Cytokine Profiles in Primary and Secondary Pulmonary Granulomas of Guinea Pigs with Tuberculosis

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Abstract
The cytokine mRNA profiles of primary (arising from inhaled bacilli) and secondary (arising from hematogenous reseeding of the lung) granulomas from the lung lobes of bacillus Calmette-Guerin (BCG)- vaccinated and unimmunized guinea pigs challenged with virulent Mycobacterium tuberculosis by the pulmonary route were assessed in situ using laser capture microdissection (LCM) at 6 weeks after infection. The challenge dose chosen was so low that some lung lobes did not receive an implant from the airway. In unimmunized guinea pigs, some lobes contained either large, necrotic primary lesionsorsmall,non-necroticsecondarylesions,orboth.Thelobesof BCG-vaccinatedanimalscontainedonlynon-necroticprimarytuber- cles, and no secondary lesions were visible. Real-time PCR analysis of the acquired RNA clearly demonstrated that primary tubercles from BCG-vaccinated guinea pigs were overwhelmed with mRNA from the anti-inflammatory cytokine, transforming growth factor (TGF)-b, with some IFN-g and IL-12p40 mRNA. In contrast, primary lesions from unimmunized animals were dominated by proinflam- matory TNF-a mRNA. The cytokine mRNA profile of secondary lesions from unimmunized animals was strikingly similar to the profile of primary lesions from BCG-vaccinated guinea pigs (i.e., a predominance of TGF-b mRNA with some IL-12p40 and IFN-g mRNA),indicatingthatthelunglobesfromwhichtheselesionswere retrieved had been naturally ''vaccinated'' by the time the blood- borne bacilli returned to the lung at 3 to 4 weeks after infection. Furthermore, cytokine mRNA analysis of splenic granulomas from nonvaccinatedandvaccinatedanimalsshowedcloseresemblanceto primary granulomas recovered from the lungs of the same animal, that is, high levels of TNF-a mRNA in unimmunized animals, and mostlyTGF-bmRNAinBCG-vaccinatedguineapigs.Takentogether, these data indicate that mycobacteria returning to the lungs of unimmunized guinea pigs 3 to 4 weeks after infection induce a local cytokineresponsethatis fundamentallydifferentfromthe response to inhaled bacilli and is reminiscent of the primary response in a vaccinated animal.

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