Cytolytic T lymphocytes (CTL) specifically adhere to and kill histoincompatible, virally-infected, and tumor cells. An understanding of the molecular basis of this process should suggest many avenues for therapy and diagnosis in neoplasms and immune disorders. Therefore, several surface molecules lymphocyte function associated antigens (LFA) that participate in adhesive interactions between T lymphocytes and other cells will be structurally and functionally characterized. The step in CTL-mediated killing in which the LFA-1, -2, and -3 molecules participate has been found to be killer-effector conjugate formation. The arrangement in the membrane and domain structure of the LFA-1 antigen will be studied by proteolytic fragmentation in intact cells, MAb reactivity, and amino acid sequence. Mouse LFA-1 will be partially sequenced. Human LFA-1 cDNA clones will be obtained by crosshybridization with mouse probes or screening of lambda expression libraries and will be sequenced. The amino acid sequence will be deduced and aligned with sequences with surface exposure. The LFA-2 molecule will be studied similarly and as to biosynthesis. Another objective is to study a family of molecules related to LFA-1, which have identical beta subunits. One of the molecules, Mac-1/OKM1, participates in myeloid cell complement receptor-mediated adhesion, and the second molecule, p150,95, is of unknown function on myeloid cells. MAb to the p150,95 alpha subunit will be obtained and used to isolate it for chemical studies and to identify its function. The biosynthesis, expression, structure, and gene organization of the family will be studied at the protein and DNA level. The biochemical basis for a recently discovered defect in surface expression of members of this protein family in patients with recurring bacterial infections will be elucidated. Results thus far indicate the primary deficiency is of the common beta subunit. Long-term goals of this second project are structure-function comparisons of cell adhesion proteins and diagnosis of heterozygous carriers and treatment of homezygous patients with the genetic defect. (AG)

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA031798-05
Application #
3169911
Study Section
Allergy and Immunology Study Section (ALY)
Project Start
1981-07-01
Project End
1989-06-30
Budget Start
1985-07-01
Budget End
1986-06-30
Support Year
5
Fiscal Year
1985
Total Cost
Indirect Cost
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
149617367
City
Boston
State
MA
Country
United States
Zip Code
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