Antagonist of interferon‐inducible protein 10/CXCL10 ameliorates the progression of autoimmune sialadenitis in MRL/lpr mice

Abstract

Objective. Mononuclear cell infiltration of the salivary glands is a major feature of Sjögren's syndrome (SS) and its animal model. Local generation of chemokines and the presence of chemokine receptors on the infiltrating cells may be involved in this process. We undertook the present study to investigate the expression of chemokines during the development of autoimmune sialadenitis in MRL/lpr mice and the therapeutic effect of chemokine antagonists on sialadenitis.Methods. NH 2 -terminal-truncated interferoninducible protein 10 (IP-10)/CXCL10 analogs were transfected into a nonmetastatic fibroblastoid cell line, MRL/N-1, and injected subcutaneously into MRL/lpr mice, and the effects on sialadenitis were monitored.Results. IP-10 analogs truncated by 5 or more amino acid residues from the N-terminal failed to induce chemotaxis and calcium influx by CXCR3-expressing cells. Of these, the most potent antagonist (AT) (IP-10-AT) was a molecule with methionine added after removal of the 5 N-terminal amino acid residues. Significantly increased expression of the Th1-associated chemokines IP-10, monokine induced by interferon-␥/ CXCL9, and interferon-inducible T cell chemoattractant/CXCL11 was induced in the ductal epithelium by interferon-␥ produced in the salivary glands, whereas expression of the Th2-associated chemokines thymus and activation-regulated chemokine (TARC)/ CCL17 and monocyte-derived chemokine/CCL22 was almost undetectable during sialadenitis. Inoculation of IP-10-AT into MRL/lpr mice during the early stage of sialadenitis significantly reduced periductal mononuclear cell infiltration and parenchymal destruction compared with these features in control and TARC-ATbearing mice. This was due to a significant reduction in infiltration of CXCR3؉ T cells, predominantly Th1 cells, resulting in decreased interferon-␥ production.Conclusion. We prepared a novel potent IP-10 antagonist and demonstrated its ability to ameliorate the progression of autoimmune sialadenitis. This agent may provide a new therapeutic approach to SS.

Microarray Analysis of Glomerular Gene Expression in Murine Lupus Nephritis

“…Therefore, therapy aiming to prevent Th1 cell recruitment by interrupting these chemokines-chemokine-receptor interactions would be promising in treating lupus nephritis. In fact, a CXCL10 antagonist ameliorated the progression of autoimmune sialadenitis of MRL / lpr mice in which lesion up-regulation of Th1-associated CXCL9, CXCL10, and CXCL11 mRNA was evident, whereas Th2-associated chemokines were almost undetectable (23). Unfortunately, these authors did not mention whether renal injury was also affected.…”

Aquaporin gene therapy corrects Sjögren’s syndrome phenotype in mice

“…Salivary gland epithelia are reported to play an immune regulatory role as nonprofessional antigen-presenting cells and directly produce proinflammatory cytokines, such as IFN-γ, IL-17, IL-23, and chemokines (43)(44)(45)(46)(47). It is possible that the restoration of immune homeostasis may result from the external effect of AQP1 on the restoration of flow.…”

Peroxisome Proliferator-Activated Receptor α and γ Agonists Together with TGF-β Convert Human CD4+CD25− T Cells into Functional Foxp3+ Regulatory T Cells

“…The expression of PPARa and PPARg was quantified by real-time PCR, as described previously (38). Briefly, for quantitative real-time PCR (qRT-PCR) analysis, total RNAs were extracted from cells using an RNeasy kit (Qiagen, Valencia, CA).…”