibodies. To identify mechanisms of CD8-mediated tissue-specific autoimmune reactions and to identify potential treatments, we generated a double-transgenic (DTg) murine model of autoimmunity by crossing keratin-14 (K14)-soluble chicken ovalbumin (sOVA) mice, which express sOVA predominantly in external ear skin, with OT-I mice whose CD8 T cells express Vα2/Vβ5 regions of the TCR and are specific for SIINFEKL peptide (chicken ovalbumin (OVA) peptide 257-264) in association with class I major histocompatibility complex. The K14-sOVA/OT-I DTg mice develop a destructive process selectively targeting the external ear pinnae in the first 6 days of life.
View Article and Find Full Text PDFMissense mutations in the C-terminal B30.2 domain of pyrin cause familial Mediterranean fever (FMF), the most common Mendelian autoinflammatory disease. However, it remains controversial as to whether FMF is due to the loss of an inhibitor of inflammation or to the activity of a proinflammatory molecule.
View Article and Find Full Text PDFObjectives: To determine the percentage of patients with dermatitis herpetiformis (DH) who experience at least 2 years of remission and to identify factors associated with DH remission.
Design: Retrospective cohort study.
Setting: National Institutes of Health (NIH).
Major advances in skin biology and skin diseases are heralding new and more specific forms of treatment that are based on better characterization of pathological mechanisms involved in the individual diseases. The advances that we have seen are being made by dermatologists, skin biologists, and others who have come to appreciate the skin as an organ that is reflective of many important systemic mechanisms. In this commentary, I identify some of what I feel are the most important advances that will be the basis for many future studies.
View Article and Find Full Text PDFA major emphasis of our studies has been on developing a better understanding of how and why the skin serves as a target for immune reactions as well as how the skin evades becoming a target for destruction. For these studies we developed transgenic mice that express a membrane-tethered form of a model self antigen, chicken ovalbumin (mOVA), under the control of a keratin 14 (K14) promoter. K14-mOVA transgenic mice that express OVA mRNA and protein in the epithelia have been assessed for their immune responsiveness to OVA and are being used as targets for T cells obtained from OT-1 transgenic mice whose CD8+ T cells carry a Vα2/Vβ5-transgenic T cell receptor with specificity for the OVA(257-264)-peptides (OVAp) in association with class I MHC antigens.
View Article and Find Full Text PDFBackground: There is no current method to precisely assess pruritus despite its importance as a major symptom in many skin diseases. Pruritus induces scratching that worsens various inflammatory skin diseases.
Objective: The purpose of this study was to determine the effects of scratching on allergic skin reactions using murine contact hypersensitivity (CH) as a model and to assess classical "anti-pruritic" agents using this model.
J Bone Joint Surg Am
November 2009
Although the pathogenic role of B cells and CD4 T cells has been studied extensively, less is known about the role of CD8 T cells in autoimmunity and self-tolerance. To evaluate the role of CD8 T cells in autoimmunity and its modulation using self-peptides, we used mice expressing soluble OVA (sOVA) under control of the keratin-14 promoter. Spontaneous autoimmunity occurred when sOVA mice were crossed with OT-I mice, whose CD8 T cells carry a Valpha2/Vbeta5-transgenic TCR with specificity for the OVA(257-264) peptide.
View Article and Find Full Text PDFThe precise contribution(s) of skin dendritic cells (DCs) to immune responses in the skin has not been well delineated. We developed an intradermal (i.d.
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