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

Department of Bone Marrow Transplantation, Hadassah University Hospital, Jerusalem 91120, Israel.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 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.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: CD44 is expressed on the cell surface of lymphocytes and other hematopoietic and non-hematopoietic cells, where regulates cell-cell and environment-cell interactions by binding different components of extracellular matrix. CD44 is implicated in several other cellular processes, such as regulation of growth, survival, differentiation and motility, both under physiological and pathologic conditions. Studies on CD44-null or transgenic mice also established its involvement in diseases such as cancer, atherosclerosis and myocardial infarction. Its regulation involves several control mechanisms among which a fundamental role is played by alternative splicing of its pre-mRNA and by post-translational modifications. Here we review the mechanisms of regulation upstream and downstream of CD44.
    International Trends in Immunology. 09/2013;
  • Source
    [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.
    Diabetes 01/2013; · 7.90 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Adhesion molecule CD44 is expressed by multiple cell types and is implicated in various cellular and immunological processes. In this study, we examined the effect of global CD44 deficiency on the myelin oligodendrocyte glycoprotein peptide (MOG)-induced experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis. Significantly greater disease severity was observed in CD44-deficient mice compared to C57BL/6 wild-type mice. The CD44-deficient mice presented with greater numbers of immune cells in the central nervous system and increased anti-MOG antibody and proinflammatory cytokine production, especially those associated with T helper (Th17) cells. Further, decreased numbers of peripheral CD4(+)CD25(+)FoxP3(+) regulatory T cells (Tregs) were observed in the CD44-knockout mice throughout the disease course. CD44-knockout CD4 T cells exhibited reduced transforming growth factor-β receptor type I (TGF-β RI) expression that did not impart a defect in Treg polarization in vitro, but did correlate with enhanced Th17 polarization in vitro. Further, EAE in bone marrow-chimeric animals suggested CD44 expression on both circulating and noncirculating cells limited disease severity. Expression of CD44 on endothelial cells was found to be important in limiting T-cell adhesion to and transmigration through murine endothelial monolayers in vitro. Importantly, we also identified increased permeability of the blood-brain barrier in vivo in CD44-deficient mice before and following immunization. These data suggest that CD44 has multiple protective roles in EAE, with effects on cytokine production, T-cell differentiation, T-cell-endothelial cell interactions, and blood-brain barrier integrity.
    American Journal Of Pathology 02/2013; · 4.60 Impact Factor

Full-text (2 Sources)

Available from
May 20, 2014