Abstract
The C-X-C chemokine receptor (CXCR)3 and its chemokines (CXCL9, CXCL10, CXCL11) are involved in the pathogenesis of autoimmune disesases. Under the influence of interferon( IFN)γ, the IFNγ-inducible chemokines are secreted by lymphocytes, and by target cells (fibroblasts, epithelial cells, etc). In target tissues, Th1 lymphocytes are recruited; hence IFNγ is enhanced, which stimulates IFNγ-inducible chemokines (CXCL9, CXCL10, CXCL11) secretion reiterating the autoimmune process. Many studies have evaluated if blockade of CXCR3 or its chemokines have therapeutic significance in autoimmune diseases (for example in thyroid autoimmune disorders, etc). Peroxisome proliferator-activated receptor (PPAR)γ or -α agonists show a strong inhibitory effect on the expression and production of CXCR3 chemokines in vitro, in various kinds of cells, such as denditric cells, monocytes, macrophages, endothelial and vascular smooth muscle cells, intestinal cells, thyrocytes, fibroblasts, preadipocytes and mesangial cells, and in vivo in animal models. Further studies are ongoing to explore the use of new molecules that act as antagonists of CXCR3, or block CXCL10, in autoimmune disorders, and many interesting patents have been recently applied. Phase II studies have assessed the efficacy and safety of fully human, monoclonal antibodies to CXCL10, for the treatment of autoimmune disorders (for example rheumatoid arthritis, or ulcerative colitis). Keywords: CXCR3 chemokines, autoimmune thyroiditis, graves’ disease and ophthalmopathy, inflammatory myopathies, rheumatoid arthritis, type 1 diabetes.
Highlights
Chemokines are a family of small cytokines that are able to induce chemotaxis in responsive cells
Further studies are ongoing to explore the use of new molecules that act as antagonists of CXCR3, or block CXCL10, in autoimmune disorders, and many interesting patents have been recently applied
Interferon (IFN)γ-inducible chemokines [IFNγ-induced protein 10 (IP-10/CXCL10), monokine induced by IFNγ (Mig/CXCL9), and IFN-inducible T-cell chemoattractant (I-TAC/CXCL11)] were initially identified as chemokines that were induced by IFNγ and in various cell types, such as neutrophils, endothelial cells, keratinocyte, fibroblasts, hepatocytes and thyrocytes; these chemokines are preferentially expressed on T helper (Th)1 lymphocytes [5, 6]
Summary
Chemokines are a family of small cytokines that are able to induce chemotaxis in responsive cells. The secretion of CXCR3 chemokines was absent in basal conditions in retrobulbar fibroblasts and preadipocytes from GO patients in primary cultures; the stimulation with IFNγ alone and/or TNFα induced the release of these chemokines, suggesting that these cells participate in the self-perpetuation of inflammation through the release of chemokines [47]. The involvement of PPAR-γ in the regulation of IFNγ-induced chemokine expression in human autoimmunity has been shown recently, and PPAR-γ ligands attenuate the recruitment of activated T cells to areas of Th1-mediated inflammation [50,51,52]. PPAR-α activators inhibit the IFNγ-induced secretion of CXCR3 chemokines in primary cells (thyrocytes, fibroblasts and preadipocytes) suggesting that PPAR-α may be involved in the modulation of the immune response in AT, GD, and GO [16, 57]. The response rate was significantly higher in patients treated with MDX-1100 (54%) than among placebocontrol patients (17%), suggesting that MDX-1100 is well tolerated and can be considered an effective treatment in RA patients not responders to traditional therapies
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