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Biomedical subjects

R A Good

Publications and source records attributed to R A Good.

At least 181 records · Page 10Linked to original sources
PubMed1992

Nutrition and cellular immunity.

We have investigated the influence of nutrition on immune function in animals and man over the past two decades. The profound impairment of immune function that had not been observed in children in developing countries could not consistently be reproduced in the laboratory setting; paradoxically, moderate nutritional restriction could even enhance T-cell-based cell-mediated immune responses in experimental animals. Studies of the crucial role of the element zinc in maintenance of vigorous cellular immunity provided at least a partial explanation of this paradox. Zinc, shown to be absolutely crucial for development and expression of both T- and B-cell functions, was commonly deficient as were other micronutrients under many conditions of protein-calorie malnutrition. Indeed, administration of adequate zinc alone could correct some of the T-cell-mediated immune functions in children with protein-calorie malnutrition. In later investigations we found that as long as all essential nutrients were supplied in adequate amounts, 40% chronic energy (calorie) restriction will regularly extend lifespan and maintain vigorous immunologic function while preventing numerous cancers and immunologically based diseases of aging, such as profound and destructive autoimmune diseases in genetically short-lived mice strains, as it was known to do for moderately long-lived rats and long-lived strains of mice. Such undernutrition without malnutrition appears to influence a wide range of critical metabolic and physiologic processes in both short-lived and long-lived animals. One of the most challenging of these influences was a down-regulation of cellular proliferation and cell turnover in each of the rapidly replicating tissues studied.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Ethanol calories do not enhance breast cancer in isocalorically fed C3H/Ou mice.

Mammary tumorigenesis is augmented when C3H/Ou mice are fed diet ad libitum but delayed when calories are restricted by 40%. Three feeding experiments were done to evaluate the effect of ethanol on mammary tumorigenesis in isocalorically fed C3H/Ou mice: 1) ad libitum feeding of semipurified solid diet, with one group receiving 12% ethanol (15 g/kg/day) in the drinking water while controls received water alone; 2) isocaloric pair feeding of semipurified solid diet, with ethanol (4 g/kg/day) administered by gavage five time per week; and 3) isocaloric pair feeding of Lieber-DeCarli liquid diet, with one group receiving 29% of calories as ethanol (20 g/kg/day) in the diet. Despite administration of ethanol to isocalorically fed C3H/Ou mice for 65 weeks by three different methods, mammary tumor development was not enhanced. In two of the three ethanol-consuming groups, weight gain and mean body weight were less in the ethanol-consuming mice than in the controls, despite equal total calorie consumption. In only one ethanol-consuming group, where mice received ethanol as a 12% solution in the drinking water, was any difference noted in the tendency to develop mammary tumors. In this case, delay in tumorigenesis was apparent in the ethanol-consuming animals (p = 0.03). These findings do not support the hypothesis that ethanol calories augment the risk of breast tumorigenesis among breast cancer-prone mice consuming isocaloric diets. Instead, reductions in weight gain and body weight among ethanol-consuming mice and an apparent reduction in mammary tumorigenesis in one of three experimental groups suggest that ethanol may decrease metabolic utilization of calories and hence contribute to lowered energy availability.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Clonal elimination of self reactive V beta 6+ T cells induced by H-2 products expressed on thymic radio-resistant components.

The role of thymic radio-resistant cells on clonal elimination of V beta 6+ T cells that are reactive to minor lymphocyte stimulatory (Mls)-1a plus I-E antigens has been investigated. Previous studies with allogeneic bone marrow chimeras revealed that radio-sensitive I-E+ cells derived from donor bone marrow in the thymus play a major role in the clonal elimination of V beta 6+ T cells. However, we could show that not only the thymic bone marrow derived components but also the radio-resistant ones (presumably thymic epithelial cells) might be involved in induction of clonal elimination of the self-reactive T cells. The proportion of V beta 6+ T cells present varied with the H-2 haplotype of the thymus and the cell types presenting Mls-1a products, which might be attributable to differences in the affinity of the H-2 products to T cell antigen receptors and differences in the amount of tolerogens expressed on the stromal cells.

Animals↗
PubMed1992

Development and characterization of monoclonal antibodies to lymphocyte cell surface antigens of the rhesus monkey.

