Letter: Unsaturated fatty acids and cellular immunity.
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Biomedical subjects
Publications and source records attributed to E J Field.
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The following parameters of the cytopherometric test system have been studied. 1. Temperature is less important for the production of macrophage slowing factor (MSF) by lymphocyte-antigen interaction than it is for the activity of MSF on macrophages. 2. Lymphocyte number titration curves allow discrimination between 'weak' and 'strong' antigen responses. 3. Lymphocyte-antigen reaction reaches a plateau after 30 min incubation, whilst maximum MSF-macrophage reaction requires 60 min. 4. Interaction of MSF with macrophages is sensitive to cycloheximide. 5. Irradiation of peritoneal exudate cells (200 rad) is essential in order to obtain a maximal result in the MEM test. In the 'split MEM test, 200 rad to the indicator peritoneal exudate cells produces a greater result, i.e. it in some way amplifies the macrophage response to MSF. 6. Excess of peritoneal exudate cells, especially when non-irradiated, suppresses the test result. This is not due to consumption of MSF produced. Probably macrophages rather than lymphocytes are responsible for the suppression.
The mixed lymphocyte reaction (MLR) between donor and recipient lymphocytes has been measured by the macrophage electrophoretic mobility (MEM) test and the modified (MOD-MEM) test. Its value as a measure of compatibility has been assessed by comparison with conventional HL-A serotyping and with the outcome of renal transplantation. Thirty-six living donor/recipient pairs and 59 cadaver donor/recipient pairs for transplantation have been studied. Whilst uniovular twins gave lymphocyte interactions, measured as macrophage slowings of about 1%, the slowing produced by paired allogeneic lymphocytes ranged from 2% to 26% depending on the number of HL-A matches. The test measurement of lymphocytic interaction was significantly correlated with histocompatibility measured by HL-A serotyping, in both living and cadaver donors. One way MEM-MLR showed the dominant role of the second HL-A sublocus in mixed lymphocyte reactivity. The long term success of the renal graft correlated with the pre-transplant initial reaction between donor and recipient lymphocytes. The test has advantages in the field of human histocompatibility assessment since no particular reference to individual antigens is made and it may be performed in a matter of hours.
Multiple Sclerosis (MS) is shown to have no relation to scrapie and the evidence for a "slow infective" aetiology is very meagre. It is not related to an ageing process during which scrapie-like antigens make their appearance as they do in young animal with the disease. The emergence of scrapie-like antigens in ageing tissues is discussed. The increased sensitization of MS lymphocytes to scrapie, as opposed to normal brain (or spleen), is not characteristic of the disease, but occurs in other conditions with astroglial overgrowth. On the other hand, special lymphocyte sensitivity to inhibition by linoleic acid is limited to MS (and not shared by scrapie). The familial background of MS is briefly discussed, and an important line of study which might bring together classical genetic markers, HLA studies, and linoleic acid lymphocyte study is indicated. The role commonly ascribed to measles is critically reviewed. Measles may be of special importance in one (childhood-acquired) group of MS subjects, but there is no evidence of a special role in most cases. Raised antibodies to viruses other than measles have, however, been described. It is concluded that an immunological mechanism is still the most likely "final common path" by which MS lesions develop.
Following intramuscular injection of Kuru and Jakob-Creutzfeldt brain material into chimpanzees, circulating lymphocytes became sensitized to scrapie mouse brain (and spleen) to a greater degree than to normal tissue. This sensitization subsided after about a month, to be followed some 90 days later by a secondary peak attributed to establishment of changes in the nervous system. Special sensitization to scrapie material occurs in Kuru and Jakob-Creutzfeldt disease, but is not specific to them. The immunological evidence suggests that parenchymatous destruction may precede astroglial hypertrophy in these diseases. An early peak occurred in animals inoculated with multiple sclerosis brain and normal brain, but neither showed a delayed second peak. Thus there was no evidence of establishment of infection, even though all four animals were in intimate contact for over 200 days, and no evidence of the injection of MS material itself having established an infection. Biohazards in Kuru, Jakob-Creutzfeldt and MS work appear to be very low. The significance of the increased sensitilization to scrapie material in Kuru and Jakob-Creutzfeldt disease, especially in relation to normal ageing (where it also increases), is discussed.
Using the macrophage electrophoretic mobility (MEM) test, the in vitro effects of oleic, linoleic and arachidonic acid, as well as Naudicell oil and methyl gamma-linolenate, on lymphocyte response to various antigens (PPD, thyroid antigen and EF) were studied in patients with mutiple sclerosis, patients with other neurological diseases, and in normal subjects. In all three groups, linoleic and arachidonic acid showed a significant inhibition; the latter was greater than the former, when tested at physiological concentrations, suggesting that unsaturated fatty acids may exert an immunoregulatory effect in vivo. The methylester of gamma-linolenate is the most powerful suppressing agent yet tested. The inhibitory activity of linoleic and arachidonic acids was consistently greater in MS than in other subjects and forms the basis of an in vitro test for the disease. The possible relationship of these findings to widespread alterations in the fatty acid composition of the tissues and to the pathogenesis of MS is discussed.
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Lymphocytes from patients with multiple sclerosis are much more susceptible to the inhibitory activity of linoleic acid (0.08 mg/ml) when tested for sensitization to thyroid by the macrophage electrophoretic mobility test (91% inhibition) than are those from normal subjects (57% inhibition). Cells from patients with a variety of other neurological diseases give 47% inhibition with linoleic acid. These differences are specific for multiple sclerosis and can be used as an in-vitro diagnostic test for the disease. Nearly 43% of clinically normal near relatives of patients with multiple sclerosis show an "anomalous" figure of about 77%; in the remainder the figure is the same as in the general population (57%). An anomalous result is compatible with lifelong freedom from M.S. Possibly a congenital anomalous handling of unsaturated fatty acids is a constant feature of the disease.
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