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


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.

Download full-text


Available from: Patrizia Cohen
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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.
    Full-text · Article · Dec 2015 · Cell host & microbe
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Antibodies to CD44 have been used to successfully ameliorate murine models of autoimmune disease. The most often studied disease model has been murine inflammatory arthritis, where a clear mechanism for the efficacy of CD44 antibodies has not been established. We have recently shown in a murine passive-model of the autoimmune disease immune thrombocytopenia (ITP) that some CD44 antibodies themselves can induce thrombocytopenia in mice, and the CD44 antibody causing the most severe thrombocytopenia (IM7), also is known to be highly effective in ameliorating murine models of arthritis. Recent work in the K/BxN serum-induced model of arthritis demonstrated that antibody-induced thrombocytopenia reduced arthritis, causing us to question whether CD44 antibodies might primarily ameliorate arthritis through their thrombocytopenic effect. We evaluated IM7, IRAWB14.4, 5035-41.1D, KM201, KM114, and KM81, and found that while all could induce thrombocytopenia, the degree of protection against serum-induced arthritis was not closely related to the length or severity of the thrombocytopenia. CD44 antibody treatment was also able to reverse established inflammation, while thrombocytopenia induced by an anti-platelet antibody targeting the GPIIbIIIa platelet antigen, could not mediate this effect. While CD44 antibody-induced thrombocytopenia may contribute to some of its therapeutic effect against the initiation of arthritis, for established disease there are likely other mechanisms contributing to its efficacy. Humans are not known to express CD44 on platelets, and are therefore unlikely to develop thrombocytopenia after CD44 antibody treatment. An understanding of the relationship between arthritis, thrombocytopenia, and CD44 antibody treatment remains critical for continued development of CD44 antibody therapeutics.
    Full-text · Article · Jun 2013 · PLoS ONE
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Increased deposition of specific extracellular matrix (ECM) components is a characteristic of insulin resistant skeletal muscle. Hyaluronan (HA) is a major constituent of the ECM. The hypotheses that 1) HA content is increased in the ECM of insulin resistant skeletal muscle and 2) reduction of HA in the muscle ECM by long-acting pegylated human recombinant PH20 hyaluronidase (PEGPH20) reverses high fat (HF) diet-induced muscle insulin resistance were tested. We show that muscle HA was increased in HF diet induced obese (DIO) mice and that treatment of PEGPH20, which dose-dependently reduced HA in muscle ECM, decreased fat mass, adipocyte size, hepatic and muscle insulin resistance in DIO mice at 10mg/kg. Reduced muscle insulin resistance was associated with increased insulin signaling, muscle vascularization, and percent cardiac output to muscle rather than insulin sensitization of muscle per se. Dose response studies revealed that PEGPH20 dose-dependently increased insulin sensitivity in DIO mice with a minimally effective dose of 0.01mg/kg. PEGPH20 at doses of 0.1 and 1mg/kg reduced muscle HA to levels seen in chow-fed mice, decreased fat mass, and increased muscle glucose uptake. These findings suggest that ECM HA is a target for treatment of insulin resistance.
    Full-text · Article · Jan 2013 · Diabetes
Show more