Three monoclonal antibodies directed against rhesus lymphocyte cell surface antigens are described. A pan-T mAb, T64, and a T suppressor mAb, T35, showed phenotypic and functional specificity for both human and rhesus cells. In contrast, a third mAb, N42, identifying natural killer cells in rhesus peripheral blood leukocytes, was not crossreactive with the corresponding homologous human cells. N42 reacted with the same cells identified by Leu 11a and Leu 11b in rhesus PBL and in a functional assay decreased NK activity by 80%. N42 precipitated a 50KD protein from rhesus PBL lysates and was reactive with the Fc receptor domain of the NK cell. The T-S functional activity of cells reactive with mAb T35 was demonstrated in a pokeweed-mitogen-driven system for Ig synthesis: removal of the T35 positive cells by complement-mediated lysis led to an enhanced production of Ig by rhesus PBL, and the addition of T35 positive cells to a culture of T helper and B cells resulted in a reduction of this response. T35 was determined to be an IgG2a immunoglobulin and precipitated a 34KD protein from rhesus cell lysates. An IgM immunoglobulin, mAb T64 delineated all T lymphocytes, inhibited E-rosette formation, interfered with the proliferation of cells stimulated with mitogens, and precipitated a 52KD membrane protein. The potential utilization of these mAbs in vivo for organ or tissue transplantation in the rhesus monkey is discussed.

Animals↗
PubMed1992

Functional evaluation of T helper, T suppressor, and B lymphocytes in lethally irradiated rhesus monkeys injected with autologous bone marrow.

Lethally irradiated rhesus monkeys were treated with autologous bone marrow that had either been (1) nontreated, i.e., normal; (2) depleted of T lymphocytes with a monoclonal antibody directed against rhesus T lymphocytes; (3) fractionated with the soybean agglutinin (SBA- fraction); or (4) fractionated with SBA and further depleted of T cells by E-rosetting. There was no difference in hematologic reconstitution among the animals, but all showed a marked lowering of the T helper/T suppressor ratio during the first 10 months posttransplant and reduced capability of their peripheral blood leukocytes (PBL) to produce Ig upon stimulation with pokeweed mitogen. This subnormal ability of PBL to produce Ig, as measured by plaque-forming cells in a reverse hemolytic plaque assay, was not explained entirely by the altered T-H/T-S ratio but was correlated with the functional status of the T-H, T-S, and B lymphocytes. Isolated populations of the different lymphocyte subsets from PBL of the experimental animals were cocultured with normal cells of the appropriate subset to obtain Ig synthesis when stimulated with PWM. Animals treated with normal bone marrow showed recovery of T-H cell function after 5 months, but their T-S cells showed excessive suppressor activity that persisted for 20 months posttransplant. In contrast, those animals receiving treated marrow (mAb plus complement, or SBA) showed a much-delayed (12 months or more) return to normal T-H cell function and an earlier return of T-S cells expressing a normal level of suppressor activity. Since the SBA- fraction of marrow contains very few or no T-H cells and T cell depletion of marrow with mAb also removes these cells, it is suggested that the kinetics of immune recovery of the different lymphocyte subsets of PBL is influenced by the presence or absence of T-H cells in the marrow inocula.

Animals↗
PubMed1992

RNA/nucleotide enhances antibody production in vitro and is moderately mitogenic to murine spleen lymphocytes.

Suppression of immune functions was demonstrated in both humans and animals when exogenous RNA was eliminated from the diet. However, direct actions of RNA/nucleotide on the immune system are virtually unknown. Thus, in this study, we explored effects of RNA and nucleotide on lymphocyte functions in vitro. Yeast whole RNA, which is free of endotoxin, was supplemented to culture media, and changes in mitogen responses, thymocyte proliferation, or in vitro antibody production by murine spleen lymphocytes were analyzed. Yeast whole RNA potentiated the proliferation of spleen lymphocytes and it also strikingly enhanced in vitro antibody production in response to sheep red blood cells at least 10-fold. However, it did not potentiate the proliferation of thymocytes (immature lymphocytes). These enhancing activities of yeast RNA were significantly reduced by RNAse treatment, but not by treatments with DNAse or polymyxin B. Certain mononucleotides exhibited less, but similar, action on murine spleen lymphocytes. The whole yeast RNA employed was already degraded to small nucleotide (less than 1 kb). Therefore, it may be suggested that certain components of RNA degraders can function as powerful immunomodulators, indicating that exogenous RNA or nucleotide may be important in facilitating immune responses under certain circumstances.

Animals↗
PubMed1992

Effects of calorie restriction on immunologic functions and development of autoimmune disease in NZB mice.

