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

摘要

Inflammatory destruction of insulin-producing β cells in the pan- creatic 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 anal ysis of diabetic pancreata revealed that mononuclear cells infil- trating 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 endo- thelium. 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 ox- azolone was not influenced by this treatment. A similar antidia- betic effect was observed even when the anti-CD44 mAb admin- istration 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 dem- onstrate that CD44-positive inflammatory cells may be a potential therapeutic target in insulin-dependent diabetes.