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      Targeting CCL5 in inflammation

      review-article
      , MSc a , , PhD b , , MSc PhD a , c , , MD PhD DTMH FBPharmacolS , a
      Expert Opinion on Therapeutic Targets
      Taylor & Francis
      CCL5, disease pathogenesis, infection, inflammation, RANTES

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          Abstract

          Introduction: Chemokines play important roles in inflammation and in immune responses. This article will discuss the current literature on the C–C chemokine ligand 5 (CCL5), and whether it is a therapeutic target in the context of various allergic, autoimmune or infectious diseases.

          Areas covered: Small-molecule inhibitors, chemokine and chemokine receptor-deficient mice, antibodies and modified chemokines are the current tools available for CCL5 research, and there are several ongoing clinical trials targeting the CCL5 receptors, CCR1, CCR3 and CCR5. There are fewer studies specifically targeting the chemokine itself and clinical studies with anti-CCL5 antibodies are still to be carried out.

          Expert opinion: Although clinical trials are strongly biased toward HIV treatment and prevention with blockers of CCR5, the therapeutic potential for CCL5 and its receptors in other diseases is relevant. Overall, it is not likely that specific targeting of CCL5 will result in new adjunct strategies for the treatment of infectious diseases with a major inflammatory component. However, targeting CCL5 could result in novel therapies for chronic inflammatory diseases, where it may decrease inflammatory responses and fibrosis, and certain solid tumors, where it may have a role in angiogenesis.

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          Most cited references117

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          Origin and physiological roles of inflammation.

          Inflammation underlies a wide variety of physiological and pathological processes. Although the pathological aspects of many types of inflammation are well appreciated, their physiological functions are mostly unknown. The classic instigators of inflammation - infection and tissue injury - are at one end of a large range of adverse conditions that induce inflammation, and they trigger the recruitment of leukocytes and plasma proteins to the affected tissue site. Tissue stress or malfunction similarly induces an adaptive response, which is referred to here as para-inflammation. This response relies mainly on tissue-resident macrophages and is intermediate between the basal homeostatic state and a classic inflammatory response. Para-inflammation is probably responsible for the chronic inflammatory conditions that are associated with modern human diseases.
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            Points of control in inflammation.

            Inflammation is a complex set of interactions among soluble factors and cells that can arise in any tissue in response to traumatic, infectious, post-ischaemic, toxic or autoimmune injury. The process normally leads to recovery from infection and to healing, However, if targeted destruction and assisted repair are not properly phased, inflammation can lead to persistent tissue damage by leukocytes, lymphocytes or collagen. Inflammation may be considered in terms of its checkpoints, where binary or higher-order signals drive each commitment to escalate, go signals trigger stop signals, and molecules responsible for mediating the inflammatory response also suppress it, depending on timing and context. The non-inflammatory state does not arise passively from an absence of inflammatory stimuli; rather, maintenance of health requires the positive actions of specific gene products to suppress reactions to potentially inflammatory stimuli that do not warrant a full response.
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              Chemokine expression in melanoma metastases associated with CD8+ T-cell recruitment.

              Despite the frequent detection of circulating tumor antigen-specific T cells, either spontaneously or following active immunization or adoptive transfer, immune-mediated cancer regression occurs only in the minority of patients. One theoretical rate-limiting step is whether effector T cells successfully migrate into metastatic tumor sites. Affymetrix gene expression profiling done on a series of metastatic melanoma biopsies revealed a major segregation of samples based on the presence or absence of T-cell-associated transcripts. The presence of lymphocytes correlated with the expression of defined chemokine genes. A subset of six chemokines (CCL2, CCL3, CCL4, CCL5, CXCL9, and CXCL10) was confirmed by protein array and/or quantitative reverse transcription-PCR to be preferentially expressed in tumors that contained T cells. Corresponding chemokine receptors were found to be up-regulated on human CD8(+) effector T cells, and transwell migration assays confirmed the ability of each of these chemokines to promote migration of CD8(+) effector cells in vitro. Screening by chemokine protein array identified a subset of melanoma cell lines that produced a similar broad array of chemokines. These melanoma cells more effectively recruited human CD8(+) effector T cells when implanted as xenografts in nonobese diabetic/severe combined immunodeficient mice in vivo. Chemokine blockade with specific antibodies inhibited migration of CD8(+) T cells. Our results suggest that lack of critical chemokines in a subset of melanoma metastases may limit the migration of activated T cells, which in turn could limit the effectiveness of antitumor immunity.
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                Author and article information

                Journal
                Expert Opin Ther Targets
                Expert Opin. Ther. Targets
                IETT
                iett20
                Expert Opinion on Therapeutic Targets
                Taylor & Francis
                1472-8222
                1744-7631
                2013
                03 October 2013
                : 17
                : 12
                : 1439-1460
                Affiliations
                [a ]Immunopharmacology, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais , Belo Horizonte, Brazil 55 31 34092649; rempsufmg@ 123456gmail.com
                [b ]Institute of Infection, Immunity and Inflammation, University of Glasgow , Glasgow, Scotland E-mail: rguabiraba@ 123456gmail.com
                [c ]Laboratory of Immunology and Pulmonary Mechanics, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais , Belo Horizonte, Brazil 55 31 34092938 E-mail: remo@ 123456ufmg.br
                Author notes
                [] Author for correspondence
                Article
                837886
                10.1517/14728222.2013.837886
                7103722
                24090198
                59cc987c-f135-458b-8ef7-76fc174bba63
                © Informa UK, Ltd.

                This article is made available via the PMC Open Access Subset for unrestricted re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the COVID-19 pandemic or until permissions are revoked in writing. Upon expiration of these permissions, PMC is granted a perpetual license to make this article available via PMC and Europe PMC, consistent with existing copyright protections.

                History
                Page count
                Figures: 1, Tables: 2, References: 143, Pages: 22
                Categories
                Reviews

                ccl5,disease pathogenesis,infection,inflammation,rantes
                ccl5, disease pathogenesis, infection, inflammation, rantes

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