Most research on age-dependent immunodeficiencies has used inbred rodent models. We recently demonstrated significant age- related declines in the hepatobiliary secretion of nonspecific and alpha-cholera toxin immunoglobulin A (IgA) in male rats and attributed this to a concomitant loss of specific IgA receptors from hepatocytes. However, the extrapolation of data derived in rodents to humans may be unwarranted. Biliary secretion of IgA is species specific and appears to be relatively unimportant in primates. The general consensus is that IgA synthesized by plasma cells in the wall of the small intestine is transported by epithelial cells (enterocytes, gall bladder or biliary tract epithelium) into the gut via receptor-mediated endocytosis, vesicular translocation and exocytosis. Both experimental and epidemiological evidence suggest that aging compromises the mucosal immune response. There are data which suggest that age-related dysfunctions in both immune and nonimmune cell types contribute to reduced mucosal immunity. We will determine whether or not aging significantly impairs the GI mucosal immune response in primates and, if so, whether this dysfunction corresponds to specific nonimmune cell deficits, e.g. reduced IgA receptor synthesis or IgA transport by epithelial cells. We will evaluate the hepatic capacity to remove circulating immune complexes since these moieties are suspected of contributing to the high incidence of renal dysfunction in geriatrics. Preliminary studies have already demonstrated the feasibility and rationale for the experimental design. A major advantage is that it begins at the organism level (intact monkey), extends to the cellular level (epithelial cell receptor status) and terminates at the molecular level (receptor transcript status) within a very appropriate animal model. There is a significant void in our understanding of the mucosal immune system and its responsiveness in the elderly. This necessitates a comprehensive analysis of mucosal immunity in an animal model which will yield information easily extrapolated to humans and which may ultimately permit perturbations to enhance the immune responsiveness of geriatric patients.
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| Schmucker, D L; Vesell, E S (1993) Underrepresentation of women in clinical drug trials. Clin Pharmacol Ther 54:11-5 |
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