It is clear from large clinical studies that selected chemokine receptors are often up-regulated in a large number of common human cancers, including those of the breast, lung, prostate, colon, and ...melanoma. Chemokine receptors and their corresponding chemokine ligands have been demonstrated to play a number of nonredundant roles in cancer metastasis to vital organs as well as regional lymph nodes, the most frequent site of cancer metastasis. Chemokine receptors may potentially facilitate tumor dissemination at several key steps of metastasis, including adherence of tumor cells to endothelium, extravasation from blood vessels, metastatic colonization, angiogenesis, proliferation, and protection from the host response via activation of key survival pathways such as phosphatidylinositol-3 kinase and Akt. It is interesting that many of these roles are reminiscent of their functions in leukocyte and stem cell trafficking. Lastly, we discuss therapeutic applications for chemokine receptor antagonists in cancer therapy.
Cytokine components of Th17 pathway play vital roles in human psoriasis. Although much is known about TCR αβ T cells in psoriasis, the role of unconventional T cells, including γδ T cells, is ...unclear. In this study, using an IL-23 skin injection model of psoriasiform dermatitis in mice, we demonstrate that IL-22, IL-17A, and the IL-23R were highly enriched in a population of CCR6(+), TCR γδ-low expressing (GDL) T cells that accumulated in the epidermis after IL-23 injections. GDL cells were distinct from resident TCR γδ-high, Vγ3(+),CCR6(-) T cells in the epidermis that did not change appreciably in numbers following IL-23 injection. Large numbers of CCR6(+) cells were detected at or above the level of the epidermal basement membrane by confocal microscopy 5 d after repeated IL-23 injections at the same time GDL cells increased in numbers in the epidermis. TCR δ-deficient mice (lacking γδ T cells) exhibited decreased ear swelling and downregulated expression of IL-22 and IL-17A in the epidermis following IL-23 injection. Our data suggest that a subset of γδ T cells play a critical role in IL-23-mediated psoriasiform dermatitis.
Cytokine components of Th17 pathway play vital roles in human psoriasis. Although much is known about TCR alpha beta T cells in psoriasis, the role of unconventional T cells, including gamma delta T ...cells, is unclear. In this study, using an IL-23 skin injection model of psoriasiform dermatitis in mice, we demonstrate that IL-22, IL-17A, and the IL-23R were highly enriched in a population of CCR6+, TCR gamma delta -low expressing (GDL) T cells that accumulated in the epidermis after IL-23 injections. GDL cells were distinct from resident TCR gamma delta -high, V gamma 3+,CCR6- T cells in the epidermis that did not change appreciably in numbers following IL-23 injection. Large numbers of CCR6+ cells were detected at or above the level of the epidermal basement membrane by confocal microscopy 5 d after repeated IL-23 injections at the same time GDL cells increased in numbers in the epidermis. TCR delta -deficient mice (lacking gamma delta T cells) exhibited decreased ear swelling and downregulated expression of IL-22 and IL-17A in the epidermis following IL-23 injection. Our data suggest that a subset of gamma delta T cells play a critical role in IL-23-mediated psoriasiform dermatitis.
Programmed cell death 1 (PD-1) is a key regulatory molecule that has been targeted in human cancers, including melanoma. In clinical testing, Abs against PD-1 have resulted in psoriasiform dermatitis ...(PsD). To determine whether PD-1 regulates PsD, we compared skin responses of PD-1-deficient (PD-1KO) mice and wild-type (WT) controls in an imiquimod (IMQ)-induced murine model of psoriasis. PD-1KO mice showed severe epidermal hyperplasia, greater neutrophilic infiltration, and higher expression of Th17 cytokines (versus WT mice). IMQ exposure increased PD-1 expression by skin γδ-low (GDL) T cells and enhanced expression of PD-L1 by keratinocytes. Three-fold increases in the percentage of IL-17A(+) GDL T cells were observed in skin cell suspensions derived from IMQ-treated PD-1KO mice (versus WT controls), suggesting that the lack of PD-1 has a functional effect not only on αβ T cells, but also on GDL T cells, and that PD-1 may play a regulatory role in PsD.
Programmed cell death 1 (PD-1) is a key regulatory molecule that has been targeted in human cancers, including melanoma. In clinical testing, Abs against PD-1 have resulted in psoriasiform dermatitis ...(PsD). To determine whether PD-1 regulates PsD, we compared skin responses of PD-1-deficient (PD-1KO) mice and wild-type (WT) controls in an imiquimod (IMQ)-induced murine model of psoriasis. PD-1KO mice showed severe epidermal hyperplasia, greater neutrophilic infiltration, and higher expression of Th17 cytokines (versus WT mice). IMQ exposure increased PD-1 expression by skin gamma delta -low (GDL) T cells and enhanced expression of PD-L1 by keratinocytes. Three-fold increases in the percentage of IL-17A+ GDL T cells were observed in skin cell suspensions derived from IMQ-treated PD-1KO mice (versus WT controls), suggesting that the lack of PD-1 has a functional effect not only on alpha beta T cells, but also on GDL T cells, and that PD-1 may play a regulatory role in PsD.
