The immunosuppressive activity of proinflammatory cytokines in experimental models: potential for therapeutic intervention in autoimmunity.
The role of cytokines in the pathogenesis of T cell-mediated diseases, and in particular autoimmune responses, has been the subject of intense investigation in the past few years. Transgenic strains of mice have been generated, each expressing individual cytokines in organs targeted by autoimmunity. These animal models provide the most advanced tool available for analyzing the relationship between cytokines and T-dependent autoimmune responses. On the one hand, these experiments confirm that the local expression of proinflammatory cytokines is pivotal in initiating and maintaining pathogenic responses to self. On the other hand, and somewhat unexpectedly, these models have also revealed that cytokine factors controlling autoimmunity can act both as potentiating and inhibitory agents, depending upon the site and timing of exposure. As a result, one major concept emerging from different experimental models, including those originally established in our laboratory, is that proinflammatory cytokines may ameliorate autoimmunity. In this review, we analyze the mechanisms whereby cytokines that are considered as proinflammatory may in contrast suppress immune responses to self antigens. Besides emphasizing that the proinflammatory/immunogenic properties of a given cytokine may not be an intrinsic property, we review evidence that the regulation imposed by the cytokine network on autoimmunity is a finely tuned balance between activation and downmodulation of an individual autoreactive T cell repertoire. By emphasizing that factors such as the duration of cytokine exposure and the type of cell population involved strongly influence that balance, we underline the potential therapeutic implications of cytokine-mediated modulation of autoimmunity.
Grohmann
U
U
Department of Experimental Medicine, University of Perugia, Perugia, Italy. ugrohmann@tin.it
Puccetti
P
P
D000818:Animals; D000938:Antigen-Presenting Cells / Q000187:drug effects; D001327:Autoimmune Diseases / Q000188:drug therapy* / Q000209:etiology; D016207:Cytokines / Q000494:pharmacology* / Q000627:therapeutic use; D003713:Dendritic Cells / Q000187:drug effects; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007371:Interferon-gamma / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology; D014364:Tryptophan / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D016207:Cytokines; D007166:Immunosuppressive Agents; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D007371:Interferon-gamma; D014364:Tryptophan