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

Inflammatory destruction of insulin-producing beta cells in the pancreatic islets is the hallmark of insulin-dependent diabetes mellitus, a spontaneou s autoimmune disease of non-obese diabetic mice resembling human juvenile ( type I) diabetes. Histochemical analysis of diabetic pancreata revealed tha t mononuclear cells infiltrating the islets and causing autoimmune insuliti s, as well as local islet cells, express the CD44 receptor; hyaluronic acid , the principal ligand of CD44, is detected in the islet periphery and isle t endothelium. Injection of anti-CD44 mAb 1 hr before cell transfer of diab etogenic splenocytes and subsequently on alternate days for 4 weeks induced considerable resistance to diabetes in recipient mice, reflected by reduce d insulitis. Contact sensitivity to oxazolone was not influenced by this tr eatment. 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 w eeks after cell transfer. Administration of the enzyme hyaluronidase also i nduced appreciable resistance to insulin-dependent diabetes mellitus, sugge sting that the CD44-hyaluronic acid interaction is involved in the developm ent of the disease. These findings demonstrate that CD44-positive inflammat ory cells may be a potential therapeutic target in insulin-dependent diabet es.