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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG013874-03
Application #
6043064
Study Section
Immunobiology Study Section (IMB)
Project Start
1997-09-30
Project End
2001-07-31
Budget Start
1999-08-01
Budget End
2000-07-31
Support Year
3
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Loyola University Chicago
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
791277940
City
Maywood
State
IL
Country
United States
Zip Code
60153
Zook, Erin C; Zhang, Shubin; Gerstein, Rachel M et al. (2013) Enhancing T lineage production in aged mice: a novel function of Foxn1 in the bone marrow niche. J Immunol 191:5583-93
Birjandi, Shirin Z; Ippolito, Jill A; Ramadorai, Anand K et al. (2011) Alterations in marginal zone macrophages and marginal zone B cells in old mice. J Immunol 186:3441-51
Zook, Erin C; Krishack, Paulette A; Zhang, Shubin et al. (2011) Overexpression of Foxn1 attenuates age-associated thymic involution and prevents the expansion of peripheral CD4 memory T cells. Blood 118:5723-31
Wols, Heather A Minges; Johnson, Kara M; Ippolito, Jill A et al. (2010) Migration of immature and mature B cells in the aged microenvironment. Immunology 129:278-90
Minges Wols, Heather A; Witte, Pamela L (2008) Plasma cell purification from murine bone marrow using a two-step isolation approach. J Immunol Methods 329:219-24
Minges Wols, Heather A; Ippolito, Jill A; Yu, Zheng et al. (2007) The effects of microenvironment and internal programming on plasma cell survival. Int Immunol 19:837-46
Pifer, Jeannette; Stephan, Robert P; Lill-Elghanian, Deborah A et al. (2003) Role of stromal cells and their products in protecting young and aged B-lineage precursors from dexamethasone-induced apoptosis. Mech Ageing Dev 124:207-18
Minges Wols, Heather A; Underhill, Gregory H; Kansas, Geoffrey S et al. (2002) The role of bone marrow-derived stromal cells in the maintenance of plasma cell longevity. J Immunol 169:4213-21
Gray Parkin, Kirstin; Stephan, Robert P; Apilado, Ron-Gran et al. (2002) Expression of CD28 by bone marrow stromal cells and its involvement in B lymphopoiesis. J Immunol 169:2292-302
Underhill, Gregory H; Minges Wols, Heather A; Fornek, Jamie L et al. (2002) IgG plasma cells display a unique spectrum of leukocyte adhesion and homing molecules. Blood 99:2905-12

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