Biomedical subjects
Publications and source records attributed to W H Stimson.
The structure and function of immunoglobulins, and the nature of the antibody-antigen interaction are described. Applications of the molecular recognition properties of antibodies are discussed in the areas of immunotherapy, immunoassay, immunotargeting and catalytic antibodies.
A monoclonal antibody (mAb) has been produced to aflatoxin B1 (AF B1) after successful immunization of mice and fusion of sensitized spleen cells with myeloma cancer cells. The mice were immunized with AF B1-oxime-protein conjugate. Positive mAbs were screened using an indirect ELISA specific for AF B1. The selected mAb was then developed in direct competitive ELISA and immunoaffinity column chromatography methods for aflatoxin detection in foods and feeds. Both assays are rapid, sensitive, specific and require only the minimum of sample preparation. Both immunological assays have now been commercialized and are produced in convenient ready-made kit formats.
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The leucocyte migration-inhibition assay was employed to assess the reactivity of cells from postpartum women to placental antigen preparations. Leucocytes from normal primigravidae responded to their own placental antigens and displayed a limited degree of cross-reactivity with allogeneic preparations. Autologous plasma suppressed this antigen recognition and the factor responsible was shown to be an IgG antibody. Leucocytes from five women with spontaneous abortions also responded to autologous placental preparations but no immunosuppressive factor could be detected in their blood. It is suggested that target antigens for maternal lymphocytes are present on the placenta, a structure critical to the continuance of pregnancy, and that the presence of the blocking antibody is necessary for fetal well-being.
Dapsone has been shown to possess anti-inflammatory activity in a variety of animal models. It possesses oral anti-oedema activity especially pronounced in novel models of acute inflammation, viz. anti-IgG and reversed passive Arthus oedemas. However, it is not very active in the guinea pig u.v. erythema model. It is effective in chronic models such as adjuvant arthritis and the cotton pellet granuloma although multiple administration may also produce cyanosis. Antipyretic and analgesic effects for dapsone have been demonstrated and are similar to those produced by phenylbutazone. It inhibits zymosan-induced beta-glucuronidase release from cultured macrophages and also the activity of this enzyme. Dapsone does not appear to be ulcerogenic in the rat.
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The prevalence of elevated serum levels of 5 potential tumour-associated antigens was determined in patients with lung cancer sampled at the time of initial presentation, using age- and sex-matched patients with benign lung disease as controls. Elevated levels (greater than upper 95th centile of controls) were found as follows: carcinoembryonic antigen (CEA), 17%; pregnancy-associated alpha-macroglobulin (PAM), 16%; casein 14%; human chorionic gonadotrophin (HCG) 6%; alpha-foetoprotein (AFP), 1.5%. The prevalence of elevated CEA levels (but not other markers) was higher in patients with evidence of extra-thoracic tumour spread (23%) mainly due to anaplastic tumours and adenocarcinomas. A degree of concordance of elevated marker levels occurred with CEA, HCG, casein and AFP, but there was a striking discordance of elevated CEA and PAM levels. Simultaneous assays of CEA and PAM will detect the majority of patients with elevations of any of the markers studied, and are likely to be the most useful biochemical markers in following the response of lung tumours to therapy.
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Human sera and anti-inflammatory drugs were compared for their ability to inhibit the zymosan-induced release of beta-glucuronidase from cultured rat peritoneal macrophages. Late pregnancy serum was the most potent in this respect and produced a dose-related suppression with a maximum of 94% when 15% (v/v) serum was incorporated into the culture medium. The effect was not shown by male serum and was associated with compounds of low molecular weight. However, steroids, commonly elevated in level during pregnancy, did not appear to be responsible for the inhibition of enzyme release.
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Pregnancy-associated alpha-macroglobulin (PAM) was identified on the surface membranes of human peripheral blood leucocytes by immunofluorescent staining. Subjects having a high serum-level of the glycoprotein (pregnant and contraceptive steroid-treated women) were shown to possess a significantly greater proportion of PAM-positive cells than those (normal males) with a low concentration. However, no correlation was found between the serum values and the percentage of PAM-associated leucocytes. Studies employing purified leucocyte-types and the simultaneous detection of PAM and lymphocyte surface markers indicated that only subpopulations of T lymphocytes (23%) and monocytes (40%) were associated with this serum protein.
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Nine of 30 mammary cancer patients developed metastases during 13-94 months after mastectomy. All 9 patients had elevated blood levels of pregnancy-associated alpha-macroglobulin (PAM) 1-21 months before conventional detection of metastases. Seven of the clinically well patients had PAM rises exceeding 90 per cent above the baseline and in 4 of these the PAM later fell to lower levels. PAM appears to have potential as an indicator of the growth of micrometastases.
A pregnancy-associated serum glycoprotein was shown to have an inhibitory effect on several in vitro methods of immunological assessment. This suppressing activity was evident at physiological concentrations and did not appear to be due to cytotoxicity. Transformation, induced by agents often regarded as preferential stimulators of T lymphocytes (concanavalin A, phytohaemagglutinin, allogeneic cells and tuberculin) was significantly depressed by the alpha-globulin. However, this phenomenon was much less evident when lipopolysaccharide or goat anti-human F(ab')2 serum was employed to selectively stimulate B-cells. The glycoprotein also blocked antigen-induced inhibition of leucocyte migration and caused a significant reduction in the number of lymphocytes binding sheep erythrocytes, in the spontaneous rosette test. It is proposed that the non-specific inhibitory activity of the alpha-macroglobulin depends upon some direct effect exerted on the lymphocyte itself and that it is levelled primarily at the cell-mediated immune response.
Complement-inactivated allogeneic serum was found to contain a factor capable of suppressing BCG-induced inhibition of leukocyte migration in vitro. Although serum from late pregnancy was the most potent in this context, the ability to antagonize the leukocyte response appears to be an intrinsic property of human serum. The inhibitory factor was purified by salf fractionation and gel chromatography and the effect found to be associated with alpha-globulins of high lipid content which are probably alpha-lipoproteins. Estrogens, progesterone, or corticosteroids, associated with the lipoprotein, did not appear to be the cause of the observed suppression. The factor appears to block the immune response at the level of the lymphocyte and its nonspecific immunosuppressive properties could contribute to acceptance of the fetus by the mother.
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