With recent advances in genetic engineering there is concern that pandemic influenza or avian influenza might emerge as a bioterror agent. In addition, the majority of deaths (90%) attributed to influenza are in persons age 65 or older. Elderly individuals have suboptimal responses to current influenza vaccine preparations and significantly reduced levels of protective antibody titers. While age-related decline in T cell function has been demonstrated and is being actively investigated, remarkably little is known about how aging affects Ag presenting cells (APC). These cells (especially dendritic cells (DC)) are critical for induction of both humoral and cell mediated immunity. Our preliminary data suggests abnormally elevated IFN-a and depressed IL-12 production by DC in geriatric individuals. This cytokine pattern may lead to a decline in T helper cell generation. In addition our data suggests that class II MHC (MHC-II) levels are reduced in DC in geriatric individuals. This could result in reduced Ag presentation by DC leading to suboptimal generation of CD4+ T helper cells. ? ? It is our overall hypothesis that APC defects contribute to decreased T and B cell responses to influenza in geriatrics. A better understanding of specific defects in geriatric APC might allow a targeted approach to engineer vaccines for the elderly. We will approach this with the following specific aims: ? ? Aim 1. To determine the specific defects in innate immune responses of DC to influenza in geriatric individuals. We will compare innate responses of plasmacytoid DC and myeloid DC to influenza in individuals aged >65 and those aged 21-35. Specifically, we will analyze DC for production of cytokines and chemokines, and maturation, costimulation, and homing markers after influenza stimulation. We will examine several potential mechanisms for the cytokine dysregulation in geriatric DC. ? ? Aim 2. To determine if DC and B cells from geriatric individuals have a MHC class II defect in Ag processing and presentation of influenza. We will determine if MHC-II Ag processing and presentation of influenza in DC and B cells from elderly individuals is defective using HLA-DR matched T cell hybridomas. If defects are observed, mechanisms of the defects will be explored. Ag processing and presentation efficiency of B cells is important for them to receive optimal costimulation from CD4+ T helper cells. ? ? ?
| Simmons, Daimon P; Wearsch, Pamela A; Canaday, David H et al. (2012) Type I IFN drives a distinctive dendritic cell maturation phenotype that allows continued class II MHC synthesis and antigen processing. J Immunol 188:3116-26 |
| Clark, H L; Banks, R; Jones, L et al. (2012) Characterization of MHC-II antigen presentation by B cells and monocytes from older individuals. Clin Immunol 144:172-7 |
| Bartley, Matthew B; Canaday, David H (2011) T cell hybridomas to study MHC-II restricted B-cell receptor-mediated antigen presentation by human B cells. J Immunol Methods 370:35-42 |
| Canaday, David H; Amponsah, Naa Ayele; Jones, Leola et al. (2010) Influenza-induced production of interferon-alpha is defective in geriatric individuals. J Clin Immunol 30:373-83 |
| Simmons, Daimon P; Canaday, David H; Liu, Yi et al. (2010) Mycobacterium tuberculosis and TLR2 agonists inhibit induction of type I IFN and class I MHC antigen cross processing by TLR9. J Immunol 185:2405-15 |