Abstract Chemokine receptors are G-protein-coupled, seven-transmembrane-spanning surface receptors that play key roles in cell trafficking, cell motility, and survival. These receptors are activated ...by small molecular weight chemotactic cytokines called chemokines. Chemokine receptors and their corresponding chemokine ligands play roles in the migration and localization of normal T cells (and other cells) during physiological responses in inflamed or infected skin. In psoriasis, the chemokine receptor CCR6 is expressed on the Th17 cells and γδ T cells, which produce a variety of cytokines (IL17 and IL22 among others), that play a role in the immunological activation. CCR6 and its ligand, CCL20, are highly expressed in psoriatic skin lesion and CCR6 is essential for the development of the psoriasiform phenotype following IL23 injection in mouse skin. In this review, we focus on the roles of chemokine receptors, particularly of CCR6, in the pathogenesis of psoriasis and discuss chemokine receptors as novel therapeutic targets for psoriasis.
There is growing evidence that supports a role of gut dysbiosis in the pathogenesis of psoriasis (Pso). Thus, probiotic supplementation and fecal microbiota transplantation may serve as promising ...preventive and therapeutic strategies for patients with Pso. One of the basic mechanisms through which the gut microbiota interacts with the host is through bacteria-derived metabolites, usually intermediate or end products produced by microbial metabolism. In this study, we provide an up-to-date review of the most recent literature on microbial-derived metabolites and highlight their roles in the immune system, with a special focus on Pso and one of its most common comorbidities, psoriatic arthritis.
Macrophages have key roles in tumor development and invasion in several human cancers, but little is known about their pathogenic role in cutaneous T-cell lymphoma (CTCL). Herein, we used PCR arrays ...to profile the expression of inflammatory cytokines in 12 patients with mycosis fungoides (MF), the most common variant of CTCL. Compared with normal controls, MF skin displayed increased mRNA levels of macrophage-related cytokines. Moreover, we detected CD163, a reliable marker of tumor-associated macrophages, in the tumor microenvironment of MF biopsies. To demonstrate that macrophages had a role in CTCL tumorigenesis, we xenografted human CTCL tumor cells in immunocompromised mice and compared tumor development using clodronate-containing liposomes to deplete macrophages in mice. Mice treated with clodronate-containing liposomes show markedly less tumor growth compared with mice treated with phosphate-buffered saline-containing liposomes (P<0.001). We also noted a strong correlation between macrophage depletion and decreased expression of vascular marker, CD31, and lymphatic marker, podoplanin, suggesting a role for macrophages in angiogenesis. In vitro, clodronate-containing liposomes killed activated murine M2 macrophages, but not Hut78 cells, demonstrating selective ability to induce apoptosis in macrophages. Our data indicate that macrophages have a critical role in the progression of Hut78 cell tumor formation in skin, thus providing a new therapeutic strategy for CTCL.
Mycosis fungoides and Sézary syndrome Hwang, Sam T, Dr; Janik, John E, MD; Jaffe, Elaine S, MD ...
The Lancet (British edition),
03/2008, Letnik:
371, Številka:
9616
Journal Article
Recenzirano
Summary Mycosis fungoides and Sézary syndrome are the most common of the cutaneous T-cell lymphomas, which are a heterogeneous group of neoplasms that affect the skin as a primary site. Although the ...aetiologies of mycosis fungoides and Sézary syndrome are unknown, important insights have been gained in the immunological and genetic perturbations that are associated with these diseases. Unlike some B-cell lymphomas, cutaneous T-cell lymphomas as a group are rarely if ever curable and hence need chronic-disease management. New approaches to treatments are being investigated and include biological and cytotoxic drugs, phototherapy, and monoclonal antibodies that are directed towards novel molecular targets. New molecular technologies such as complementary-DNA microarray have the potential to increase the accuracy of diagnosis and provide important prognostic information. Treatments can be combined to greatly improve clinical outcome without substantially increasing toxic effects in advanced disease that is otherwise difficult to treat. Although present treatment strategies are generally not curative, there is hope that experimental treatments, particularly immunotherapy, might eventually reverse or suppress the abnormalities of mycosis fungoides and Sézary syndrome to the point at which they become non-life-threatening, chronic diseases.
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