It is critical that antigen transport to follicular dendritic cells (FDCs) which initiates cellular events for the maintenance of the secondary antibody response becomes defective with age. FDC dendrites receiving the transported antigen, mature and produce iccosomes (immune complex coated bodies) which deliver the antigen to follicular B cells for endocytosis, processing and presentation to T cells. This sequence of events - the """"""""alternative antigen pathway,"""""""" begins with the transport cells (ATCs) in the afferent lymph and ends with the delivery of the antigen to follicular B cells. The investigators designated this path the ATC-FDC-iccosome-B cell axis of antigen transport. The age-related defect results in an incomplete antigen transport. The atrophic and immature FDCs retain little antigen and produce few, if any, iccosomes. This results in a paucity of germinal centers where B memory (Bm) cells form. Clinically, this correlates with the depressed ability of the aged to produce a secondary antibody response to booster immunizations with antigens such as tetanus toxoid. Morphological and phenotypic evidence with anti-FDC monoclonal antibodies suggest that ATCs are pre-FDCs. This has not been substantiated by direct experiments, yet it may be a major process affected by aging. The investigators therefore hypothesize that ATCs mature to form FDCs under the influence of B and T cells. This is suggested by reconstitution studies with bone marrow, thymus, B and T cells. These workers also predict that iccosomes are important for antigen uptake by B cells for antibody and/or Bm cell production. The investigators propose two specific aims; 1) to assess whether ATCs mature into FDCs autonomously or with B and T cell help; and 2) to assess B cell iccosome requirements for antigen uptake, antigen presentation and production of antibody forming and Bm cells. They will study the first aim in vitro and in SCID mice, in athymic nude mice, and in vitro germinal centers. Dr. Szakal and coworkers will use old mice as a model of antigen transport deficiency and test the capacity of their ATCs, B and T cells to perform in the above models to elucidate the mechanisms of antigen transport. In the second aim, they will test the ability of old B cells to present in vivo obtained antigen in vitro and the iccosome requirements of B cells for antigen uptake. presentation, antibody forming and Bm cell production. To this end, they will use isolated ATC/FDC populations enriched with the aid of monoclonal antibody for cell culture, in vivo cell transfers, antigen presentation, Bm, and radioimmunoassays, immunocytochemistry and electron microscopy.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG005374-06
Application #
2049028
Study Section
Immunobiology Study Section (IMB)
Project Start
1985-09-30
Project End
1996-03-31
Budget Start
1993-04-01
Budget End
1996-03-31
Support Year
6
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Virginia Commonwealth University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
City
Richmond
State
VA
Country
United States
Zip Code
23298
Caffrey, R E; Kapasi, Z F; Haley, S T et al. (1994) DHEAS enhances germinal center responses in old mice. Adv Exp Med Biol 355:225-9
Kapasi, Z F; Kosco-Vilbois, M H; Shultz, L D et al. (1994) Cellular origin of follicular dendritic cells. Adv Exp Med Biol 355:231-5
Kapasi, Z F; Burton, G F; Shultz, L D et al. (1993) Induction of functional follicular dendritic cell development in severe combined immunodeficiency mice. Influence of B and T cells. J Immunol 150:2648-58
Burton, G F; Kosco, M H; Szakal, A K et al. (1991) Iccosomes and the secondary antibody response. Immunology 73:271-6
Smith, J P; Lister, A M; Tew, J G et al. (1991) Kinetics of the tingible body macrophage response in mouse germinal center development and its depression with age. Anat Rec 229:511-20
Szakal, A K; Taylor, J K; Smith, J P et al. (1990) Kinetics of germinal center development in lymph nodes of young and aging immune mice. Anat Rec 227:475-85
Kosco, M H; Burton, G F; Kapasi, Z F et al. (1989) Antibody-forming cell induction during an early phase of germinal centre development and its delay with ageing. Immunology 68:312-8
Smith, J P; Kosco, M H; Tew, J G et al. (1988) Thy-1 positive tingible body macrophages (TBM) in mouse lymph nodes. Anat Rec 222:380-90