ROLE OF CYTOKINES IN THE PATHOGENESIS AND TREATMENT OF AUTOIMMUNE DISEASE

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Abstract

Studies in infectious disease and autoimmunity models have shown that immune responses to both self and foreign antigens are frequently dominated by induction of a particular Th1/Th2 subset with profound consequences for clinical outcome. Although the inflammatory effector function of Th1 cells is essential for the clearance of intracellular pathogens, it is also responsible for the tissue damage typical of organ-specific autoimmunity. Th2 cells which play an important role in the clearance of many helminthic infections function as suppressor cells or ineffectual bystanders in organ-specific autoimmune diseases. We have selected Experimental Allergic Encephalomyelitis (EAE) as our major model for the study of the role of the Th1/Th2 balance in the regulation of organ-specific autoimmunity. EAE is a demyelinating disease of the central nervous system (CNS) induced either by active immunization with myelin proteins or by the adoptive transfer of myelin protein reactive T cells. EAE is mediated by CD4+ T cells and the T cells responsible for disease induction produce Th1 type cytokines; myelin protein reactive Th2 T cells are non-encephalitogenic and in rare cases may be protective. As IL-12 produced by monocytes/dendritic cells has been shown to the most critical factor in the regulation of the development and differentiation of Th1 cells, we have focused our efforts on (1) the role of the IL-12/IL-12Rbeta2 pathway in the generation of autoreactive effector T cells which mediate EAE, (2) the potential contribution of IL-2 and IL-18 as costimulatory factors in the regulation of the IL-12/IL-12Rbeta2 pathway, (3) the downregulatory role of Th2 cytokines on this pathway, and (4) the role of the IL-12/IL-12Rbeta2 pathway in unmasking latent autoimmune effector T cells. We have demonstrated that the primary effect of IL-18 on Th1 differentiation is mediated by its capacity to directly upregulate IL-12 receptor expression which thereby enhances IL-12 mediated signaling. The enhancement of IL-12 receptor expression by IL-18 may be particularly important for the differentiation of foreign antigen- or autoantigen-specific Th1 cells when the stimulatory concentration of IL-12 in the microenvironment is just below the threshold required for Th1 development. We also demonstrated that IL-10 plays a critical role in the regulation of the IL-12/IL-12Rbeta2 pathway. Addition of IL-10 to cultures of primed T cells strongly inhibited upregulation of the IL-12Rbeta2 subunit. Presumably, IL-10 acted on the antigen presenting cell in these cultures to inhibit IL-12 production, but a direct effect of IL-10 on the responding T cell has not been excluded. The other major factors which we have identified as important in regulation of IL-12 receptor expression are costimulatory signals delivered to the antigen-specific T cells by interactions of the CD80/CD86 molecules on antigen presenting cells with CD28 on the T cell. We have demonstrated that costimulation is required for production of both IL-2 and IL-12 and that both of these cytokines are critical for the ability of T cells to express IL-12 receptors and to differentiate into pathogenic autoreactive T cells. We developed a novel system for induction of EAE by substituting CpG oligonucleotides for Freund's complete adjuvant. CpG oligos were potent adjuvants, but the results of these studies also suggested that they could potentially trigger autoimmune disease in susceptible individuals.