Modulation of the Pulmonary Type 2 T-Cell Response toCryptococcus neoformansby Intratracheal Delivery of a Tumor Necrosis Factor Alpha-Expressing Adenoviral Vector

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Abstract
C57BL/6 mice develop an allergic bronchopulmonary mycosis following intratracheal inoculation ofCryptococcus neoformans24067. We determined that only low levels of tumor necrosis factor alpha (TNF-α) are produced in the lungs following infection. Thus, the objective of the present studies was to determine whether treatment with a TNF-α-expressing adenoviral vector (adenoviral vector with the murine TNF-α transgene under the control of the human cytomegalovirus promoter [AdTNFα]) could switch the type 2 (T2) T-cell response/T1 T-cell response balance toward the T1 T-cell response. AdTNFα induced an increase in TNF-α expression at days 3 and 7. At days 7 to 14, the number of cryptococcal lung CFU continued to increase in both untreated and control adenoviral vector (empty adenovirus type 5 backbone)-treated mice, but the number was ultimately 100-fold lower following AdTNFα treatment. AdTNFα markedly increased neutrophil and macrophage numbers, and pulmonary eosinophilia did not develop. CXCL1, CXCL2, and gamma interferon were also up-regulated, while eotaxin, interleukin-4 (IL-4), and IL-5 were down-regulated. AdTNFα treatment also increased the number of CD80+and CD40+cells and decreased the number of CD86+cells (CD11b+and CD11c+) in the lungs. Major histocompatibility complex class II levels on CD11b+cells were increased. Whole-lung expression of inducible nitric oxide synthase was increased, while YM2 expression and acidic mammalian chitinase expression were decreased. None of these effects were observed with the control (empty) adenoviral vector. Overall, these results support the hypothesis that early TNF-α expression promotes a shift in T-cell and macrophage polarization from T2/alternatively activated macrophages toward T1/classically activated macrophages, resulting in control of the fungal infection and prevention of the allergic response.

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