The goals of this project are the delineation of the biological roles and molecular regulation of lymphotoxin (LT; LT alpha; TNF beta) as an entity in itself and with regard to its relationship to the other members of the LT/TNF family, tumor necrosis factor (TNF alpha) and LT beta. LT alpha can assume two molecular forms: a secreted homotrimer, or a cell-associated heterotrimeric LT alpha/beta complex. LT alpha has been implicated in the pathogenesis of autoimmune diseases and participates in defense against cancer through its ability to kill cells by apoptosis and promote inflammation. Mice genetically deficient in LT alpha have no lymph nodes or Peyer's patches and exhibit splenic disorganization indicating a crucial role in lymphoid organ development. Mice transgenic for LT alpha under the control of the insulin promoter (RIPLT) exhibit inflammation at the sites of transgene expression. This inflammation has most of the characteristics or organized lymphoid tissue, suggesting that LT-induced chronic inflammation is lymphoid neogenesis. The RIPLT transgene restores LN but not splenic architecture to LT alpha -/- mice.
The specific aims are to: 1) Determine whether LT beta contributes to lymphoid organ development; 2) Identify the temporal limits and physical forms by which ectopic LT restores lymphoid organs; 3) Identify the mechanisms by which LT induces lymphoid organogenesis; 4) Determine which cells produce LT alpha in development and define the molecular basis of its regulation.
These aims will be accomplished by analyzing LT beta -/- mice; by studying the reconstitution of LN in RIPLT.LT alpha -/- mice and in a new LTtet inducible system; by analyzing LT's effects in reconstituted RIPLT.LT alpha -/- and doxycycline induced tetLT.LT alpha -/- mice on adhesion molecules, chemokines, and dendritic cells; and analyzing developmentally regulated LT expression in mice transgenic for LT alpha regulatory regions driving expression of human CD8 alpha or beta-galactosidase reporter genes.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Immunobiology Study Section (IMB)
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Yale University
Public Health & Prev Medicine
Schools of Medicine
New Haven
United States
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