Sequential changes of thymocyte surface antigens with presence or absence of graft-vs-host reaction following allogeneic bone marrow transplantation.
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Biomedical subjects
Publications and source records attributed to G Fernandes.
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Spleen and lymph node cells from normal or adrenalectomized (Adx) rats were assessed for a variety of in vitro immunological measures, including mitogen responsiveness, antibody-dependent cellular cytotoxicity (ADCC), and natural killer (NK) cell activity. Proliferation in response to mitogens was evaluated with or without 2-mercaptoethanol (2-ME) in the culture media. Compared to spleen cells from normal rats, those from Adx rats demonstrated enhanced responsiveness to all mitogens tested. 2-ME increased proliferation of spleen cells from both normal and Adx rats, and the effect was additive to that of adrenalectomy. In contrast, lymph node cells from Adx rats manifested decreased mitogenic responsiveness compared to those of control rats and, with the addition of 2-ME, this difference disappeared for one of the mitogens tested (phytohemagglutinin). Compared to unoperated rats, ADCC and NK activities were significantly decreased in both the spleen and lymph nodes of the Adx rats. Alteration of normal leukocyte circulatory and homing patterns are suggested as a likely means by which adrenalectomy produces differential effects on lymphoid cells in various organs of the immune system.
The effect of carlorie intake on the development of spontaneous mammary tumors in virgin C3H mice was studied. Only about 10% of the mice fed a low-calorie diet [10 kcal/day (1 kcal = 4.184 kJ)] since weaning developed mammary tumors, compared to about 60% of those mice that were reared on high-calorie diets (16 kcal/day or lab chow ad lib). In order to understand the mechanism by which a low-calorie diet decreases the occurrence of mammary tumors in mice, we compared the sex cycle, the amounts of circulating thyroid-stimulating hormone (thyrotropin), growth hormone, and prolactin, the production of type A and B virus particles in the mammary glands, and the morphology of the mammary glands of mice fed low- and high-calorie diets. The amount of serum prolactin and the synthesis of type A and B particles in mammary tissues of mice fed a low-calorie diet was markedly decreased compared to those of age-matched mice fed high-calorie diets. In addition, in young mice fed a low-calorie diet, there were fewer mammary alveolar lesions than in mice fed a high-calorie diet, although the size of the lesions was similar. However, in older mice fed the high-calorie diet, the number and size of these lesions were greater than in the mice raised on the low-calorie diet. The other factors that we studied were not affected by calorie restriction. Our findings suggest that the reduction in serum prolactin level, mammary tumor virus production, and proliferation of mammary alveolar lesions associated with dietary calorie restriction is responsible for lowering the incidence of mammary tumors in mice.
Bone marrow T leukaemic blasts from four patients with T-cell acute lymphoblastic leukaemia (ALL) were examined as effectors in natural killing (NK) and antibody-dependent cytotoxicity (ADCC). T leukaemic blasts demonstrated both Nk (against K-562 cells as targets) and ADCC (against chicken erythrocytes (CRBC) and cells of SB cell line as targets). NK activity and ADCC (against SB cells) were comparable to NK and ADCC (against SB cells) of peripheral blood T cells from healthy controls. ADCC against CRBC by leukaemic blasts was lower than that of peripheral T cells from normal controls. Of leukaemic blasts 20-42% possessed IgG Fc receptors. This study demonstrates that T leukaemic blasts are effectors in NK and ADCC assays.
Nutrition exerts profound influence on immunological functions effecting both cell-mediated (humoral) and T cell-mediated (cellular) immune functions. Even the interaction of the immune systems can be profoundly influenced by restrictions or excesses of dietary constituents. In experimental systems where it is possible to control precisely the influence of specific nutriments, development and expression of autoimmune diseases and the associated immunodeficiencies of aging can be delayed by restrictions of dietary protein, protein and calories, fat, zinc, or even essential fatty acids. Tumor immunities likewise can be affected and sometimes even enhanced by restriction of protein, calories, or protein and calories, an influence associated with major delay in development of the experimental cancers--e.g. breast cancer. T cell-mediated immunodeficiencies associated with clinically apparent protein or protein calorie malnutrition are often attributable not to the major nutriment deficiencies per se but to accompanying zinc deficiency, a finding reflecting the vital role of zinc in many immunological functions. Dietary zinc deficiency appears to be responsible, at least in part, for the immunodeficiency that is so regularly associated with certain human cancers, such as epidermoid cancers of the head and neck region.
