INTERLEUKIN-4 AND INTERLEUKIN-10 SYNERGIZE TO INHIBIT CELL-MEDIATED-IMMUNITY IN-VIVO

The lack of cell-mediated (Th1-like) immunity that is often associated with strong humoral immune responses is thought to be due in part to the inhibition of Th1 effector function by the Th2-derived cytokine in terleukin-10 (IL-10). This hypothesis, however. is based entirely on r esults from in vitro studies, wherein IL-10 has been shown to inhibit Th1 cytokine synthesis. In this study we have compared the regulatory effects of both IL-4 and IL-10 on the development of a more complex Th 1 effector function in vivo, the development of delayed-type hypersens itivity (DTH) to Leishmania major in mice immune to Leishmania. The re sults revealed two findings unexpected from in vitro studies with Th1 clones. First, optimal inhibition of the DTH response (up to 70%), ass essed by footpad swelling and leukocytic infiltration, required the co mbination of IL-4 and IL-10, indicating that these two activities syne rgized to inhibit DTH reactivity. Second, IL-4 inhibited interferon-ga mma (IFN-gamma) production by lymph node cells draining the site of an tigen challenge as well as did IL-10. The combination of both cytokine s was no more effective than either alone. The mechanism by which IL-4 and IL-10 acted to inhibit DTH responses did not appear to be through inhibition of IFN-gamma or tumor necrosis factor production as treatm ent with antibodies which neutralized these activities failed to inhib it DTH responses. Inhibition of the DTH with IL-4 and IL-10 is the mos t effective specific regulator of DTH responses reported and the only one capable of modulating tuberculin DTH. These data establish IL-4 an d IL-10 as potent inhibitors of Th1 effector function in vivo and sugg est their utility in controlling deleterious Th1-mediated inflammatory responses such as occur in some infectious and autoimmune diseases.