Administration of sulfatide to ameliorate type I diabetes in non-obese diabetic mice.

The endogenous glycosphingolipid sulfatide is a ligand for CD1d-restricted type II natural killer T (NKT) lymphocytes. Through the action of these cells,sulfatide treatment has been shown to modulate the immune response in mouse models for autoimmune diseases, infections and tumour immunity. Sulfatide exists naturally in different organs including the pancreas, where sulfatide colocalizes with insulin within the Langerhans islet b-cells, targets for the immune destruction in type 1 diabetes (T1D). Human T1D patients, but not patients with type 2 diabetes nor healthy individuals, have autoantibodies against sulfatide in serum, suggesting that sulfatide induces an immune response in the natural course of T1D in humans. Here, we investigate sulfatide as an autoantigen and a modulator of autoimmune disease in the murine model forT1D, the non-obese diabetic (NOD) mice. We demonstrate that aged NOD mice displayed serum autoantibody reactivity to sulfatide; however, this reactivity did not correlate with onset of T1D. Repeated administration of sulfatide did not result in an increase in serum reactivity to sulfatide. Moreover, a multidose sulfatide treatment of female NOD mice initiated at an early (5 weeks of age),intermediate (8 weeks of age) or late (12 weeks of age) phase of T1D progression did not influence the incidence of disease. Thus, we demonstrate that a fraction of NOD mice develop autoantibody reactivity to sulfatide; however, we fail to demonstrate that sulfatide treatment reduces the incidence of T1D in this mouse strain.

Immunomodulatory type II natural killer T lymphocytes in health and disease.

Natural killer T (NKT) lymphocytes are αß T cells activated by lipid-based ligands presented on the non-polymorphic CD1d-molecule. Type I NKT cells that carry an invariant Vα14 (in the mouse) or Vα24 (in humans) T cell receptor α-chain rearrangement have received significant attention for their involvement in a diversity of immune reactions. Their sister population, CD1d-restricted type II NKT cells, has been more difficult to study because of the lack of molecular markers that specify these cells. In the last few years, however, significant progress has been made, demonstrating that type II NKT cells have unique functions in immune responses to tumours and infections, in autoimmunity, obesity and graft-versus-host disease. Type II NKT cells appear more frequent than type I NKT cells in humans and accumulate in certain diseases such as ulcerative colitis, hepatitis and multiple myeloma. Recently, novel type II NKT cell ligands have been identified, and it is becoming clear that the type II NKT cell population may be oligoclonal. Here, we review the recent progress in the study of type II NKT cells, supporting the view that type II NKT cells may be attractive targets for immunotherapy.