The p47(phox-/-) mouse model of chronic granulomatous disease has normal granuloma formation and cytokine responses to Mycobacterium avium and Schistosoma mansoni eggs

Chronic granulomatous disease (CGD) is a genetic disorder of NADPH oxidase in which phagocytes are defective in generating reactive oxidants. CGD pati ents suffer from recurrent infections and exuberant and persistent tissue g ranuloma formation. We hypothesized that abnormal granulomata in CGD may re sult from aberrant T-cell-mediated cytokine responses. To assess Th-1-type cytokine responses and granulomata, we challenged p47(phox-/-) and wild-typ e mice with avirulent (SmD) or virulent (SmT) variants of Mycobacterium avi um 2-151. To assess Th-2-type cytokine responses and granulomata, we used S chistosoma mansoni eggs (SME). Mononuclear cells were harvested, and cytoki ne responses were determined by enzyme-linked immunosorbent assay or revers e transcriptase PCR. Following SmD or SmT challenge, splenocytes from p47(p hox-/-) and mild-type mice generated similar polar Th-l responses (increase d levels of gamma interferon and basal levels of interleukin 4 [IL-4] and I L-5). By 8 weeks after SmT challenge, exuberant splenic granulomata develop ed in p47(phox-/-) and wild-type mice. After SME challenge, thoracic lymph node mononuclear cells from p47(phox-/-) and wild-type mice generated simil ar mixed Th-1 and Th-2 cytokine responses to SME antigen and concanavalin A . Peak lung granuloma sizes and rates of regression were similar in p47(pho x-/-) and wild-type mice. These results suggest that exuberant granulomatou s inflammation in CGD is probably not the result of skewing of T-cell respo nses toward the Th-1 or Th-2 pole. Appropriate regression of established ti ssue granulomata in p47(phox-/-) mice challenged with SME suggests that abn ormal granuloma formation in CGD is stimulus dependent and is not an invari ant feature of the disease.