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

Abstract

Inflammatory destruction of insulin-producing ␤ 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.T he inflammatory cascade in affected organs of autoimmune diseases is a complex process that involves triggering of the immunological response, release of chemokines, cytokines, and toxic agents (e.g., reactive oxygen) by the activated cells, stimulation of endothelial cells, up-regulation of cell surface adhesion molecules, transendothelial cell migration, and a shift in the Th1͞Th2 balance in favor of the Th1 cells (1). Hence, the destructive autoimmune inflammatory process depends substantially (but not exclusively) on cell migration and cell interaction with matrix components of target organs. The destruction of pancreatic islet ␤-cells in insulin-dependent diabetes mellitus (IDDM) by invading leukocytes and the consequent deterioration of the insulin-dependent glucose homeostasis is an excellent example of such an autoimmune process (2, 3), although neither the nature of the triggering self-antigen nor the molecules associated with its recognition and presentation have been unequivocally identified.Whereas the function of selectins and integrins in supporting inflammatory cell migration and lodgment has been well established (4), the role of cell surface CD44 has only recently attracted attention (5). Alternative splicing and͞or posttranslation modifications generate many CD44 isoforms. The large array of CD44 isoforms is mainly attributable to the insertion of amino acid sequences, encoded by different combinations of 10 variant exons, into a membrane proximal position of the extracellular domain. Transcripts in which these variant exons are spliced out encode the most common and widely expressed 85-kDa isoform, known as standard CD44. The expression of CD44 isoforms containing s...

Small hyaluronan oligosaccharides induce inflammation by engaging both toll-like-4 and CD44 receptors in human chondrocytes

“…The interaction of HA degradation products with CD44 also provides signals to initiate inflammation [8,10,27]. Other data support the hypothesis that a balance between low molecular weight HA and high molecular weight HA may control the activation of inflammation [28].…”

RHAMM, a receptor for hyaluronan-mediated motility, compensates for CD44 in inflamed CD44-knockout mice: A different interpretation of redundancy

“…Disruption of CD44 function by anti-CD44 mAbs (20)(21)(22)(23)(24) or hyaluronidase (24) reduces the pathology of experimental inflammatory diseases such as CIA (20,21) and diabetes in NOD mice (24). CIA is, therefore, a CD44-dependent disease, and injection of type II collagen into CD44-deficient mice could reasonably be predicted to fail to induce joint inflammation.…”

“…24. Stained sections were digitally photographed at ϫ40 magnification at identical exposure times and saved as TIF files.…”

Defining the roles of T cell membrane proteinase and CD44 in type 1 diabetes

“…The interactions of T cell CD44 with its abundant endothelial hyaluronan ligand are essential for firm adhesion (3,4). Neutralizing antibodies to CD44 protect NOD mice from diabetes (5). CD44 is required for homing and engraftment of leukemic stem cells (6,7).…”