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Infection and Immunity, April 1999, p. 1659-1665, Vol. 67, No. 4
0019-9567/99/$04.00+0

The p47phoxminus /minus Mouse Model of Chronic Granulomatous Disease Has Normal Granuloma Formation and Cytokine Responses to Mycobacterium avium and Schistosoma mansoni Eggs

Brahm H. Segal,1 T. Mark Doherty,2 Thomas A. Wynn,2 Allen W. Cheever,2 Alan Sher,2 and Steven M. Holland1,*

Laboratory of Host Defenses1 and Laboratory of Parasitic Diseases,2 National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892

Received 11 September 1998/Returned for modification 19 October 1998/Accepted 19 January 1999

Chronic granulomatous disease (CGD) is a genetic disorder of NADPH oxidase in which phagocytes are defective in generating reactive oxidants. CGD patients suffer from recurrent infections and exuberant and persistent tissue granuloma formation. We hypothesized that abnormal granulomata in CGD may result from aberrant T-cell-mediated cytokine responses. To assess Th-1-type cytokine responses and granulomata, we challenged p47phox-/- and wild-type mice with avirulent (SmD) or virulent (SmT) variants of Mycobacterium avium 2-151. To assess Th-2-type cytokine responses and granulomata, we used Schistosoma mansoni eggs (SME). Mononuclear cells were harvested, and cytokine responses were determined by enzyme-linked immunosorbent assay or reverse transcriptase PCR. Following SmD or SmT challenge, splenocytes from p47phox-/- and wild-type mice generated similar polar Th-1 responses (increased levels of gamma interferon and basal levels of interleukin 4 [IL-4] and IL-5). By 8 weeks after SmT challenge, exuberant splenic granulomata developed in p47phox-/- and wild-type mice. After SME challenge, thoracic lymph node mononuclear cells from p47phox-/- and wild-type mice generated similar 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 p47phox-/- and wild-type mice. These results suggest that exuberant granulomatous inflammation in CGD is probably not the result of skewing of T-cell responses toward the Th-1 or Th-2 pole. Appropriate regression of established tissue granulomata in p47phox-/- mice challenged with SME suggests that abnormal granuloma formation in CGD is stimulus dependent and is not an invariant feature of the disease.

* Corresponding author. Mailing address: Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 10 Center Dr., Dr. MSc. 1886, Bethesda, MD 20892. Phone: (301) 402-7684. Fax: (301) 402-4369. E-mail: smh{at}nih.gov.

Infection and Immunity, April 1999, p. 1659-1665, Vol. 67, No. 4
0019-9567/99/$04.00+0


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