Chronic energy (calorie) intake restriction (CEIR) prolonged life, inhibited autoimmune disease, and influenced immunologic and hematologic parameters in NZB mice. Abnormalities in numbers and proportions of T and B cells populations were corrected. Deficient responses to phytomitogens, mixed lymphocyte reactions, formation of plaque-forming cells to sheep red blood cells in vitro, production of cytotoxic T lymphocytes after in vitro stimulation, and interleukin 2 production were also corrected. CEIR prevented the extreme splenomegaly that normally occurs with age in NZB mice. This influence was associated with reduction of a greatly expanded non-T, non-B lymphoid cell population. Calorie restriction also prevented in NZB mice the rapid decrease in total numbers of colony-forming B cells in bone marrow that is also characteristic of mice of this strain. The influences of CEIR on immune parameters and hematopoiesis were generally less marked in non-autoimmune-prone DBA/2 mice than in autoimmune-prone NZB mice. CEIR has been shown to produce profound influences on several strains of autoimmune-prone mice (NZB x NZW)F1, MRL/lpr, BXSB, and NZB herein). In each of these strains, the pathogenesis and manifestations of autoimmune disease are dissimilar. Therefore, it seems likely that calorie restriction acts on an as yet elusive mechanism that operates to foster development of the diseases associated with aging common to each of these autoimmune strains as well as autoimmune-resistant mice and rats. Further investigation of the molecular and cellular bases of the benefits of CEIR seems urgent.

Animals↗
PubMed1992

Effects of ultraviolet-inactivated feline leukemia virus on the production of alpha/beta interferon by feline peripheral blood mononuclear cells.

The effects of ultraviolet-inactivated feline leukemia virus (UV-FeLV) on the production of alpha and/or beta interferon (IFN) by mononuclear cells stimulated with the Newcastle disease virus (IFN-NDV) was investigated. The production of IFN-NDV and gamma IFN was suppressed by 50% as compared to the control in the presence of 200 ng/ml or 200 micrograms/ml of UV-FeLV, respectively. The presence of UV-FeLV decreased the rate of the production, but the time to reach the plateau of the IFN activity in the culture supernatant was not shortened in both IFNs. It was suggested that the suppressive effects of UV-FeLV against both IFNs were through rather similar mechanisms. The suppressive effects of UV-FeLV on IFN-NDV production was most evident in the cultures to which UV-FeLV was added at the early stages of the culture, and could not be demonstrated when UV-FeLV was added 8 hr after initiation of the culture. These data therefore indicate that non-infectious feline leukemia viral particles can modify the production of feline IFNs by peripheral blood mononuclear cells.

Animals↗
PubMed1992

Enrichment of murine bone marrow natural suppressor activity in the fraction of hematopoietic progenitors with interleukin 3 receptor-associated antigen.

Natural suppressor (NS) activity has been identified in several sites of active hematopoiesis. In this study we characterized NS activity in murine bone marrow (BM) using monoclonal antibodies (mAbs) to interleukin 3 (IL-3) receptor-associated antigen (IL-3RAA) and various cytokines that exert a strong influence on hematopoiesis or lymphocyte interaction. NS activity of BM cells of relatively low density was enhanced by IL-3 or granulocyte-macrophage colony-stimulating factor (GM-CSF). When the BM cells were separated into IL-3RAA+ cells and IL-3RAA- cells, the IL-3RAA+ cells demonstrated potent NS activity, whereas IL-3RAA- cells had either no or weak NS activity. The IL-3RAA+ cells showed non-T- and non-B-cell phenotype and had high affinity to wheat germ agglutinin (WGA), a marker for hematopoietic progenitors. In assays for hematopoietic activity, it appeared that the early differentiating progenitors (day 8 spleen colony-forming units [CFU-S], granulocyte-macrophage colony-forming units [CFU-GM]) were enriched in the IL-3RAA+ cell population, whereas more immature multipotent progenitors (day 12 CFU-S, granulocyte erythrocyte macrophage megakaryocyte colony-forming units [CFU-GEMM]) were contained in the IL-3RAA- cell population. Both suppressor cells and IL-3RAA+ cells spontaneously developed from the IL-3RAA- cell population. These findings suggest that NS cells in murine BM are early hematopoietic progenitors and are probably committed to the myeloid lineage. Hybridoma cells established between the IL-3RAA+ cells and BW5147 cells produced suppressor factor(s). This finding suggests that the NS cells produce soluble mediator(s) that may be responsible for their suppressive action.

Animals↗
PubMed1991

Calorie restriction suppresses subgenomic mink cytopathic focus-forming murine leukemia virus transcription and frequency of genomic expression while impairing lymphoma formation.

