Yee-Hon Chin

Lymphocyte-homing receptors and preferential migration pathways.

Summary Over the next few years, research can be expected to focus on the regulation of expression of the tissue-specific homing receptors, the molecular nature of the corresponding endothelial ligands, and the spectrum of factors regulating the adhesiveness of high endothelial venule cells in vivo. In addition, it would be important to elucidate whether other adhesion molecules also play a role in tissue-specific lymphocyte entry and localization into distinct regions of the lymphoid organ. The results of these studies should provide important insights into the mechanisms controlling lymphocyte trafficking into lymphoid tissues as well as chronic inflammatory sites.

UVB therapy decreases the adhesive interaction between peripheral blood mononuclear cells and dermal microvascular endothelium, and regulates the differential expression of CD54, VCAM-1, and E-selectin in psoriatic plaques

Summary A dermal lymphocytic infiltrate is a characteristic feature of psoriasis, and may be involved in the pathogenesis of the disease. We have previously shown that specialized dermal microvascular endothelial cells (DMEC) in psoriatic lesions promote the selective adherence of the CD4 CD45Ro helper T‐cell subset. In this study, we examined the adhesive interaction between peripheral blood mononuclear cells and psoriatic DMEC in patients treated with ultraviolet B light (UVB), and correlated the results with the expression and function of endothelial adhesion molecules on DMEC. Seven psoriatic patients were exposed to one MED of UVB daily for 14 days, and the binding properties of their peripheral blood mononuclear cells (PBMC), and tissue specimens taken from their lesions on days 0, 2, 3, 6, 8, 11 and 14 of UVB treatment, were studied. The ability of psoriatic PBMC to adhere to non‐irradiated control or UVB‐treated psoriatic plaques was reduced by 70% after treatment with 2–3 MED, and complete inhibition was obtained after 8–11 MED. In contrast, exposure of psoriatic plaques to 2–3 MED had no effect on the capacity of DMEC to support normal PBMC binding, which was only reduced after 8–11 MED. In addition, psoriatic plaques which were shielded from direct UVB exposure also showed decreased PBMC binding, suggesting a systemic effect of UVB treatment. Immunoperoxidase staining revealed that CD54 (ICAM‐1) and E‐selectin were strongly expressed on dermal vessels in untreated psoriatic plaques. Treatment of patients with 6–8 MED significantly decreased CD54 and E‐selectin, but was markedly induced following UVB treatment. In functional blocking studies, preincubation of tissue from untreated psoriatic plaques with anti‐E‐selectin antibody, but not antibodies against CD54 and VCAM‐1, significantly inhibited the ability to bind normal PBMC. These observations suggest that UVB treatment interferes with the adhesive properties of both psoriatic PBMC and endothelial cells, and differentially regulates the expression of endothelial adhesion molecules. The study also provided direct evidence for the involvement of E‐selectin in the adhesion of circulating lymphocytes to psoriatic endothelial cells.

Differential regulation of tissue-specific lymph node high endothelial venule cell adhesion molecules by tumour necrosis factor and transforming growth factor-beta 1.

Lymphocytes migrate from blood into lymph nodes (LN) of rats specifically at segments of venules lined by high endothelium (HEV). We have previously shown that pretreatment of LN HEV cells with pro‐inflammatory cytokines such as tumour necrosis factor‐α (TNF‐α) and interferon‐γ (IFN‐γ), augments their adhesiveness for thoracic duct lymphocytes (TDL). Here we report that a mouse monoclonal antibody, 3C10, recognized tissue‐specific endothelial determinants on rat LN HEV cells and blocked their adhesiveness for TDL and EL‐4J cells transfected with rat L‐selectin. In contrast, 3C10 antibody did not inhibit lymphocyte attachment to Peyers patch (PP) frozen sections or cultured PP HEV cells. The antibody immunoprecipitated from LN HEV cells two proteins with apparent molecular weights of 90 000 and 50 000. The expression of 3C10 antigen on LN HEV cells was increased by incubation with TNF‐α or IFN‐γ. Furthermore, pretreatment of cytokine‐stimulated LN HEV cells with 3C10 antibody blocked TDL binding in a dose‐dependent manner. In contrast, 3C10 antigen expression on LN HEV cells was significantly decreased following incubation of cells with transforming growth factor‐β1 (TGF‐β1). In addition, TGF‐β1 also abrogated the adhesiveness of LN HEV cells stimulated with TNF‐α, IFN‐γ or both cytokines. Together, these data suggest that endothelial determinants recognized by the 3C10 antibody are tissue‐specific ligands for lymphocyte adhesion and cytokines such as TNF‐α and TGF‐β differentially regulate their expression and function.

Intracellular signaling of tumor necrosis factor-α in brain microvascular endothelial cells is mediated by a protein tyrosine kinase and protein kinase C-dependent pathway

The intracellular signaling pathways responsible for tumor necrosis factor (TNF)-alpha stimulation of lymphocyte adhesion to brain microvascular endothelial cells (BMEC) were studied using inhibitors of protein kinase C (bisindolylmaleimide HCl, H-7, or staurosporine), or protein tyrosine kinase (genistein). Each of these blocked the ability of BMEC to respond to TNF-alpha. In contrast, BMEC treated with H-89, an inhibitor of protein kinase A, or the adenylate cyclase inhibitor, dideoxyadenosine, responded normally to TNF-alpha. Forskolin, an adenylate cyclase agonist, significantly increased lymphocyte adhesion to BMEC. These data indicate that intracellular signaling by TNF-alpha in BMEC is mediated through a protein kinase C and tyrosine kinase dependent pathway.