The annual incidence of invasive aspergillosis (IA) ranges from 10 to15% in allogeneic hematopoietic stem cell (HCT) recipients, with mortality approximating 80%;as such, this infection has become a prominent cause of infection-related death after HCT. Infection now occurs primarily late in the course of allogeneic HCT, after neutrophil engraftment. Epidemiology is consistent with the recent recognition that effective immunity in animal models requires robust CD4+ T helper type-1 (Th1) responses. However, no large studies have been performed to evaluate Aspergillus-specific immune reconstitution. We have developed the methods to measure cellular responses to Aspergillus antigens, and demonstrated reproducibly variable responses in healthy volunteers. We propose a longitudinal immune-reconstitution study to evaluate the hypothesis that CD4+ T cell reconstitution is important to protect from IA late after allogeneic HCT, with multiple factors, including donor transferred immunity, potentially impacting immune reconstitution.
Specific aims will be to: 1. Determine if reconstituted cellular immunity predicts risks for, and outcomes of IA. Patients will be enrolled in a longitudinal study to evaluate whether reconstituted cell numbers (DC1, DC2, T cell subtypes, NK cells and B cells) and functional responses to A. fumigatus hyphal antigen predict risks for, and outcomes of IA.
In Aim 2, studies will determine the significance of variable frequencies of reactive CD4+ T cells and cytokine patterns in healthy donors. Donor responses will be evaluated to test the hypothesis that low frequencies of IFN-gamma producing CD4+ T cells in healthy people are associated with MHC alleles, potentially including specific Class II haplotypes and/or polymorphism(s) in the Class III region (TNF-alpha gene). The impact of donor responses on recipient reconstitution will be evaluated. Studies in Aim 3 will identify Aspergillus fumigatus antigens presented to healthy human CD4+ T cells. Aspergillus-specific CD4+ T cell clones will be generated from healthy subjects by sequential stimulation with hyphal antigens. Classical HLA-restricted CD4+ clones will be used to screen pooled libraries of A. fumigatus cDNA, with sequential screens identifying individual T-cell antigens. This study will be performed with the goal of defining the mechanisms of post-transplant immune protection against Aspergillus species. This information will be valuable for development of strategies to prevent and treat fungal infections in immunocompromised people.
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