The capacity of the mammalian immune system diminishes with age, including decreased IgM production both in vivo and in vitro from B-cells and less affinity maturation/somatic hypermutation. Interestingly, there are age-related changes in B-lymphopoiesis, with deficiencies detectable as early as the pro-B-cell stage. Furthermore, the function of non-lymphoid stromal cells also decreases with age and both alterations appear to involve the important pre-B cytokine IL-7. Paradoxically, while there is a substantial decrease in the pre-B subset in bone marrow, the numbers of newly formed B-cells detected in the spleen do not decline with age, suggesting the possibility that the marrow releases an increasing proportion of functionally defective B-cells with age. The unifying hypothesis of this application is that age-related functional deficiencies in peripheral B-cells result from alterations in marrow B-lymphopoiesis.
Specific Aim 1 proposes to study the rate of production of newly-formed B-cells and the entry of these cells into spleen will be determined in mice of different ages by measuring the uptake of BrdU.
Specific Aim 2 proposes to test for alterations in functional competence, the frequency and burst size of antigen-specific B-cells will be assessed as a function of age using optimal T-cell help, provided by carrier-specific Th1 and Th2 T-cell clones.
Specific Aim 3 proposes to document IL-7 deficiency which will be supplemented by injections of IL-7 and IGF-1 that expand the pre-B-cell pool in order to examine whether such treatment restores functional competence in the newly formed B-cell subset.
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