title: An epithelial target site in experimental graft-versus-host disease and cytokine-mediated cytotoxicity is defined by cytokeratin 15 expression.
abstract: The identity of cells within squamous epithelia that represent primary targets in acute graft-versus-host disease (GVHD) has been an enigma. Murine effector T cells implicated in the alloresponse by Vbeta complementarity-determining region-3 spectratype analysis were detected with a Vbeta-specific monoclonal antibody within discrete microdomains of tongue (lingual) squamous epithelium. These microdomains, termed rete-like prominences (RLPs), are similar to the rete ridges of human skin. Cells forming the basal layer of RLPs and of human skin rete ridges were shown to express a distinctive pattern of keratin expression defined by antibodies to cytokeratin 15 (K15). In experimental murine GVHD elicited across minor histocompatibility antigen barriers (miHA), early lesions involved selective apoptosis and loss of K15(+) staining within lingual RLPs. An in vitro organ culture model designed to investigate target cell injury by short-term exposure to tumor necrosis factor-alpha and interleukin-1beta, mediators relevant to GVHD, showed a similar pattern of apoptosis and loss of K15(+) reactivity within RLPs. In aggregate, these findings establish a novel cytoskeletal marker for target epithelial subpopulations that should facilitate evaluation of mechanisms of host cell injury in GVHD. These data may also enable the development of therapeutic approaches to abrogate disease at the level of target cell blockade.
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology; D016026:Bone Marrow Transplantation / Q000276:immunology; D017252:CD3 Complex / Q000032:analysis; D015704:CD4 Antigens / Q000032:analysis; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002465:Cell Movement / Q000276:immunology; D002470:Cell Survival / Q000187:drug effects; D022801:Complementarity Determining Regions / Q000032:analysis; D016207:Cytokines / Q000494:pharmacology / Q000502:physiology*; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000737:chemistry / Q000473:pathology* / Q000648:ultrastructure; D005434:Flow Cytometry; D015870:Gene Expression; D006086:Graft vs Host Disease / Q000276:immunology* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007375:Interleukin-1 / Q000494:pharmacology / Q000502:physiology; D053569:Keratin-15; D007633:Keratins / Q000032:analysis*; D008035:Lingual Frenum / Q000737:chemistry / Q000473:pathology / Q000648:ultrastructure; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008854:Microscopy, Electron; D008856:Microscopy, Fluorescence; D010446:Peptide Fragments / Q000032:analysis; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000032:analysis; D012867:Skin / Q000737:chemistry / Q000166:cytology; D013601:T-Lymphocytes / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology / Q000502:physiology
chemical_list: D017252:CD3 Complex; D015704:CD4 Antigens; D022801:Complementarity Determining Regions; D016207:Cytokines; D007375:Interleukin-1; C116015:KRT15 protein, human; D053569:Keratin-15; C492053:Krt15 protein, mouse; D010446:Peptide Fragments; D016693:Receptors, Antigen, T-Cell, alpha-beta; C113249:T cell receptor peptide Vbeta8.1; C109168:T-cell receptor Vbeta 8.2; D014409:Tumor Necrosis Factor-alpha; D007633:Keratins