MOLECULAR MECHANMISM OF LYMPHOCYTE MEDIATED TUMOR LYSIS

  • Podack, Eckhard R, (PI)

Project: Research project

Description

The objective of this application is to understand the molecular mechanism
by which cytotoxic lymphocytes kill target cells such as virus infected
cells and tumor cells. Lymphocyte mediated cytolysis may be of importance
for protection against cancer by immune surveillance systems. In addition
it is one of the fundamental defences of the immune system against virus
infection. Based on the observation that granules isolated from killer
lymphocytes are highly cytolytic, that they cause the release of
cytoplasmic and nuclear (DNA) markers from attacked targets and that they
form two types of membrane lesions on target cells, it is postulated that
granules contain the entire or at least a large part of the killing
mechanism of cytolytic lymphocytes. It is therefore planned to study the
composition of granules and to isolate from granules the molecules
responsible for formation of membrane lesions and for DNA degradation in
target cells. In addition, the characterization of all granule proteins
may result in the discovery of new activities. It is also planned to study
the granule membrane and to analyze the regulation of the release of
granules by killer lymphocytes in the cytolitic reaction. Based on the
finding that killer lymphocytes can lyse several target cells in succession
the question will be addressed how cytolytic lymphocytes escape the
destructive force of their own cytolytic granules during the cytolytic
reaction. Granule proteins will be characterized by conventional biochemical and
immunological techniques and this information will be used to obtain cDNA
clones from an expression cDNA library of cytolytic lymphocyte clones.
Cloned cDNA will be used for structural studies by DNA sequencing, for the
expression of encoded proteins in E. coli, and for the preparation of
monospecific antisera. DNA probes will also facilitate the analysis of the
regulation of cytolytic granule proteins in related studies. These
projects should result in a more detailed understanding of the molecules of
cytolytic granules responsible for cell killing, which in turn may be
useful for immunotherapeutic or diagnostic approaches to cancer,
autoimmunity, and transplantation.
StatusFinished
Effective start/end date6/1/845/31/11

Funding

  • National Institutes of Health: $276,443.00
  • National Institutes of Health: $283,337.00
  • National Institutes of Health: $238,886.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $228,750.00
  • National Institutes of Health
  • National Institutes of Health: $222,845.00
  • National Institutes of Health: $269,612.00
  • National Institutes of Health
  • National Institutes of Health: $202,349.00
  • National Institutes of Health: $222,845.00
  • National Institutes of Health
  • National Institutes of Health: $297,755.00
  • National Institutes of Health
  • National Institutes of Health: $213,868.00
  • National Institutes of Health: $290,438.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $222,845.00
  • National Institutes of Health: $257,830.00

Fingerprint

Perforin
Lymphocytes
Neoplasms
T-Lymphocytes
Deficiency Diseases
Macrophages
Porins
Natural Killer Cells
Proteins
Membranes
Research Personnel
Graft vs Host Disease
Clone Cells
Receptors, Tumor Necrosis Factor, Member 25
Transgenes

ASJC

  • Medicine(all)