INFLAMMATORY GRANULOMA-FORMATION IS MEDIATED BY TNF-ALPHA-INDUCIBLE INTERCELLULAR-ADHESION MOLECULE-1

Recent studies have demonstrated a crucial role for TNF during inflamm atory granuloma formation. In addition, TNF has been shown to up-regul ate adhesion molecules that participate in cellular recruitment and ly mphocyte activation. In the present study, we have examined the mechan ism of TNF activation during Schistosoma mansoni egg granuloma formati on and its relationship to the expression of ICAM-1. Our initial studi es showed that high affinity human soluble TNFR coupled to the Fc port ion of an Ig (sTNFR:Fc construct) could effectively diminish granuloma formation and lymphocyte activation in vivo. We have also assessed th e increased expression of ICAM-1, its contribution to granuloma develo pment, and its relationship with TNF during lesion formation. Increase d steady state ICAM-1 mRNA expression was observed in primary egg gran ulomas when compared with normal lung and foreign body (Sephadex bead) granulomas, which suggests a role for ICAM-1 in Ag-induced lesion for mation. Subsequent studies have demonstrated that sTNFR:Fc treatment d own-regulated granuloma formation and ICAM-1 expression, thus suggesti ng one mechanism of TNF involvement in granuloma formation was through the induction of ICAM-1. Anti-ICAM-1 decreased the soluble egg Ag-spe cific T cell proliferation in vitro. In addition, passive immunization of mice with anti-ICAM-1 mAb during primary granuloma formation resul ted in an attenuation of lesion development as compared with lesion de velopment 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 d emonstrate that both TNF and ICAM-1 participate in lymphocyte activati on and granuloma formation and suggest that one mechanism of TNF in gr anuloma development is through TNF-induced ICAM-1 expression.