[118, 119] Similar to see more some of the EAE models, stimulation of type I NKT cells with αGalCer results in disease exacerbation associated with a Th1 cytokine release profile.[118-121] In the latter cases, type I NKT cell activation by αGalCer or its analogues may lead to the tolerization of APC populations. In turn, this outcome may inhibit the activity of most Th1/Th17/Th2 secreting effector cells and thereby lead to protection from autoimmune disease. Generally, activation of type II NKT cells with self-glycolipid

sulphatide may control both antigen-induced and spontaneously arising autoimmune disease. During EAE, sulphatide-reactive type II NKT cells, but not type I NKT cells, are increased several fold in the CNS. This greater abundance of type II NKT cells in the CNS inverts the usual ratio of type II : type I NKT cells (type II NKT cells, 3–4%; and type I NKT cells, 0·6–0·9%) and affords BIBW2992 molecular weight protection from EAE.[27, 61] Furthermore, administration of sulphatide to activate type II NKT cells decreases the number of IFN-γ- and IL-17-secreting myelin basic protein and proteolipid protein-reactive encephalitogenic CD4+

T cells. The net outcome is protection from EAE via a CD1d-dependent regulatory pathway (Maricic et al., submitted). This type II NKT-mediated immunoregulatory pathway results in (i) inactivation of type I NKT cells that now function as regulatory T cells, (ii) tolerization

of conventional DCs, (iii) tolerization of microglia in the CNS and (iv) inhibition of the effector Benzatropine functions of pathogenic MHC-restricted CD4+ T cells. As APCs that activate pathogenic Th1 and Th17 cells in lymphoid organs and the CNS are tolerized following sulphatide administration, activation of type II NKT cells induced by sulphatide is much more potent in the regulation of autoimmune demyelination than only the inactivation of type I NKT cells by αGalCer (Maricic et al., submitted). Activation of type II NKT cells by sulphatide was recently reported to protect NOD mice from type 1 diabetes.[28, 89] Pre-treatment of NOD mice with the C24:0 but not C18:0 sulphatide analogue was found to protect against the transfer of type 1 diabetes.[89] These data suggest that the longer C24:0 sulphatide analogue should be examined for its therapeutic value in clinical trials in human subjects at risk for or newly diagnosed with type 1 diabetes. Our preliminary studies suggest that activation of type II NKT cells following administration of sulphatide significantly prevents lupus nephritis in (NZB × NZW) F1 mice, indicating that the protective capacity of sulphatide activated type II NKT cells can counteract potentially pathogenic type I NKT cells.