Article

Induction of resistance to diabetes in non-obese diabetic mice by targeting CD44 with a specific monoclonal antibody

Hebrew University of Jerusalem, Yerushalayim, Jerusalem, Israel
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 01/2000; 97(1):285-90. DOI: 10.1073/pnas.97.1.285
Source: PubMed

ABSTRACT

Inflammatory destruction of insulin-producing beta cells in the pancreatic islets is the hallmark of insulin-dependent diabetes mellitus, a spontaneous autoimmune disease of non-obese diabetic mice resembling human juvenile (type I) diabetes. Histochemical analysis of diabetic pancreata revealed that mononuclear cells infiltrating the islets and causing autoimmune insulitis, as well as local islet cells, express the CD44 receptor; hyaluronic acid, the principal ligand of CD44, is detected in the islet periphery and islet endothelium. Injection of anti-CD44 mAb 1 hr before cell transfer of diabetogenic splenocytes and subsequently on alternate days for 4 weeks induced considerable resistance to diabetes in recipient mice, reflected by reduced insulitis. Contact sensitivity to oxazolone was not influenced by this treatment. A similar antidiabetic effect was observed even when the anti-CD44 mAb administration was initiated at the time of disease onset: i.e., 4-7 weeks after cell transfer. Administration of the enzyme hyaluronidase also induced appreciable resistance to insulin-dependent diabetes mellitus, suggesting that the CD44-hyaluronic acid interaction is involved in the development of the disease. These findings demonstrate that CD44-positive inflammatory cells may be a potential therapeutic target in insulin-dependent diabetes.

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Available from: Patrizia Cohen
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    • "The polymer, composed of repeating units of the disaccharide D-glucuronic acid b1-3-N-acetyl-D-glucosamine b-1,4, is found in the extracellular matrix of nearly all tissues and is synthesized by many cell types, including fibroblasts, endothelial cells, and keratinocytes (Jiang et al., 2007). Its primary and most obvious function is to contribute toward the stability and structure of the extracellular matrix, but a broad literature also suggests its involvement in a number of other physiologic and pathologic conditions, including cancer, atherosclerosis, pulmonary fibrosis, pulmonary emphysema, nephritis, arthritis, cerebral infarct, and diabetes (Back et al., 2005; Cuff et al., 2001; Hall and Turley, 1995; Jiang et al., 2007; Li et al., 2011; Mikecz et al., 1995; Weiss et al., 2000). A major function of HA appears to be immune surveillance. "
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    ABSTRACT: In response to tissue injury, hyaluronan (HA) polymers are cleaved by host hyaluronidases, generating small fragments that ligate Toll-like receptors (TLRs) to elicit inflammatory responses. Pathogenic bacteria such as group B Streptococcus (GBS) express and secrete hyaluronidases as a mechanism for tissue invasion, but it is not known how this activity relates to immune detection of HA. We found that bacterial hyaluronidases secreted by GBS and other Gram-positive pathogens degrade pro-inflammatory HA fragments to their component disaccharides. In addition, HA disaccharides block TLR2/4 signaling elicited by both host-derived HA fragments and other TLR2/4 ligands, including lipopolysaccharide. Application of GBS hyaluronidase or HA disaccharides reduced pulmonary pathology and pro-inflammatory cytokine levels in an acute lung injury model. We conclude that breakdown of host-generated pro-inflammatory HA fragments to disaccharides allows bacterial pathogens to evade immune detection and could be exploited as a strategy to treat inflammatory diseases.
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    • "This may indicate that platelets are more likely involved in disease initiation, while the anti-inflammatory pathway initiated by IM7 can reverse established disease. IM7 has been shown to be effective in several different animal models of autoimmunity [12], [14], [34], [35]. This antibody can induce the formation of platelet-neutrophil complexes in proteoglycan-induced arthritis (PGIA) [14], but whether this is related to the effects seen in this study are unknown. "
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    Full-text · Article · Jun 2013 · PLoS ONE
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    • "Collagen VI, the collagen isoform enriched in adipose tissue, is increased in adipose tissue of obese subjects (4). Previous studies show that hyaluronan (HA), an anionic, nonsulfated glycosaminoglycan is increased in injured aorta of insulin-resistant rats (8) and pancreatic islets of nonobese diabetic mice (9). Increased HA is also seen in the kidney with diabetes (5,10). "
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