CYTOKINE RESPONSES DURING MYCOBACTERIAL AND SCHISTOSOMAL ANTIGEN-INDUCED PULMONARY GRANULOMA-FORMATION - PRODUCTION OF TH1 AND TH2 CYTOKINES AND RELATIVE CONTRIBUTION OF TUMOR-NECROSIS-FACTOR

Synchronized pulmonary granulomas (GRs) were induced in presensitized mice by intravenous embolization of polymer beads bound with purified protein derivative (PPD) of Mycobacteria tuberculosis or soluble antig ens derived from Schistosoma mansoni eggs (SEA). Uncoated beads served as a foreign body control (CON). Antigen-coated beads elicited GRs wi th characteristic epithelioid macrophages and multinucleate giant cell s by 4 days after embolization. Unlike PPD GR, SEA bead lesions contai ned eosinophils, whereas CON beads elicited only a limited mononuclear infiltrate. GRs and draining lymph nodes (LN) were assessed on days 2 , 4, and 8 for Th1-(interleukin-2 [IL-2], interferon-gamma[IFN]) and T h2-type (IL-4, IL-5, and IL-10) cytokines. CON GR produced only a smal l amount of IFN-gamma on day 2 and failed to induce a significant resp onse in draining LN. In contrast, both PPD and SEA antigen-coated bead s induced reactive lymphoid hyperplasia but differed greatly in local and regional cytokine profiles. PPD GR produced IFN-gamma on day 2 and the draining LN produced predominantly Th1 cytokines on days 2 and 4. In contrast, SEA bead GRs were dominated by Th2 cytokines. The corres ponding LN produced IL-2 and IL-4 on day 2; IL-2, IL-4, IFN-gamma, and IL-10 on day 4; then IL-2, IFN-gamma, and IL-4 on day 8, probably ref lecting maturational changes of T cells. Macrophages (MP) from bead GR also showed different patterns of IL-6 and tumor necrosis factor (TNF ) production. Compared with CON GR, MPs from PPD GR were weak sources of IL-6, whereas those of SEA GR showed enhanced and accelerated produ ction. In contrast, MP of PPD GR had augmented TNF-producing capacity, whereas those of SEA GR showed delayed TNF production. In vivo deplet ion of TNF, respectively, caused 40 and 10% decreases in PPD GR and SE A GR but had no effect on CON GR area, indicating that TNF contributed to a greater degree to the PPD response. These data show that dependi ng on the inciting agent, GR can be mediated by different cytokines. C haracterization of inflammatory lesions by cytokine profiles should al low design of more rational therapeutic interventions.