Biomedical subjects
Publications and source records attributed to A Temple.
Human adherent mononuclear cells have been shown to become cytolytic to autologous and allogeneic erythrocytes after 1-2 days in culture. Cytolysis is not inhibited by cytochalasin B, but is inhibited by extremely low steroid concentrations. Cytolysis cannot be demonstrated earlier than 12 hours after adding the target cells.
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A method is described which demonstrates that human adherent mononuclear cells have a strong capacity to kill human nucleated target cells. Cytotoxicity was measured by the release of 51chromium from two established cell lines. Freshly prepared monolayers killed both non-sensitized and anti-body coated K562 and CLA-4 target cells. These spontaneous events decreased after short term culture. A second peak of cytotoxic activity was induced by activating the effector cells with endotoxin-treated serum or phytohaemagglutinin. Cytotoxicity was inhibited by silica particles. Studies with alpha-naphthyl esterase showed that 95% of freshly prepared cells and 99% of monolayers cultured for 68 h were monocytes. These studies suggest that adherent monocytes are the predominant cytotoxic effector cell although a contributing effect by the small numbers of contaminating lymphocytes can not be excluded. Evaluation of monocyte cytotoxicity should have a useful role in clinical investigation.
This report describes the preparation and characterization of antisera to human trophoblast membranes. Rabbit antisera were raised to trophoblast microvilli prepared by differential ultracentrifugation. Antibodies to serum proteins were removed by solid-phase immunoabsorption with normal human serum, and indirect immunofluorescence experiments with cryostat sections of human placentas showed that the absorbed anti-trophoblast sera reacted with trophoblasts as well as with stromal cells and endothelium of chorionic villi. The antisera also produced membrane fluorescence when studied on viable lymphocytes and certain human cell lines. These anti-trophoblast sera were also lymphocytotoxic, and this reaction was abolished by prior absorption of the antisera with leukocytes. The leukocyte-absorbed anti-trophoblast sera retained their ability to react with trophoblasts and certain human cell lines, but no longer reacted with lymphocytes or placental stromal cells and endothelium. Two categories of trophoblast membrane antigens are thus defined: one present on trophoblasts and certain human cells lines (tentatively designated TA(1)), and the other on trophoblasts and lymphocytes, villous fibroblasts, and endothelium (tentatively designated TA(2)). A working hypothesis is proposed stating that normal pregnancy involves the generation of anti-TA(2) subsequent to blastocyst implantation and entrance of trophoblasts into the maternal circulation. This involves a mechanism similar to allogeneic cell stimulation and results in antibodies that block either the recognition or cytotoxicity of TA(1). Failure to mount this response allows TA(1) recognition and trophoblast immunopathology. Experimental and clinical studies in support of this working hypothesis, particularly involving abortion and toxemia, are cited from published reports.
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The uptake by human blood monocytes of sheep erythrocytes treated with rabbit anti-sheep antibody with or without mouse complement was assessed by a radioactive method to discover whether immune complexes would inhibit this reaction. It was found that sera from SLE patients inhibited uptake whereas normal sera enhanced. Some rheumatoid sera and rheumatoid joint fluids inhibited uptake whereas sera from juvenile rheumatoid patients did not.
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Mouse fibroblasts form spontaneous rosettes with sheep erythrocytes and with red cells from several other species. They do not form C3 or Fc rosettes, and they do not bind small amounts of aggregated gammaglobulin. Spontaneous rosette formation is maximum at 37 degress and minimum at 4 degrees. The reaction is complete in 30 min. Antisera to fibroblast membrane components do not inhibit rosette formation. Rosetting is inhibited by fixation of the cells with formaldehyde or glutaraldehyde as well as by killing with phenol or by prolonged incubation with sodium azide. The rosette reaction is inhibited by vinblastine but not by cytochalasin B. From these data on the kinetics, temperature and drug sensitivities it is suggested that T cells and fibroblasts form spontaneous rosettes by different mechanisms.
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We have identified a genetic polymorphism of factor VII that is strongly associated with plasma factor VII coagulant activity (factor VIIc) in healthy individuals from the United Kingdom. This polymorphism was detected after Msp I digestion of polymerase chain reaction-amplified genomic DNA. In a sample of 284 men, the frequency of the M2 allele (loss of cutting site) is 0.1, and individuals with the M1M2 genotype have factor VIIc levels 22% below the sample mean (p less than 0.0001). Msp I genotype was found to be the strongest predictor of factor VIIc, accounting for 20.2% of the variance, with cholesterol accounting for an additional 3.5%. The base change that gives rise to the Msp I polymorphism is a G-to-A substitution in the codon for amino acid 353, leading to replacement of arginine (Arg) with glutamine (Gln) in the protein product of the M2 allele (designated Gln 353). Three individuals homozygous for the M2 allele have both low factor VIIc and low factor VII protein concentrations. The conformation of the Gln 353 molecule may be different from that of the Arg 353 protein, affecting its intracellular processing, secretion, turnover in plasma, or activity. In view of its association with lower factor VIIc levels, possession of the M2 allele may confer protection against thrombosis and myocardial infarction.