Calorie restriction suppresses mammary proviral mRNA expression and protooncogene activation in breast tumor-prone C3H/Ou mice while inhibiting tumor formation. To determine whether the beneficial effects of chronic energy-intake restriction (CEIR) can be extended to an organ site of retrovirus-induced tumorigenesis where the dynamics of growth and sexual maturity are not paramount as they are in breast tissue, calorie restriction of 40% was imposed on thymic lymphoma-prone AKR mice when 4 weeks old. Recombination between various murine leukemia virus (MuLV) mRNAs, resulting in the generation of an 8.4-kilobase genomic-length transcript with mink cytopathic focus-forming (MCF) characteristics, is considered the proximal retroviral event in AKR lymphomagenesis. Thymic expression of subgenomic MCF MuLV mRNA was uniformly suppressed among 6- and 8-week-old CEIR mice (P less than 0.02). This suppression of MuLV transcription preceded a 25% reduction in the appearance of genomic-length MCF transcripts among CEIR mice and a 28% reduction in cumulative lymphoma mortality. The latency to median tumor incidence was extended greater than 3 months by calorie restriction, and median lifespan was extended approximately 50%. Survival curves for the full-fed and CEIR dietary cohorts were found to be significantly different (P less than 0.0001), with full-fed mice experiencing a 3 times greater risk of lymphoma mortality. These findings extend the known range of pathologic states influenced by CEIR in inbred mice and show that retroviral mechanisms involved in generation of lymphoid malignancy can be significantly impaired by calorie restriction.

Animals↗
PubMed1991

T-cell depletion of HLA-identical transplants in leukemia.

We analyzed the effects of T-cell depletion on the outcome of HLA-identical sibling bone marrow transplants for leukemia by comparing 731 T-cell-depleted transplants with 2,480 non-T-cell-depleted transplants. T-cell depletion decreased acute graft-versus-host disease (GVHD) (relative risk [RR] 0.45; P less than .0001) and chronic (GVHD) (RR 0.56; P less than .0001). However, it increased graft failure (RR 9.29; P less than .0001). Leukemia relapse also was increased. In first remission acute leukemia or chronic phase chronic myelogenous leukemia, leukemia relapse was 2.75 times more likely after T-cell-depleted transplants (P less than .0001). T-cell depletion increased the risk of treatment failure (RR 1.35; P less than .0003) and decreased leukemia-free survival. We also studied controllable variables associated with outcome of T-cell-depleted transplants. The unique findings were that among recipients of T-cell-depleted transplants for early leukemia, radiation doses greater than or equal to 11 Gy (RR 0.54; P less than .01), dose rates greater than 14 cGy/min (RR 0.56; P less than .002), and additional posttransplant immune suppression with cyclosporine alone (RR 0.53; P less than .0006) or cyclosporine plus methotrexate (RR 0.36; P less than .01) were associated with fewer treatment failures. Use of monoclonal antibodies rather than physical techniques for T-cell depletion (RR 2.01; P less than .03) and fractionated radiation (RR 1.69; P less than .05) were associated with increased treatment failure and lower leukemia-free survival. These data may be useful in designing strategies to improve results of T-cell-depleted transplants.

Adolescent↗
PubMed1991

Influence of dimethyl myleran on tolerance induction and immune function in major histocompatibility complex-haploidentical murine bone-marrow transplantation.

To study murine major histocompatibility complex (MHC)-haploidentical bone-marrow transplantation (BMT), B6C3F1 mice (H-2b/k) underwent BMT using syngeneic [B6C3F1 (H-2b/k)], haploidentical [CB6F1 (H-2d/b)], or fully allogeneic [DBA/2 (H-2d)] donor mice. As pretreatment, dimethyl myleran (DMM), an alkylating agent that produces effective myeloablation but little immunosuppression, was used with total body irradiation (TBI). Four conditioning regimens were studied: TBI 800 rads (1 rad = 0.01 Gy), TBI 950 rads, TBI 800 rads plus DMM (0.2 mg per mouse), and TBI 950 rads plus DMM. Survival rates, chimerism, proliferative responses in mixed-lymphocyte culture, specific cell-mediated lympholysis, and in vivo plaque-forming cell responses to several antigens were compared. TBI 800 rads plus DMM was maximally effective. Haploidentical BMT was as successful in inducing long-term survival and immune and hematologic reconstitution as was syngeneic BMT. This regimen plus haploidentical BMT of T-cell-purged marrow yielded survivors tolerant of donor and recipient major histocompatibility complex. Such myeloablation and immunosuppression prevented graft rejection, immunodeficiency due to histoincompatibility, and damage to a radiosensitive cell population. A microenvironmental influence crucial to some antibody responses was thus revealed. Delayed recovery of antibody production after BMT in humans may be due partly to suboptimal myeloablation or excess irradiation.

Animals↗
PubMed1991

Dietary restriction permits normal parturition and lactation but suppresses mouse mammary tumor virus proviral transcription even after mammary involution.

