Three basic questions on T lymphocyte biology are addressed in this proposal: 1) How is the peripheral T cell pool, including the functionally distinct CD4 and CD8 T cell subsets, maintained at homeostatic """"""""constant"""""""" levels throughout the life of an adult mouse? 2) What is the composition and function of the atrophic thymus in adult mice? and 3) Which are the mechanisms for the decline of T cell functions with aging observed in mice? Answers to the first two questions are essential for the elucidation of the third one. The proposed studies use a variety of """"""""heterochronic"""""""" models, with thymus grafts and thymus in situ, to determine the roles of: prethymic hemopoietic cell migration to thymus (Aim 1), intrathymic expansion and thymic export to periphery (Aim 2) and postthymic expansion and maintenance of the exported T cells at steady state levels, depending on cell input (Aim 3). """"""""Heterochronic"""""""" means transplantation of """"""""young"""""""" and """"""""old"""""""" components into young or old hosts, and assessment of each component. The studies will use only syngeneic or congenic combinations. Prethymic or postthymic cells with recognizable markers, such as chromosome, surface antigens or retroviral vector inserted genes (such as beta-galactosidase lacZ) will be used for the population analysis, especially the characterization of postthymic progenitors capable of extensive antigen and thymus independent expansion in periphery, when injected in thymus deprived hosts. The lacZ marker allows recognition of cells by histochemical methods and analysis of progeny by vector integration sites. The working hypothesis is that such progenitors could act as a postthymic generative compartment which is critical for normal T cell renewal, guided predominantly by internal signals and not by nominal antigen. The role of some lymphokines, including tumor necrosis factor (TNF) in T cell maintenance will also be studied. Answering the questions above will increase both our understanding of T cell development and renewal, as well as favor a better comprehension of immunological aging.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG002152-10
Application #
3114341
Study Section
Immunobiology Study Section (IMB)
Project Start
1980-12-01
Project End
1993-03-31
Budget Start
1991-04-01
Budget End
1992-03-31
Support Year
10
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
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Macphail, S; Stutman, O (1993) H-2 I-E molecules isolated from Mls1a stimulatory cells do not activate Mls1a-responsive T cells but do present exogenous staphylococcal enterotoxins. Eur J Immunol 23:90-5
Hernandez-Caselles, T; Stutman, O (1993) Immune functions of tumor necrosis factor. I. Tumor necrosis factor induces apoptosis of mouse thymocytes and can also stimulate or inhibit IL-6-induced proliferation depending on the concentration of mitogenic costimulation. J Immunol 151:3999-4012
Macphail, S; Stutman, O (1989) Specific neonatal induction of functional tolerance to allogeneic Mls determinants occurs intrathymically and the tolerant state is Mls haplotype-specific. J Immunol 143:1795-800
Macphail, S; Stutman, O (1988) Mls allo-determinants are recognized in an MHC class II antigen-dependent but unrestricted fashion by a discrete set of T cells. J Immunogenet 15:87-99
Macphail, S; Stutman, O (1987) L3T4+ cytotoxic T lymphocytes specific for class I H-2 antigens are activated in primary mixed lymphocyte reactions. J Immunol 139:4007-15
Ishizaka, S T; Carnaud, C; Stutman, O (1986) Differential susceptibility of cytotoxic and helper T cell precursors to neonatal tolerization to histocompatibility antigens. J Immunol 137:2093-9
Lattime, E C; Stutman, O (1986) L3T4+, B2A2+ thymocytes from infant mice produce IL 2 after interaction with accessory cells expressing self class II antigens. J Immunol 136:2741-6
Stutman, O (1986) Postthymic T-cell development. Immunol Rev 91:159-94

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