Granulomatous disease is a major cause of impaired lung function and is an integral component of visceral larva migrans syndrome (VLM) due to Toxocara canis. Recent seroepidemiological findings indicate 3 percent of the population may be infected with this nematode. This proposal seeks to model VLM in the mouse in order to analyze the cellular and molecular mechanisms underlying granuloma formation in the lungs. Previous work by this investigator strongly suggests a delayed-type hypersensitive etiology as the basis for the eosinophil-rich granulomatous component of VLM. It is proposed that microscopic particles coated with T. canis larval proteins and embolized into the pulmonary vasculature will serve as the nidus of a uniform, synchronous artificial granuloma. This lesion can then be subjected to morphometric analysis and the cellular constituents of the granuloma enumerated in histologic section. The functional responses occurring in the spleen during the establishment of the granuloma will be determined by analysis of mitogenic potential in the lymphocyte transformation assay. The spleen will be further characterized by analytical fluorescence-activated cell sorting to determine the phenotypes of the cells present in the speen during the course of infection. Finally, the role played by cells expressing these various phenotypes will be examined histologically following adoptive transfer of phenotype-enriched or depleted lymphocyte populations from R. canis-infected mice into naive mice subsequently challenged with T. canis-coated particles. When executed, these studies will increase our understanding of the mechanism of nematode-elicited inflammation and granuloma formation as well as establish a unique model for long range studies of a relevant pulmonary disease process.
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