Article

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.

0 Bookmarks
 · 
65 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Hyaluronan is an extracellular matrix glycosaminoglycan that is present in pancreatic islets but little is known about its involvement in the development of human type 1 diabetes (T1D). We have evaluated whether pancreatic islets and lymphoid tissues of T1D and non-diabetic organ donors differ in the amount and distribution of hyaluronan and hyaluronan binding proteins (hyaladherins) such as inter-α-inhibitor (IαI), versican, and tumor necrosis factor-stimulated gene-6 (TSG-6). Hyaluronan was dramatically increased both within the islet and outside the islet endocrine cells, juxtaposed to islet microvessels in T1D. In addition, hyaluronan was prominent surrounding immune cells in areas of insulitis. IαI and versican were present in hyaluronan-rich areas of islets and both molecules accumulated in diabetic islets and regions exhibiting insulitis. TSG-6 was observed within the islet endocrine cells and in inflammatory infiltrates. These patterns were only observed in tissues from younger donors with disease duration of less than 10 years. Furthermore, hyaluronan and IαI amassed in follicular germinal centers and in T-cell areas in lymph nodes and spleens in T1D compared to controls. Our observations highlight potential roles for hyaluronan and hyaladherins in the pathogenesis of diabetes.
    Diabetes 03/2014; · 7.90 Impact Factor
  • 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

Full-text (2 Sources)

Download
14 Downloads
Available from
May 20, 2014