Recent studies have demonstrated a crucial role for TNF during inflammatory granuloma formation. In addition, TNF has been shown to up-regulate adhesion molecules that participate in cellular recruitment and lymphocyte activation. In the present study, we have examined the mechanism of TNF activation during Schistosoma mansoni egg granuloma formation and its relationship to the expression of ICAM-1. Our initial studies showed that high affinity human soluble TNFR coupled to the Fc portion of an Ig (sTNFR:Fc construct) could effectively diminish granuloma formation and lymphocyte activation in vivo. We have also assessed the increased expression of ICAM-1, its contribution to granuloma development, and its relationship with TNF during lesion formation. Increased steady state ICAM-1 mRNA expression was observed in primary egg granulomas when compared with normal lung and foreign body (Sephadex bead) granulomas, which suggests a role for ICAM-1 in Ag-induced lesion formation. Subsequent studies have demonstrated that sTNFR:Fc treatment down-regulated granuloma formation and ICAM-1 expression, thus suggesting one mechanism of TNF involvement in granuloma formation was through the induction of ICAM-1. Anti-ICAM-1 decreased the soluble egg Ag-specific T cell proliferation in vitro. In addition, passive immunization of mice with anti-ICAM-1 mAb during primary granuloma formation resulted in an attenuation of lesion development as compared with lesion development in a control Ab-treated group. The proliferative response to soluble egg Ag was also significantly reduced in ex vivo experiments that used spleen cells from the anti-ICAM-1 treated mice. These data demonstrate that both TNF and ICAM-1 participate in lymphocyte activation and granuloma formation and suggest that one mechanism of TNF in granuloma development is through TNF-induced ICAM-1 expression.