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The effect of dietary restriction on the expression of retroviral envelope glycoprotein, gp70, and the formation of gp70-anti gp70 immune complexes was investigated in lupus-prone NZB x NZW F1 hybrid mice. Restricting total calorie intake from the usual 20 to only 10 calories per day after weaning markedly reduced serum levels of both free and antibody-complexed gp70, prevented renal disease, and increased the life spans of these mice. The reduction in serum gp70 was evident after only 2 wk of feeding these animals the low-calorie diet, and the concentration remained virtually unchanged throughout the course of 10 mon experimentation. However, serum concentrations of the major structural protein, p30, of endogenous retroviruses were not altered by restricting calories. Amounts of the serum glycoprotein, haptoglobin, decreased parallel to those of gp70 but amounts of albumin did not. These results suggest that the expression of gp70 in serum is controlled independently of the production of complete viral particles, and regulated by a mechanism similar to that for other serum glycoproteins, such as haptoglobin.
A comprehensive immunologic and serologic analysis was performed on 31 untreated patients with Hodgkin's disease. Immune evaluations stressed T-cell functional activity and included traditional parameters (PHA responsiveness and delayed hypersensitivity skin reactivity), as well as newer functional assays (T-cell colony formation, chemotaxis, spontaneous and antibody-dependent cytotoxicity, and concanavalin A-induced suppressor cell activity (CISA). Serum factors included ferritin, prostaglandins, zinc, copper, immune complexes, and thymic hormone activity. Every patient exhibited at least one T-cell or serum abnormality. The greatest percentage of patients exhibited T-cell defects in chemotaxis (85%), colony formation (81%). and PHA reactivity (64%). Immune defects were more common with advanced disease but were not related to absolute T-cell or monocyte count, skin test anergy, or abnormalities of T mu/T gamma cell proportions. Linear relationships were identified among abnormalities in the three assays employing mononuclear cells (PHA, colony formation, CISA) which may have reflected the inhibitory influence of monocytes present in the mononuclear cell preparations. Low serum zinc correlated with marked impairment of T-cell chemotaxis. Elevated prostaglandins were associated with high PHA reactivity and with depressed colony formation. Our results indicate that many complex factors, including intrinsic T-cell defects, contribute to the impaired immunity associated with Hodgkin's disease.
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Natural killer (NK) and antibody-dependent cellular cytotoxicity (ADCC) were examined in the peripheral blood lymphocytes and their major subpopulations from young and aging subjects. Monocyte-depleted unseparated lymphocyte-mediated NK activity (against cells of K-562) and ADCC (against IgG-coated chicken erythrocytes) were comparable between young and aging subjects. Similarly no significant difference was observed in T cell-mediated NK and ADCC and non-T cell-mediated ADCC between young and aging subjects. Non-T cell-mediated NK activity, however, was significantly (P less than 0.025) greater in aging humans compared to that of young subjects. When the data were analyzed according to gender, T cell-mediated ADCC in aging males was significantly (P less than 0.05) greater than that found in young males. No significant difference was observed between T-cell ADCC among young and aging females. T cell-mediated NK was comparable among young and aging males and young and aging females. Non-T cell-mediated NK as well as ADCC activity was significantly (P[ less than 0.025 or less than 0.05) greater in aging males compared to that in young males. Both non-T-cell NK and ADCC were comparable among young and aging females. This study demonstrates an increase in NK and ADCC activity in aging subjects that is primarily shared by males and not by females. No correlation was observed between the proportion of T gamma cells and T-cell NK or ADCC activity.
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Previous studies in this laboratory revealed that NZB mice have abnormalities of myeloid progenitor populations from an early age such that they are poorly responsive to a particular type of colony-stimulating activity (CSA). In addition, these mice develop abnormally high numbers of B cells that can be cloned in semisolid agar cultures and that are atypical in resisting inhibition by anti-mu antibodies. To investigate whether these abnormalities, like other autoimmune phenomena studied previously, are transferrable with hemopoietic cell grafts, we performed reciprocal bone marrow transplants between NZB and normal DBA/2 mice. Irradiated control mice given syngeneic marrow did not change with respect to any of the parameters that were measured. In contrast, DBA/2 recipients of NZB marrow were indistinguishable from NZB mice in terms of CSA responses and incidences of anti-mu resistant B cells. The proportions but not total numbers of clonable B cells ere elevated in these mice until at least 16 wk after grafting. Conversely, NZB mice given DBA/2 cells had all of the normal characteristics of DBA/2 mice. Transplantation did not cause significant changes in hematocrits, reticulocyte counts, or spleen weights. Therefore, all elements necessary for expression of these lymphoid and nonlymphoid abnormalities of NZB mice are intrinsic to radiosensitive hemopoietic cells.