ROLE OF ANTIGEN TRANSPORT BY DENDRITIC CELLS IN AGING

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DESCRIPTION: (Adapted from applicant's abstract): 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.