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: 9.81). 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.

Download full-text


Available from: Patrizia Cohen, Aug 26, 2015
  • Source
    • "However, studies of T1D suggested that control of inflammation can be achieved by altering the migration and survival of effector/memory T cells and T regs in addition to migration as summarized below. Type 1 diabetes represents an important example of a chronic disease that can be prevented by treatment with anti-CD44 during the prediabetic phase in the NOD mouse model (Weiss et al., 2000). Although the development of this disease is multifactorial, T cells orchestrate the inflammation that leads to destruction of insulinproducing islet β-cells. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Despite the widespread use of the cell-surface receptor CD44 as a marker for antigen (Ag)-experienced, effector and memory T cells, surprisingly little is known regarding its function on these cells. The best-established function of CD44 is the regulation of cell adhesion and migration. As such, the interactions of CD44, primarily with its major ligand, the extracellular matrix (ECM) component hyaluronic acid (HA), can be crucial for the recruitment and function of effector and memory T cells into/within inflamed tissues. However, little is known about the signaling events following engagement of CD44 on T cells and how cooperative interactions of CD44 with other surface receptors affect T cell responses. Recent evidence suggests that the CD44 signaling pathway(s) may be shared with those of other adhesion receptors, and that these provide contextual signals at different anatomical sites to ensure the correct T cell effector responses. Furthermore, CD44 ligation may augment T cell activation after Ag encounter and promote T cell survival, as well as contribute to regulation of the contraction phase of an immune response and the maintenance of tolerance. Once the memory phase is established, CD44 may have a role in ensuring the functional fitness of memory T cells. Thus, the summation of potential signals after CD44 ligation on T cells highlights that migration and adhesion to the ECM can critically impact the development and homeostasis of memory T cells, and may differentially affect subsets of T cells. These aspects of CD44 biology on T cells and how they might be modulated for translational purposes are discussed.
    Frontiers in Immunology 02/2012; 3:23. DOI:10.3389/fimmu.2012.00023
  • Source
    • "CD44 stimulation with HA plays a role in various physiological functions, such as cell-adhesion, cell-substrate interactions, and lymphocyte recruitment, as well as in pathological processes such as chronic inflammation and metastasis of malignant cells [22]. A role for CD44, as HA receptor, in the regulation of inflammation in vivo has been shown by studies in which anti-CD44 treatment reduces not only inflammation in experimental diabetes [23] [24], but also leukocyte migration in skin-associated immune disease [25]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The cluster determinant (CD44) seems to play a key role in tissues injured by diabetes type 2. CD44 stimulation activates the protein kinase C (PKC) family which in turn activates the transcriptional nuclear factor kappa B (NF-κB) responsible for the expression of the inflammation mediators such as tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), interleukin-18 (IL-18), inducible nitric oxide synthase (iNOS), and matrix metalloproteinases (MMPs). Regulation of CD44 interaction with its ligands depends greatly upon PKC. We investigated the effect of the treatment with high-molecular weight hyaluronan (HA) on diabetic nephropathy in genetically diabetic mice. BKS.Cg-m+/+Lepr(db) mice had elevated plasma insulin from 15 days of age and high blood sugar levels at 4 weeks. The severe nephropathy that developed was characterized by a marked increased in CD44 receptors, protein kinase C betaI, betaII, and epsilon (PKC(βI), PKC(βII), and PKCε) mRNA expression and the related protein products in kidney tissue. High levels of mRNA and related protein levels were also detected in the damaged kidney for NF-κB, TNF-α, IL-6, IL-18, MMP-7, and iNOS. Chronic daily administration of high-molecular mass HA for 2 weeks significantly reduced CD44, PKC(βI), PKC(βII), and PKCα gene expression and the related protein production in kidney tissue and TNF-α, IL-6, IL-18, MMP-7, and iNOS expression and levels also decreased. Histological analysis confirmed the biochemical data. However, blood parameters of diabetes were unchanged. These results suggest that the CD44 and PKC play an important role in diabetes and interaction of high-molecular weight HA with these proteins may reduce inflammation and secondary pathologies due to this disease.
    Biochimica et Biophysica Acta 11/2010; 1802(11):1118-30. DOI:10.1016/j.bbadis.2010.08.004 · 4.66 Impact Factor
  • Source
    • "The interactions of T cell CD44 with its abundant endothelial ligand (hyaluronan) are essential for firm adhesion (Butcher et al., 1999; Nandi et al., 2004; Sallusto et al., 2000; Weber, 2003). Thus, neutralizing antibodies to CD44 protect NOD mice from diabetes (Weiss et al., 2000). Chemokines, expressed in a tissue-specific manner, mediate homing specificity by activating cognate G protein-coupled receptors on the T cells (Campbell and Butcher, 2000; Savinov et al., 2003b). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The pathogenesis of type 1 diabetes begins with the activation of autoimmune T killer cells and is followed by their homing into the pancreatic islets. After penetrating the pancreatic islets, T cells directly contact and destroy insulin-producing beta cells. This review provides an overview of the dynamic interactions which link T cell membrane type-1 matrix metalloproteinase (MT1-MMP) and the signaling adhesion CD44 receptor with T cell transendothelial migration and the subsequent homing of the transmigrated cells to the pancreatic islets. MT1-MMP regulates the functionality of CD44 in diabetogenic T cells. By regulating the functionality of T cell CD44, MT1-MMP mediates the transition of T cell adhesion to endothelial cells to the transendothelial migration of T cells, thus, controlling the rate at which T cells home into the pancreatic islets. As a result, the T cell MT1-MMP-CD44 axis controls the severity of the disease. Inhibition of MT1-MMP proteolysis of CD44 using highly specific and potent synthetic inhibitors, which have been clinically tested in cancer patients, reduces the rate of transendothelial migration and the homing of T cells. Result is a decrease in the net diabetogenic efficiency of T cells and a restoration of beta cell mass and insulin production in NOD mice. The latter is a reliable and widely used model of type I diabetes in humans. Overall, existing experimental evidence suggests that there is a sound mechanistic rationale for clinical trials of the inhibitors of T cell MT1-MMP in human type 1 diabetes patients.
    Vitamins & Hormones 02/2009; 80:541-62. DOI:10.1016/S0083-6729(08)00618-3 · 1.78 Impact Factor
Show more