Serial transfer of delayed hypersensitivity with dialyzable transfer factor.
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Biomedical subjects
Publications and source records attributed to T K Smith.
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Two experiments were conducted with Hyline Leghorn hens to study the metabolism and detrimental effects of rapeseed meal (RSM) glucosinolates. Raw Target RSM was force fed to 12 hens which were killed after varying time intervals (15 min., 30 min., 60 min.) and the contents of areas of the digestive tract (crop; proventriculus and gizzard; duodenum and ileum) were analyzed for the presence of hydrolysis products of progoitrin. Nitrile compounds were found to be present in all areas of the digestive tract in much larger relative amounts than was oxazolidinethione. When commercially prepared RSMs of varying glucosinolate content were fed to laying hens at a 50% level of dietary inclusion, high glucosinolate-content RSM depressed egg production (P less than 0.05) more than low glucosinolate-content RSM but did not cause a greater frequency of liver hemorrhage. Histological examination of liver tissues from hens suffering liver hemorrhage revealed a severe reticulolysis.
Extensive studies of a 9-year-old boy with recurrent pulmonary infections and chronic mucocutaneous candidiasis disclosed a severe defect in cell-mediated immunity but normal humoral immune responses. These immunological defects were not improved by initial treatment with transfer factor. After receiving a foetal thymus transplant the patient developed positive delayed-type skin tests, could be sensitized with chlorodinitrobenzene, and showed progressive improvement of in vitro lymphocyte functions including spontaneous formation of rosettes with sheep erythrocytes and positive responses to phytohaemagglutinin, concanavalin A and allogeneic leucocytes. Moreover, lymph node cellularity increased, especially in the thymus-dependent zones. Though the in vitro responses persisted for over 1 year, skin tests became unreactive at 38 weeks. However, in contrast to the pre-transplant experience transfer factor was now effective in inducing positive skin tests. These studies provide a chronological account of the effect of the thymus on expression of lymphocyte-mediated immune responses in man and suggest that thymus-derived cells are required for acquisition of transfer factor-induced cellular immunity.
We studied the effects of dialysates from leukocyte lysates containing dialyzable transfer factor activity and other leukocyte dialysates devoid of transfer factor activity on accumulation of cyclic nucleotides in human leukocytes. Dialysates from normal leukocytes produced 4- to 11-fold increases in leukocyte cGMP, and experiments with purified cell populations revealed that the increases were predominantly, if not entirely, in blood monocytes. Substances that increased monocyte cGMP could be obtained from several cell populations including mononuclear cells from Hypaque-Ficoll gradients, plastic-adherent monocytes, nonadherent lymphocytes, and neutrophils, but were not present in dialysates of leukemic lymphocytes from patients with the Sezary syndrome. Moreover, dialysates that increased leukocyte cGMP had essentially no effect on intracellular cAMP. Dialysates of lysed mononuclear cells contained serotonin, ascorbate, and an unidentified cholinergic activity, agents known to increase leukocyte cGMP. After passage of dialyzable transfer factor from mononuclear cells through a gel-filtration column, four fractions were obtained that increased leukocyte cGMP. Two of these fractions contained ascorbate; two other active fractions, including one that also caused conversion of delayed skin tests, did not contain detectable ascorbate or serotonin. The dialysate of lysed neutrophils also increased cGMP, but this activity was limited to the column fractions which contained ascorbic acid. These observations raise the possibility that alterations in monocyte cGMP content could modulate either the specific antigen-dependent, or, more likely, the antigen-independent activities in preparations of transfer factor.
The immune response of rats to infection with Trichinella spiralis was studied serially for more than 1 year. Initial antigen-specific cellular reactivity, assessed by the lymphocyte transformation response, developed in the draining mesenteric nodes 3 days after infection. After 1 week reactive lymphocytes were detectable in the spleen and circulating blood, but the more 'remote' peripheral nodes did not harbor antigen-reactive cells until late in the second week. Thereafter, the patterns of antigen-responsiveness varied among the different lymphoid pools, but in all cases a decline in reactivity was seen after the first month. Serum hemagglutinating and homocytotropic antibodies, detectable by the tenth day, reached their peaks after 1 month of infection. Hemagglutinating titers persisted for more than 1 year but homocytotropic antibody was lost over this period. Comparisons are drawn between the evolution of the natural infection and the development of the host's immune response.
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Dialyzable transfer factor, obtained from frozen-thawed peripheral blood leukocytes from a single donor, was given to five anergic patients with chronic mucocutaneous candidiasis. Studies of immunological responses including delayed cutaneous hypersensitivity, in vitro antigen-induced thymidine incorporation, and production of macrophage migration inhibition factor (MIF) were conducted both before and after injection of transfer factor. Before transfer factor, none of the patients had delayed skin responses to any of the natural antigens studied. Their lymphocytes did not produce MIF after exposure to antigens in vitro and only one patient showed increased thymidine incorporation when his lymphocytes were cultured with candida and streptokinase-streptodornase (SK-SD). After injection of transfer factor, four patients developed delayed skin responses to antigens to which the donor was sensitive; no recipient reacted to an antigen to which the donor was nonreactive. Lymphocytes from recipients produced MIF when cultured with antigens that evoked positive delayed skin tests. Only one patient developed antigen-induced lymphocyte transformation and this response occurred only intermittently. Attempts to sensitize three of the patients with the contact allergen, chlorodinitrobenzene, both before and after transfer factor, were unsuccessful. The fifth patient, a 9-yr old boy with an immunologic profile similar to the Nezelof syndrome, did not become skin test-reactive or develop positive responses to the in vitro tests. These findings suggest that transfer factor acts on the immunocompetent cells that respond to antigens with lymphokine production, but has little, if any, effect on cells that respond to antigens by blastogenesis. The failure to sensitize the subjects with chlorodinitrobenzene illustrates the specificity of the immunologic effects of transfer factor, and implies that it does not function through nonspecific, adjuvant-like mechanisms. Failure of transfer factor to produce positive skin tests or MIF production in a patient with Nezelof's syndrome may be evidence that lymphokine-producing cells are thymus derived.
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