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      Identifying Chemokines as Therapeutic Targets in Renal Disease: Lessons from Antagonist Studies and Knockout Mice

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          Chemokines, in concert with cytokines and adhesion molecules, play multiple roles in local and systemic immune responses. In the kidney, the temporal and spatial expression of chemokines correlates with local renal damage and accumulation of chemokine receptor-bearing leukocytes. Chemokines play important roles in leukocyte trafficking and blocking chemokines can effectively reduce renal leukocyte recruitment and subsequent renal damage. However, recent data indicate that blocking chemokine or chemokine receptor activity in renal disease may also exacerbate renal inflammation under certain conditions. An increasing amount of data indicates additional roles of chemokines in the regulation of innate and adaptive immune responses, which may adversively affect the outcome of interventional studies. This review summarizes available in vivo studies on the blockade of chemokines and chemokine receptors in kidney diseases, with a special focus on the therapeutic potential of anti-chemokine strategies, including potential side effects, in renal disease.

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          Most cited references 49

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          Lymphocyte traffic control by chemokines.

          In contrast to the remarkable chemokine responses of phagocytes and monocytes that were documented early on, lymphocytes have been considered for a long time to be poor targets for chemokine action. This view has changed dramatically with the discovery that peripheral blood T cells need to be activated before they can migrate in response to inflammatory chemokines. These chemokines do not act on the bulk of resting T cells that are in circulation. The identification of a new group of chemokines that selects resting, as opposed to effector, T and B cells was very exciting. These inflammation-unrelated chemokines affect transendothelial migration and localization of progenitor and mature lymphocytes in lymphoid and nonlymphoid tissues. Here, we summarize the current view of chemokine-mediated lymphocyte traffic and focus on the molecular mechanisms by which T cell responses to chemokines are modulated. Recent developments in this area justify the hypothesis that the distinct migration patterns of lymphocytes throughout their life cycle--that is, during lymphopoiesis, antigen-dependent priming, inflammation and immune surveillance--are finely tuned by changing sets of chemokines that are selective for developmentally regulated chemokine receptors. Thus, the chemokine system assures that cell traffic during inflammatory responses occurs in the proper spatial and temporal fashion and disturbance of this system, therefore, can lead to inflammatory disease.
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            Chemokines as regulators of T cell differentiation.

            Chemokines play well established roles as attractants of naïve and effector T cells. New studies indicate that chemokines also have roles in regulating T cell differentiation. Blocking Gi protein-coupled receptor signaling by pertussis toxin as well as deficiencies in G alpha 12, chemokine receptor 2 (CCR2), CCR5, chemokine ligand 2 (CCL2, also known as monocyte chemoattractant protein 1, or MCP-1), CCL3 (macrophage inflammatory protein 1 alpha, or MIP-1 alpha) and CCL5 (RANTES) have all been found to have effects on the magnitude and cytokine polarity of the T cell response. Here we focus on findings in the CCL2-CCR2 and CCL3-CCR5 ligand-receptor systems. The roles of these molecules in regulating T cell fate include possible indirect effects on antigen-presenting cells and direct effects on differentiating T cells. Models to account for the action of chemokines and G protein-coupled receptor signals in regulating T cell differentiation are discussed.
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              Chemokines: immunology's high impact factors.

               David MacKay (2001)
              Chemokines facilitate leukocyte migration and positioning as well as other processes such as angiogenesis and leukocyte degranulation. The burgeoning knowledge on chemokines and their receptors has influenced many aspects of immunology, in part because cell migration is intimately related to leukocyte function. This overview assesses the impact that chemokines have had on our understanding of immunology and infectious diseases. These include the role of chemokines in leukocyte-endothelial cell interactions; dendritic cell function; T cell differentiation and function; inflammatory diseases; mucosal and subcutaneous immunity; and subversion of immune responses by viruses, including HIV-1. This knowledge heralds new opportunities for the manipulation of immune responses and the development of new anti-inflammatory therapies. It has also provided a new perspective on the functioning of the immune system.

                Author and article information

                Kidney Blood Press Res
                Kidney and Blood Pressure Research
                S. Karger AG
                September 2004
                08 September 2004
                : 27
                : 4
                : 226-238
                Medizinische Poliklinik Innenstadt, Klinikum der Universität München, Ludwig Maximilians University, Munich, Germany
                79867 Kidney Blood Press Res 2004;27:226–238
                © 2004 S. Karger AG, Basel

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                Figures: 2, References: 88, Pages: 13
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