ABSTRACT

The role of cytokines and chemokines in the regulation of T-cell-mediated autoimmunity has been extensively studied. Based on their cytokine profile, CD4+ T-cells can be divided into: Th1 cells that produce large amounts of interferon gamma (IFN-) and tumor necrosis factor alpha (TNF-), and, to a much lesser extent, IL-4 and IL-10; and Th2 cells that produce IL-4, IL-10, and IL-13, and, to a much lesser extent, IFN- and TNF-.9-18 More recently defined subsets comprise the Th3 cells that

factor beta (TGF-) and have been associated with oral tolerance,19 and the high-IL-10-low-IL-4producing regulatory T-cells that have been implicated in colitis.20 Th1 cells selected in response to various autoantigens transfer T-cell-mediated autoimmune diseases, whereas IL-4-secreting Th2 cells, selected in response to these same antigens, either inhibit or exert no profound effect on the inflammatory process.13,21-33 High levels of IFN- and low levels of IL-4 positively select for Th1 cells, whereas low levels of IFN- together with high levels of IL-4 mediate Th2 selection.9-14 In a recent study, Wildbaum and Youssef isolated mRNA encoding rat IFN- inducing factor (IGIF, IL-18) from the EAE brain, generated neutralizing antibodies against its gene product, and used them to explore the role of IGIF in T-cell deviation and function.34 These antibodies significantly reduced the production of IFN- by primed T-cells proliferating in response to their target MBP epitope and by Con A-activated T-cells from naive donors. When administered to rats during the development of either active or transferred EAE, these antibodies significantly blocked the development of disease. Splenic Tcells from protected rats were cultured with the encephalitogenic MBP epitope and evaluated for production of IL-4 and IFN-. These cells, which proliferated, exhibited a profound increase in IL-4 production, accompanied by a significant decrease in IFN- and TNF- production.34 This study demonstrates, again, that by simple means one may interfere in a natural mechanism by which self-tolerance is maintained by the peripheral immune system to keep autoreactive lymphocytes under control.34 As an alternative approach to treat T-cell-mediated autoimmune diseases, one may use antibodies to key adhesion molecules that mediate leukocyte migration to their target organ. Eight years ago, we defined the 4 1 integrin (VLA-4) as the key adhesion molecule that mediates T-cell and monocyte transmigration to the target autoimmune site in EAE, and demonstrated that VLA-4-specific antibodies can inhibit the development and progression of disease.35 The underlying mechanism includes blockade of the secondary influx of leukocytes that is required for the development and progression of disease.36 Once again, this form of therapy is not disease, or organ, specific and is dependent on continuing exposure to these antibodies.