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Dive into the research topics where Sam T. Hwang is active.

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Featured researches published by Sam T. Hwang.


Journal of Leukocyte Biology | 2006

Chemokines, chemokine receptors, and cancer metastasis

Takashi Kakinuma; Sam T. Hwang

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.


Journal of Immunology | 2011

Epidermal CCR6+ γδ T Cells Are Major Producers of IL-22 and IL-17 in a Murine Model of Psoriasiform Dermatitis

Tomotaka Mabuchi; Tomonori Takekoshi; Sam T. Hwang

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.


Journal of Investigative Dermatology | 2013

CCR6 is required for epidermal trafficking of γδ T cells in an IL-23-induced model of psoriasiform dermatitis

Tomotaka Mabuchi; Tej Pratap Singh; Tomonori Takekoshi; Guang Fu Jia; Xuesong Wu; Mandy C. Kao; Ido D. Weiss; Joshua M. Farber; Sam T. Hwang

A subset of CCR6+, γδ-low (GDL) T cells that express Th17 cytokines in mouse skin participates in IL-23-induced psoriasisform dermatitis. We use CCR6-deficient (KO) and wildtype (WT) mice to analyze skin trafficking patterns of GDL T cells and function-blocking mAbs to determine the role of CCR6 in IL-23-mediated dermatitis. Herein, CCL20 was highly upregulated in IL-23-injected WT mouse ear skin as early as 24 hours after initial treatment, and large numbers of CCR6+ cells were observed in the epidermis of IL-23-injected WT mice. Anti-CCL20 mAbs reduced psoriasiform dermatitis and blocked recruitment of GDL T cells to the epidermis. In CCR6 KO mice, GDL T cells failed to accumulate in the epidermis after IL-23 treatment, but total numbers of GDL T cells in the dermis of WT and CCR6 KO mice were equivalent. There was a ~70% reduction in the proportion of IL-22+ GDL T cells in the dermis of CCR6 KO mice (vs. WT mice), suggesting that effector function as well as epidermal recruitment of GDL T cells are impaired in CCR6-deficient mice. Thus, these data show CCR6 regulates epidermal trafficking of γδ T cell subsets in skin and suggest the potential of CCR6 as a therapeutic target for psoriasis.


Journal of Immunology | 2002

CXCR5-Transduced Bone Marrow-Derived Dendritic Cells Traffic to B Cell Zones of Lymph Nodes and Modify Antigen-Specific Immune Responses

Meng-tse Wu; Sam T. Hwang

Skin-derived migratory dendritic cells (DC), in contrast to bone marrow-derived DC (BMDC), express CXCR5, respond to the chemokine CXC ligand 13 (CXCL13) in vitro, and are capable of migrating to B cell zones (BCZ) in lymph nodes (LN) in vivo. Herein, we analyzed the surface phenotype of skin-derived migratory DC and found that 15–35% of MHC class IIhigh cells showed high levels of expression of CXCR5 but expressed low levels of DEC205, a suggested characteristic of dermal-type DC in mice. To study the effects of CXCR5 on the trafficking dynamics of DC, we stably expressed CXCR5 in BMDC by retroviral gene transduction. CXCR5 was detected by flow cytometry on transduced cells, which responded to CXCL13 in vitro in chemotaxis assays (3-fold over nontransduced BMDC, p < 0.01). When injected into the footpads of mice, ∼40% of injected CXCR5-BMDC were observed in BCZ of draining LN. Mice were vaccinated with CXCR5- and vector-BMDC that were pulsed with keyhole limpet hemocyanin (KLH) to induce Ag-specific cellular and humoral immune responses. Mice injected with CXCR5-BMDC (vs vector-BMDC) demonstrated marginally less footpad swelling in response to intradermal injection of KLH. Interestingly, significantly higher levels of KLH-specific IgG (p < 0.05) and IgM (p < 0.01) were found in the serum of mice injected with CXCR5-BMDC compared with mice immunized with vector-transduced BMDC. Thus, CXCR5 is predominantly expressed by dermal-type DC. Moreover, CXCR5 directs BMDC to BCZ of LN in vivo and modifies Ag-specific immune responses induced by BMDC vaccination.


Journal of Investigative Dermatology | 2009

Cutaneous T-Cell Lymphoma: Roles for Chemokines and Chemokine Receptors

Xue Song Wu; Anke S. Lonsdorf; Sam T. Hwang

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 play roles in the migration and localization of normal T cells (and other leukocytes) during physiological responses in inflamed or infected skin. In cancer cells, these receptors may also facilitate tumorigenesis, metastasis, and resistance to immune-mediated killing. This review will focus on recent data that reveal potential roles of specific chemokine receptors, including CCR4, CXCR4, and CCR10, in the pathophysiology of cutaneous T-cell lymphoma, including mycosis fungoides and Sézary syndrome.


