HELMINTH-INDUCED CHANGES IN PULMONARY IMMUNITY: ALTERNATIVELY ACTIVATED ALVEOLAR MACROPHAGES AND MODULATION OF RESPONSES TO ALLERGEN CHALLENGE
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Date
2008-02-01T19:18:51Z
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Johns Hopkins University
Abstract
The lungs are constantly exposed to microbial pathogens and environmental
stimuli that can trigger time-limited defense responses, generalized persistent
inflammatory response or no response at all. Exposure history has a profound influence
on the nature and level of immune reactivity in the lungs. To date, there is little data on
the immediate and long-term changes that take place in the lungs as a consequence of
infection. The work presented here used the Nippostrongylus brasiliensis (Nb) mouse
model of human hookworm infection to test the hypothesis that nematode infections
cause an alteration of the pulmonary environment that in turn dampens subsequent
reactivity to allergen. The transient lung phase of Nb was exploited to generate
pulmonary inflammation and histological, immunohistocytochemical, flow cytometric
and transcriptional analyses were used to evaluate the immediate and persistent molecular
and cellular changes in the lungs. The innate responses to Nb were characterized by a
dramatic and immediate increase in the transcription of the Th2 cytokine IL-13 and a
transformation of alveolar macrophages to the alternatively activated phenotype
(AAAMs). The modified immunological status of the lungs persisted weeks after the
parasite was expelled from the host and included an increase in constitutive transcription
of both Th1 and Th2 cytokines, the number of AAAMs and airway resistance. Thirty-six
days post-infection, lungs were challenged against house dust mite allergen to test the
functional consequences of these sustained immunological changes. Nb-infected lungs
had a significantly altered transcription profile, a decrease in perivascular eosinophilia
and a dampened airway hyperresponsiveness compared to the uninfected controls. In addition, an in vitro culture model of AAAM formation was developed and characterized
to determine that Nb is unable to directly induce the AAAM phenotype, but requires an
intermediate cell type to trigger the transformation. Previously unrecognized AAAM
markers (Cish, Igf1, Flt1 and Dtr/Hbegf) were identified in addition to the currently
recognized ones (Arg1, Fizz1/Retnla, Ym1/Chi3l3, Ym2/Chi3l4 and Mrc1/CD206).
These results document that a helminth infection induces persistent and significant
changes to the immunological environment of the lung. Exploiting naturally induced
suppressive mechanisms in a clinical setting might provide new tools for controlling
asthma and allergies.