Substance P receptor antagonist inhibits murine IgM expression in developing schistosome granulomas by blocking the terminal differentiation of intragranuloma B cells.

Schistosome granulomas make substance P (SP). CP96,345 is a nonpeptide SP receptor antagonist active in vivo. Granulomas that form in the presence of SP receptor blockade produce little IgM as compared to normal lesions. The objective of this study was to determine how CP96,345 modulates granuloma IgM production. Schistosome ova were embolized to the lungs of infected mice to induce granulomas of synchronous age. Animals received CP96,345 (50 mg/kg/day) for 4 days following egg embolization. Then granulomas were isolated from tissue and dispersed into single-cell preparations. The dispersed granuloma cells were cultured in vitro to measure IgM and cytokine secretion. Also, granuloma B cells were studied using an IgM ELISPOT assay and flow cytometry. As expected, mice treated with CP96,345 formed granulomas that secreted little IgM. Granulomas from CP96,345-treated mice, as compared to buffer-treated animals, contained few IgM-secreting B lymphocytes, but had appropriate numbers of B cells expressing surface IgM. Also decreased was the capacity of the granulomas to make IFN-gamma, IL-4, IL-5 and IL-6. CP96,345 treatment did not affect splenocyte IgM or cytokine synthesis. These data suggest that CP96,345 inhibits granuloma IgM secretion by blocking intragranuloma B cell maturation at a terminal stage of B cell differentiation. Moreover, SP receptor antagonist affects a variety of cytokine circuits that could influence IgM B cell maturation in vivo.