Journal of Immunology | 2001

Cutting Edge: CCR4 Mediates Antigen-Primed T Cell Binding to Activated Dendritic Cells

Meng-tse Wu; Hui Fang; Sam T. Hwang

The binding of a T cell to an Ag-laden dendritic cell (DC) is a critical step of the acquired immune response. Herein, we address whether a DC-produced chemokine can induce the arrest of T cells on DC under dynamic flow conditions. Ag-primed T cells and a T cell line were observed to rapidly (∼0.5 s) bind to immobilized DC at low shear stress (0.1–0.2 dynes/cm2) in a pertussis toxin-sensitive fashion. Quantitatively, Ag-primed T cells displayed 2- to 3-fold enhanced binding to DC compared with unprimed T cells (p < 0.01). In contrast to naive T cells, primed T cell arrest was largely inhibited by pertussis toxin, neutralization of the CC chemokine, macrophage-derived chemokine (CCL22), or by desensitization of the CCL22 receptor, CCR4. Our results demonstrate that DC-derived CCL22 induces rapid binding of activated T cells under dynamic conditions and that Ag-primed and naive T cells fundamentally differ with respect to chemokine-dependent binding to DC.


Journal of Dermatological Science | 2012

Chemokine receptors in the pathogenesis and therapy of psoriasis

Tomotaka Mabuchi; Timothy W. Chang; Suzanne Quinter; Sam T. Hwang

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.


Journal of Investigative Dermatology | 2014

Depletion of M2-like tumor-associated macrophages delays cutaneous T-cell lymphoma development in vivo.

Xuesong Wu; Brian C. Schulte; Youwen Zhou; Dipica Haribhai; Alexander C. Mackinnon; Jose A. Plaza; Calvin B. Williams; Sam T. Hwang

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.


Expert Opinion on Therapeutic Targets | 2010

CCR6 as a possible therapeutic target in psoriasis

Michael N. Hedrick; Anke S. Lonsdorf; Sam T. Hwang; Joshua M. Farber

Importance of the field: Psoriasis is a common, chronic autoimmune disease of the skin. Despite a number of effective treatments, new therapies are needed with enhanced efficacy, safety and convenience. Chemokine receptors are GPCRs that control leukocyte trafficking, and like other GPCRs, are good potential drug targets. The chemokine receptor CCR6 is expressed on the TH17 subset of CD4+ T cells, which produces IL-17A/F, IL-22, TNF-α and other cytokines, and which has been implicated in the pathogenesis of psoriasis. CCR6 and its ligand, CCL20/MIP-3α, are highly expressed in psoriatic skin and CCR6 is necessary for the pathology induced in a mouse model of psoriasis-like inflammation. Areas covered in this review: This review summarizes the evidence for the importance of the IL-23/TH17 axis, and in particular CCR6 and CCL20 in psoriasis, dating from 2000 to the present, and discusses the possibility of inhibiting CCR6 as a treatment for the disease. What the reader will gain: The review informs the reader of the current thinking on the mechanisms of inflammation in psoriasis and the possible roles for CCR6 (and CCL20) in disease pathogenesis. Take home message: We conclude that CCR6 should be investigated as a potential therapeutic target in psoriasis.


Journal of Immunology | 2006

Oncostatin M enhances CCL21 expression by microvascular endothelial cells and increases the efficiency of dendritic cell trafficking to lymph nodes.

Makoto Sugaya; Lei Fang; Adela R. Cardones; Takashi Kakinuma; Samer H. Jaber; Andrew Blauvelt; Sam T. Hwang

CCL21, a lymphatic endothelial cell (LEC)-derived chemokine, and its receptor CCR7 regulate dendritic cell (DC) trafficking to lymph nodes (LN), but it is unclear how CCL21 expression is regulated. Oncostatin M (OSM) is an IL-6-like cytokine synthesized by activated DC and other leukocytes. In vitro, OSM (but not TNF-α) stimulated CCL21 mRNA and protein expression by human dermal microvascular EC (DMEC) in an ERK1/2-dependent fashion. Conditioned medium from OSM-treated DMEC stimulated CCL21-dependent chemotaxis of mouse bone marrow-derived DC (BMDC). Cultured BMDC expressed OSM, which was increased with the addition of LPS. Topical application of the contact-sensitizing hapten, trinitrochlorobenzene, resulted in enhanced OSM expression in the skin, whereas cutaneous injection of TNF-α did not. Injection of OSM into the footpad increased CCL21 mRNA expression in the draining LN by ∼10-fold and in mouse skin by ∼4-fold without increasing CCR7 mRNA. In vitro, OSM increased the permeability of DMEC and lung microvascular EC monolayers to FITC-dextran beads, and, in vivo, it enhanced accumulation of Evans blue dye in draining LN by ∼3-fold (p = 0.0291). Of note, OSM increased trafficking of BMDC injected in footpads to draining LN by 2-fold (p = 0.016). In summary, OSM up-regulates CCL21 expression in skin and draining regional LN. We propose that OSM is a regulator of CCL21 expression and endothelial permeability in skin, contributing to efficient migration of DC to regional LN.

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Xuesong Wu

Medical College of Wisconsin

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Lei Fang

National Institutes of Health

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Anke S. Lonsdorf

National Institutes of Health

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Tomotaka Mabuchi

Medical College of Wisconsin

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