Significance of selectively targeted apoptotic rete cells in graft-versus-host disease  George F Murphy, Robert Korngold  Biology of Blood and Marrow Transplantation  Volume 10, Issue 6, Pages 357-365 (June 2004) DOI: 10.1016/j.bbmt.2004.02.005

Figure 1 STAR cells and effects of soluble and cellular effectors of GVHD. STAR cells are localized to human epidermal rete ridges and retelike prominences of the murine tongue and contain K15 (here shown by indirect immunofluorescence; upper left). In GVHD and upon exposure to TNF-α and interleukin-1 in vitro [43], they undergo apoptotic injury, as defined by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling staining (lower left). During the interval that precedes local infiltration of STAR cell regions by effector T cells (soluble phase, here depicted by inset showing RLP stained for CD3), significant apoptosis may be observed for experimental conditions in which cytokine effects are more pronounced [39] (graphically represented in blue bars [whole T-cell HSCT] versus red bars [CD8 T-cell HSCT] versus yellow bars [T cell-depleted control HSCT]). STAR cell apoptosis related to the soluble phase is then followed by a second peak associated with a local influx of effector T cells (cellular phase; here depicted by inset showing RLP stained for CD3). Biology of Blood and Marrow Transplantation 2004 10, 357-365DOI: (10.1016/j.bbmt.2004.02.005)

Figure 2 Overview of effector pathways potentially mediating STAR cell apoptosis. The conditioning regimen (eg, ionizing irradiation) produces injury to gut mucosal epithelium, which consists of mucin-producing goblet cells (cell to left in central diagram), M cells that normally communicate antigenic signals to intimately associated gut immunocytes (cell to right), and ciliated cuboidal epithelial cells (2 middle cells). This injury permits the influx of endotoxin/lipopolysaccharide and directly stimulates cytokine secretion. This initial wave of cytokines (lighter gray arrows) assists in promoting immune interactions inherent to allostimulation, in which specific Vβ donor T cells become clonally expanded. Cytokines produced during allostimulation (darker gray arrow), along with those already circulating from the conditioning regimen, together have the potential to mediate the induction of adhesion molecules in specific microvascular beds, resulting in tissue-specific homing of effector cells. Squamous epithelial targets (here diagrammatically depicted as a retelike prominence of the dorsal tongue), however, have been already altered via exposure to cytokines elicited during the conditioning regimen and allostimulation (soluble phase). This priming may result in (1) adhesion molecule induction that promotes leukocyte binding, allostimulation, or both and (2) induction of proapoptotic proteins through ligation of cytokine receptors (eg, TNFR-1) or alterations in proliferation/activation pathways. Once localized to target tissues, effector T cells (black arrows; cells with black nuclei) may mediate epithelial apoptosis and preferentially affect STAR cells (defined by cells with stippled nuclei) via cell/cell interaction through ligation of death receptors (eg, Fas/Fas ligand). Similar allospecific targeting in the gut further drives the process by enhancing liberation/secretion of proinflammatory mediators. Thus, STAR cell apoptosis is likely to involve the combined effects of soluble and cellular effector phases of disease. Biology of Blood and Marrow Transplantation 2004 10, 357-365DOI: (10.1016/j.bbmt.2004.02.005)