Allergic bronchopulmonary aspergillosis (ABPA) is a hypersensitivity lung disease resulting from a damaging immune response directed to the ubiquitous fungus, Aspergillus fumigatus (Af). It results in marked lung damage in patients with bronchial asthma or cystic fibrosis (CF). Our work has uncovered some interesting trends regarding the characteristics of the immune response in ABPA patients, and has led us to hypothesize that particular HLA alleles fashion T cell repertoires 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 particular HLA-DR2 and/or HLA-DR5 alleles. Both ABPA and Af-sensitive non-ABPA asthmatic or CF patients will be HLA serotyped and genotyped; T cells from patients of both groups will be tested and compared to ascertain the role of particular HLA alleles in T cell activation in response to Asp fl, an immunodominant antigen of Af. A clear association of HLA-DR2/5 alleles with both the disease and T cell activity in the ABPA group will strongly support our hypothesis that particular HLA- DR2/5 alleles regulate immunity which results in Th2 responsiveness and subsequent disease. In addition, these HLA studies are designed to identify """"""""at risk"""""""" or """"""""non-risk"""""""" alleles which will serve in the identification and management of asthmatic or CF patients at risk for developing ABPA, and will also be useful in the future design of definitive immunotherapy. The second specific aim is to determine qualitative and quantitative differences of Asp fl-specific CD4+ T cells in ABPA versus non-ABPA patients. T cells from both groups, in response to Asp f1, will be analyzed for cytokine profiles, HLA restriction, epitope specificity, TCR V usage, as well as the ability to induce IgE synthesis. Differences in these parameters between the ABPA and non-ABPA controls, particularly enhanced Th2 responses in ABPA but not in non-ABPA patients, will lend strong support to our hypothesis and thereby gain a better understanding of the pathophysiology of this disease.
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| Chauhan, B; Santiago, L; Hutcheson, P S et al. (2000) Evidence for the involvement of two different MHC class II regions in susceptibility or protection in allergic bronchopulmonary aspergillosis. J Allergy Clin Immunol 106:723-9 |
