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      Chemokine receptors: multifaceted therapeutic targets

      review-article
      Nature Reviews. Immunology
      Nature Publishing Group UK

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          Key Points

          • The chemokine family is responsible for the specific, specialized trafficking of leukocytes.

          • Inflammation is characterized by an excessive, inappropriate cellular recruitment.

          • Chemokine receptors are necessary for HIV infection.

          • The large number of chemokines and receptors point to a redundant system. In vitro studies support this, but in vivo studies provide evidence for specificity in the chemokine system.

          • Clinical evidence shows that chemokines and receptors are expressed abundantly in samples and biopsies from patients suffering from inflammatory disorders.

          • Patients that lack CCR5 are resistant to HIV infection.

          • Studies using gene-deleted mice, neutralization of ligands or receptors and small molecule inhibitors have all contributed to our understanding of the chemokine system.

          • Chemokine receptors are valid therapeutic targets for the treatment of inflammation and HIV infection.

          Abstract

          Chemokines and their receptors are involved in the pathogenesis of diseases ranging from asthma to AIDS. Chemokine receptors are G-protein-coupled serpentine receptors that present attractive tractable targets for the pharmaceutical industry. It is only ten years since the first chemokine receptor was discovered, and the rapidly expanding number of antagonists holds promise for new medicines to combat diseases that are currently incurable. Here, I focus on the rationale for developing antagonists of chemokine receptors for inflammatory disorders and AIDS, and the accumulating evidence that favours this strategy despite the apparent redundancy in the chemokine system.

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          Most cited references74

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          Chemokines: a new classification system and their role in immunity.

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            Mice Lacking Expression of Secondary Lymphoid Organ Chemokine Have Defects in Lymphocyte Homing and Dendritic Cell Localization

            Secondary lymphoid organ chemokine (SLC) is expressed in high endothelial venules and in T cell zones of spleen and lymph nodes (LNs) and strongly attracts naive T cells. In mice homozygous for the paucity of lymph node T cell (plt) mutation, naive T cells fail to home to LNs or the lymphoid regions of spleen. Here we demonstrate that expression of SLC is undetectable in plt mice. In addition to the defect in T cell homing, we demonstrate that dendritic cells (DCs) fail to accumulate in spleen and LN T cell zones of plt mice. DC migration to LNs after contact sensitization is also substantially reduced. The physiologic significance of these abnormalities in plt mice is indicated by a markedly increased sensitivity to infection with murine hepatitis virus. The plt mutation maps to the SLC locus; however, the sequence of SLC introns and exons in plt mice is normal. These findings suggest that the abnormalities in plt mice are due to a genetic defect in the expression of SLC and that SLC mediates the entry of naive T cells and antigen-stimulated DCs into the T cell zones of secondary lymphoid organs.
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              Acute axonal injury in multiple sclerosis. Correlation with demyelination and inflammation.

              Damage to axons is taken as a key factor of disability in multiple sclerosis, but its pathogenesis is largely unknown. Axonal injury is believed to occur as a consequence of demyelination and was recently shown to be a feature even of the early disease stages. The present study was aimed at characterizing the association of axonal injury and histopathological hallmarks of multiple sclerosis such as demyelination, cellular infiltration and expression of inflammatory mediators. Therefore, axon reduction and signs of acute axonal damage were quantified in early lesion development of chronic multiple sclerosis and correlated with demyelinating activity and inflammation. Patients with secondary progressive multiple sclerosis revealed the most pronounced axonal injury, whereas primary progressive multiple sclerosis patients surprisingly showed relatively little acute axonal injury. Acute axonal damage, as defined by the accumulation of amyloid precursor protein (APP), was found to occur not only in active demyelinating but also in remyelinating and inactive demyelinated lesions with a large inter-individual variability. Only few remyelinating lesions were adjacent to areas of active demyelination. In this minority of lesions, axonal damage may have originated from the neighbourhood. APP expression in damaged axons correlated with the number of macrophages and CD8-positive T lymphocytes within the lesions, but not with the expression of tumour necrosis factor-alpha (TNF-alpha) or inducible nitric oxide synthase (iNOS). Axonal injury is therefore, at least in part, independent of demyelinating activity, and its pathogenesis may be different from demyelination. This has major implications for therapeutic strategies, which aim at preventing both demyelination and axonal loss.
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                Author and article information

                Contributors
                amanda.proudfoot@serono.com
                Journal
                Nat Rev Immunol
                Nat. Rev. Immunol
                Nature Reviews. Immunology
                Nature Publishing Group UK (London )
                1474-1733
                1474-1741
                2002
                : 2
                : 2
                : 106-115
                Affiliations
                GRID grid.418389.f, ISNI 0000 0004 0403 4398, Serono Pharmaceutical Research Institute, ; 14 chemin des Aulx, 1228 Plan les Ouates, Geneva, Switzerland
                Article
                BFnri722
                10.1038/nri722
                7097668
                11910892
                dbdfebeb-0d62-46e2-af95-e1a4208c2f11
                © Nature Publishing Group 2002

                This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

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                © Springer Nature Limited 2002

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