Dietary restriction of C3H/Ou mice prevents development of spontaneous mammary adenocarcinoma by suppressing mammary expression of the mouse mammary tumor virus (MMTV) via a mechanism which may involve prolactin. In the present study, dietary restriction of 40% was imposed for 16 weeks on nulliparous C3H/Ou mice, interrupted by ad libitum consumption at mating and continued only during pregnancy and lactation, with 40% energy restriction reimposed at the end of lactation. The results show that mammary MMTV mRNA expression levels of chronic energy intake restricted (CEIR) mice and ad libitum fed mice are similar and elevated during early lactation, when all mice of both groups are being fed ad libitum energy levels. In spite of this, and in marked contrast, when CEIR dams are returned to 40% dietary restriction following the weaning of litters, mammary MMTV transcription is suppressed to levels 4-5-fold less than those measured in mammary glands from ad libitum fed controls. Within the 38 weeks of study, 73% of ad libitum fed uniparous mice at risk and 11% of CEIR uniparous mice at risk developed mammary tumors, yet mice of both dietary groups delivered and weaned healthy litters with comparable efficiency. When dietary restriction is maintained in CEIR mice during pregnancy and lactation, efficiency of conception and litter size are reduced, and MMTV transcription is suppressed even during lactation. Mean serum prolactin levels were not significantly different among dietary groups. These findings show that the level of MMTV transcription is rigorously influenced by dietary energy level, and that 40% dietary restriction of C3H/Ou mice not only suppresses mammary MMTV transcription and prevents mammary tumor development in uniparous mice, but also permits normal conception, gestation, lactation, and the production of healthy litters as long as the nutritional demands of gestation and lactation are met.

Adenocarcinoma↗
PubMed1991

Historic aspects of intravenous immunoglobulin therapy.

The earliest preparations of immunoglobulins (Ig) decreased the susceptibility of agammaglobulinemic patients to infections caused by pneumococci, Haemophilus influenzae, meningococci, streptococci, and Pseudomonas aeruginosa. Intramuscular administration of such preparations was painful and traumatic, especially for children. Ethanol-fractionated Ig could not be administered intravenously (IV) because the IgG molecules tended to aggregate and thus were more likely to produce anaphylactoid reactions. New Ig preparations, isolated at low pH (e.g., pH 4) in the presence of traces of pepsin to inhibit reaggregation, were well tolerated when administered IV. Thus a new era of treatment and prophylaxis of disease using IV Ig (IVIG) was launched. The IVIG preparations revolutionized the management of virtually all immunodeficiency syndromes characterized by failure of antibody responses. Amelioration of antibody deficiency secondary to certain chronic diseases or surgical trauma can be achieved with these preparations. Newer uses of IVIG include treatment of some autoimmune diseases; in some conditions, the beneficial influences may be attributable to antiidiotype antibodies present in the IVIG. Another likely explanation is that IVIG inhibits damage to cells and tissues by antibody-mediated cellular cytotoxicity or blocks phagocytosis that is facilitated by Fc receptor mechanisms. The value of IVIG in preventing infection in patients undergoing bone marrow or organ transplantation and in the treatment and prophylaxis of life-threatening infections in neonates and premature infants also is reviewed.

Animals↗
PubMed1991

Immune suppression induced by protoscoleces of Echinococcus multilocularis in mice. Evidence for the presence of CD8dull suppressor cells in spleens of mice intraperitoneally infected with E. multilocularis.

Immunoregulatory states induced by i.p. inoculation with the metazoan parasite Echinococcus multilocularis in the murine system were investigated. Proliferative responses and IL-2 production induced by Con A in spleen cells from BALB/c mice were significantly depressed at an early stage after infection with E. multilocularis protoscoleces (PSC). Addition of plastic-adherent cells from normal syngeneic mice to the nonadherent spleen cells from infected mice did not restore the depressed Con A responsiveness. On the other hand, exogenous IL-2 reconstituted completely the proliferative responses to Con A. Flow cytometry analysis revealed that CD4- CD8+ cells with a low density of CD8 Ag (CD8dull cells) increased in spleens from infected mice 2 weeks after inoculation. Addition of the spleen cell subpopulation containing the CD8dull cells, but not that depleted of the CD8dull cells, to normal spleen cells resulted in marked suppression of the Con A responses. These findings suggest that the CD8dull cells detected in spleens of mice inoculated with E. multilocularis PSC may play a key role in the suppressive regulation of immune responses. The relevance of the immune suppression seen in the early stages of experimental infection with E. multilocularis PSC to the eventual establishment of a host-parasite relationship is discussed.

Animals↗