IMMUNOPATHOGENESIS OF ALLERGIC ASPERGILLOSIS

Summary

Principal Investigator: RAYMOND SLAVIN
Abstract: Allergic bronchopulmonary aspergillosis (ABPA) is a hypersensitivity lung disease resulting from a damaging immune response directed to the ubiquitous fungus, Aspergillus fumigatus (Af). Our work has led us to hypothesize that particular HLA alleles fashion T cell repertories that ultimately either result in ABPA or protective immunity. The long term objectives of this application are to characterize AF-specific T cell responses in ABPA and non-ABPA patients in order to gain an understanding of the immune mechanisms underlying this disease, to determine the immune parameters that can be useful in diagnosis, and to identify those parameters that will be useful in future immunotherapy. The first specific aim is to determine if ABPA is associated with a combination of particular HLA-DR2, HLA-DR5 and HLA-DQ2 genotypes. We will genotype both ABPA and non-ABPA asthmatic and CF patients to establish which HLA-DR genotypes are associated with susceptibility to ABPA and which genotypes of DQ2 are associated with resistance. The second specific aim is to determine qualitative and quantitative differences of Asp f1-specific CD4+ T cells in ABPA versus non-ABPa CF and asthmatic patients. Peripheral blood and bronchoalveolar lavage T cells, from both ABPA and non-ABPA groups, will be analyzed for cytokine profiles, HLA-restriction, epitope specificity and ability of T cell clones to respond to closely related HLA-DR alleles. The third specific aim is to test our hypothesis in transgenic mice that T cells fashioned under the influence of particular HLA alleles either contribute to host susceptibility or resistance to ABPA. We will breed transgenic mice to express "at risk" HLA-DRB1*1501 alleles in the presence or absence of HLA-DQ2 and determine with appropriate sensitization and challenge whether these mice develop the acute lung responses that is requisite for ABPA.
Funding Period: 1999-03-01 - 2005-04-30
more information: NIH RePORT