Oral Tolerance is the temporary loss of systemic immunological responsiveness to a specific soluble antigen after ingestion of that antigen. Results from our lab and others indicated that CTLA-4 and lack of IL-12 played a role in the induction of low dose oral tolerance at the Th1 cell level. Previous literature suggested that IL-18 also played a role in preventing oral tolerance induction while the cytokine IL-10 had been shown to be a factor contributing to suppressed immune responses. To determine the role of CTLA-4 in conjunction with either IL-18 or IL-10 in low dose oral tolerance induction, anti-CTLA-4 mAb and either IL-18 or anti-IL-10 mAb were administered concurrently to mice fed either ovalbumin (OVA) or water. Results showed that the PLN cell proliferation of mice treated with anti-CTLA-4 mAb and IL-18 remained significantly suppressed compared with water-fed controls, while a partial abrogation of suppressed IL-4 and IFN-γ levels were observed. In contrast, mice treated with anti-CTLA-4 mAb and anti-IL-10 mAb exhibited a reversal of PLN cell proliferation and IL-4 suppression; however, IFN-γ levels remained suppressed. Results suggest that IL-10, IL-18 and CTLA-4 play roles in the induction of oral tolerance at the cell proliferation and cytokine level.