CD3 antibody-induced IL-10 in renal allograft recipients - An in vivo and in vitro analysis

Background The first administration of CD3 monoclonal antibodies, such as anti-human CD3 (OKT3), induces a massive release of several cytokines, including tumor necrosis factor alpha (TNF-alpha), interferon (IFN)-gamma interleukin (IL)-2, IL-3, IL-6, and granulocyte-macrophage colony-stimulating factor. Methods. Cytokine levels in patient's sera were measured by specific ELISA. In vitro cultures were performed using OKT3-stimulated peripheral blood mononuclear cells and/or whole blood from patients and normal controls. Results. Here we describe that OKT3 administration to human renal allograft recipients also leads to a significant release of IL-10, Contrasting with most OKT3-induced cytokines, such as TNF-alpha whose release is transient, IL-10 levels show a more progressive increase, they peak only by 4-8 hr after the first OKT3 injection and persist longer. Thus, significant IL-10 levels are still detectable at the time of the second and the third OKT3 injection. Administration of corticosteroids, 1 hr before the first OKT3 injection, significantly reduced both TNF-a and IL-10 release, Experiments were performed to evaluate the source(s) of IL-10 and its (their) influence on the initial T-cell activation, When stimulated in culture with soluble OKT3, the production of IL-10 was dependent on the cooperation between T lymphocytes and monocytes. It is important that, as assessed through the use of a specific neutralizing antibody, the endogenous IL-10 produced in the co-culture system exerted a negative feed-back on the release of the other pro-inflammatory CD3-induced cytokines, which was reproducible. Conclusion. These results are supportive of a major role of IL-10 in the down-modulation of the OKT3-triggered T-cell activation cascade.