MECHANISMS OF GRANULOMA-FORMATION IN MURINE MYCOBACTERIUM-AVIUM INFECTION - THE CONTRIBUTION OF CD4(-CELLS() T)

Infection with the virulent Mycobacterium avium strain TMC 724 caused progressive infection in C57BL/6 and BALB/c mice, while infection with a less virulent strain (M. avium SE 01) resulted in chronically persi stent bacterial loads, Livers of mice infected with TMC 724 were chara cterized by progressively expanding tumor-like infiltrations of epithe lioid macrophages, while SE 01 induced well-developed, compact epithel ioid granulomas that remained constant in size and number for at least 4 months. When C57BL/6 mice were depleted of CD4(+) T cells by i,p. a dministration of specific mAb at the time of infection, their capacity to initiate granuloma formation was completely abrogated during the f irst 4 weeks of infection, Semi-quantitative competitive RT-PCR of liv er homogenates obtained 3 weeks after infection revealed that depletio n of CD4(+) T cells was accompanied by a 25-fold reduced expression of IFN-gamma mRNA and a 5-fold reduced expression of tumor necrosis fact or (TNF)-alpha mRNA when compared to control infected mice, Granuloma morphology in response to either TMC 724 or SE 01 was similar in immun odeficient SCID mice to that observed in syngeneic BALB/c mice. Howeve r, SCID mice developed granulomas in a delayed fashion and were less e fficient in surrounding infected Kupffer cells with an inflammatory in filtration, The delayed kinetics of granuloma initiation in infected S CID mice was paralleled by a lower mRNA expression for IFN-gamma and T NF-alpha compared to that observed in infected BALB/c mice, mAb-mediat ed neutralization of IFN-gamma in BALB/c mice significantly reduced in flammatory infiltrations and granuloma formation, These data support t he conclusion that CD4(+) T cells accelerate granuloma formation by en hancing the production of TNF-alpha and IFN-gamma at the site of infec tion.