Autoimmune Sjögren's-Like Lesions in Salivary Glands of TGF-β1-Deficient Mice Are Inhibited by Adhesion-Blocking Peptides

Nancy L. McCartney-Francis, Diane E. Mizel, Robert S. Redman, Michelle Frazier-Jessen, R. Brian Panek, Ashok B. Kulkarni, Jerry M. Ward, James B Mc Carthy, Sharon M. Wahl

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54 Scopus citations

Abstract

The targeted disruption of the TGF-β1 gene in mice (TGF-β1 -/-) leads to extensive inflammation in vital organs, cachexia, and death within 3 to 4 wk. Significant inflammatory lesions develop initially in the periductal regions of the salivary glands and escalate as the animals become symptomatic. These inflammatory sites, characterized by lymphocytic infiltration and increased proliferation, cytokine mRNA expression, and IgG-positive cells, resemble lesions of Sjögren's syndrome. Moreover, the inflammatory pathology, enhanced MHC expression, and Ab production are consistent with an autoimmune-like etiology. Glandular atrophy and loss of acini with reduced saliva production appear to contribute to the wasting syndrome characteristic of the TGF-β1 -/- mice. To determine whether the structural and functional defects were developmental due to the absence of TGF-β1 or secondary to the inflammation, TGF-β1 -/- mice were treated with synthetic fibronectin peptides, which block leukocyte infiltration. Daily systemic injections of RGD, CS-1, and/or peptides derived from the heparin-binding region of the A chain not only prevented leukocyte infiltration in the salivary glands of the TGF-β1 -/- mice, but also reversed the acinar and ductal derangements. These data suggested that salivary gland development is not jeopardized in the absence of TGF-β1, but that the extensive infiltration of inflammatory cells compromises glandular structure and function. The essential nature of TGF-β1 in controlling inflammatory and immune processes is confirmed by these studies. Moreover, these TGF-β1 -/- mice provide an important model of autoimmune disease that can be used in the design of therapeutic interventions.

Original languageEnglish (US)
Pages (from-to)1306-1312
Number of pages7
JournalJournal of Immunology
Volume157
Issue number3
StatePublished - Aug 1 1996

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