Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Benzo(a)pyrene, a potent carcinogen, severely suppresses the anti-SRBC plaque-forming cell response, the mixed lymphocyte response (afferent T cell function), and an in vivo graft-vs.-host response (efferent T cell function) of mouse progeny exposed to the carcinogen during gestation (11 to 13 days). Immunodeficiency occurs early after birth (1 week) and persists for 18 months. The abnormalities in the T cell-mediated responses led us to examine the quantitative profile of T cells and subsets (Lyt 1+, Lyt 2+) present in the lymphoid organs during fetogenesis (15 to 19 days) and postnatally. In addition, we examined the ability of 3- to 8-month-old progeny and their spleen cells to resist the in vivo growth of cells from a syngeneic fibrosarcoma (a tumor that had been induced by benzo(a)pyrene). Our observations included: (1) Depletion of T cells and subsets in the thymus late (19 days) in gestation and postnatally. (2) Depleted T and Lyt 1+ cells in the spleen during gestation, while postnatally the former were enhanced and the effect on the latter was variable (enhancement and reduction). (3) In the fetal liver, the T cells were reduced, but the Lyt 1+ cells were unchanged. (4) The Lyt 2+ cells were strikingly enhanced in the fetal liver and spleen, but most dramatically for the former. (5) The Lyt 1/Lyt 2 ratio was less than 1.00 or controls in the fetal liver and spleen, a condition which persisted for 30 days postnatally in the latter organ. (6) Benzo(a)pyrene-exposed progeny or their spleen cells were relatively ineffective in resisting in vivo growth of transferred tumor cells. These results show that this carcinogenic pollutant induces a marked disorientation of T cells and subsets which can persist for at least 4 weeks postnatally. This suggests disruption of T cell differentiation during ontogenesis which may have profound implications on the ability to resist induction and growth of neoplasias after in utero exposure to the carcinogen.
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PMID:Early changes in T lymphocytes and subsets of mouse progeny defective as adults in controlling growth of a syngeneic tumor after in utero insult with benzo(a)pyrene. 350 Jan 49

Pregnant mice were exposed to 150 micrograms benzo[a]pyrene (BaP) per gram of body weight during fetogenesis (d 11-17 of gestation) and the progeny were assayed for humoral and cell mediated immune responses at different time intervals after birth. Immature offspring (1-4 wk) were severely suppressed in their ability to produce antibody-(plaque-) forming cells (PFC) against sheep red blood cells (SRBC) and in the ability of their lymphocytes to undergo a mixed lymphocyte response (MLR). Lymphocytes from these progeny showed a moderate to weak capacity to inhabit production of colony-forming units (CFU) in host spleens following transfer with semiallogeneic bone marrow (BM) cells into lethally X-irradiated recipients syngeneic to the BM (in vivo graft-versus-host response, GVHR). A severe and sustained suppression in the MLR and the PFC response occurred from the fifth month up to 18 mo. The in vivo GVHR, also subnormal later in life, was not as severely suppressed as the other two parameters. Tumor incidence in the BP-exposed progeny was 8- to 10-fold higher than in those encountering corn oil alone from 18 to 24 mo of age. These data show that in utero exposure to the chemical carcinogen BaP alters development of components needed for establishing competent humoral and cell-mediated functions of the immune apparatus and leads to severe and sustained postnatal suppression of the defense mechanism. The immunodeficiency exhibited, particularly in the T-cell compartment (MLR, GVHR), before and during the increase in tumor frequency, may provide a favorable environment for the growth of nascent neoplasms induced by BaP.
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PMID:Subnormal expression of cell-mediated and humoral immune responses in progeny disposed toward a high incidence of tumors after in utero exposure to benzo[a]pyrene. 623 29

We have studied the effect of several environmental chemicals on the transient expression of a chloramphenicol acetyltransferase (cat) reporter gene linked to the promoter sequences in the long terminal repeat (LTR) of the human immunodeficiency virus type 1 (HIV-1). Aflatoxin B1, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; dioxin) and benzo[a]pyrene cause a significant increases in CAT expression in mouse hepatoma Hepa-1 cells. The induction of CAT after TCDD treatment is abolished by administration of N-acetyl-L-cysteine or 2-mercaptoethanol and does not take place in a mutant cell line that lacks CYP1A1 enzymatic activity. Linker-scanning mutational analysis of transcription factor binding sites in the promoter revealed that both the NF kappa B and an adjacent aromatic hydrocarbon response element (AhRE) are required for TCDD-dependent CAT expression. In addition, mutation of the NFAT/AP-1 binding sites in the negative regulatory region of the promoter increases the magnitude of the TCDD effect. We conclude that induction of a functional CYP1A1 monooxygenase by TCDD stimulates a pathway that generates thiol-sensitive reactive oxygen intermediates which, in turn, are responsible for the TCDD-dependent activation of genes linked to the LTR. These data might provide an explanation for findings that TCDD increases infectious HIV-1 titers in experimental systems and for epidemiologic reports suggesting that exposure to aromatic hydrocarbons, such as found in cigarette smoke, is associated with an acceleration in AIDS progression.
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PMID:Dioxin activates HIV-1 gene expression by an oxidative stress pathway requiring a functional cytochrome P450 CYP1A1 enzyme. 760 37

1. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) was an inducer of microsomal benzo[alpha]pyrene hydroxylase (AHH) and 7-ethoxyresorufin O-deethylase (EROD) in MT-4 human lymphoid cell culture. 2. The monoclonal antibody (Mab), 1-7-1 and the immunodepleted polyclonal antibody (Pab), anti-CYP1A1(-A2), inhibit AHH and EROD activities pre-induced by 10 nM TCDD in MT-4 cells. Hence, the specific monooxygenase isoform induced in the lymphoid cells by TCDD appears to be CYP1A1 the expression of which is mediated by the Ah receptor. 3. Incubation of MT-4 cells with TCDD at 10, 50 and 150 nM for 1.5 and 48 h followed by infection of the cells with human immunodeficiency virus 1 (HIV-1) was accompanied by a 3-6-fold increase in the activity of viral RNA-dependent DNA-polymerase. The most marked effect on reverse transcriptase activity occurred with 10 nM TCDD 5-9 days after HIV-1 infection. 4. In the same period there was accumulation of viral protein, determined by ELISA, with a 4-8-fold increase in production of viral protein. The above effects of TCDD have been observed even when MT-4 cells were washed 1.5 h after beginning the incubation with TCDD.
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PMID:Stimulatory effect of the CYP1A1 inducer 2,3,7,8-tetrachlorodibenzo-p-dioxin on the reproduction of HIV-1 in human lymphoid cell culture. 768 6

T-lymphocyte E-receptor activity, mobility of the surface and deep parts of lymphocytic membrane lipid bilayer and membrane transport function were studied in 47 patients with chronic renal failure (16 had a conservatively curable and 31 terminal stages). A rosette test, polarization of the fluorescent probes I-anilino-naphthaleno-8-sulfonate and pyrene, inclusion of 14C-uridine into immunocompetent cells were employed, respectively. The investigations demonstrate morphofunctional instability of the lymphocytic membranes as indicated by shifts in RFC E-receptor activity, in reduced microviscosity of the lipid bilayer and transport dysfunction. The disturbances progress with deterioration of renal function with their peak at the terminal stage of the disease. It is suggested that morphofunctional damage to the lymphocyte membranes cause, among other factors, lymphocytopenia and secondary immunodeficiency in chronic renal failure.
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PMID:[The morphofunctional instability of the lymphocyte membrane in patients with chronic kidney failure]. 816 Mar 23

A rosette test, fluorescent probing (1-aniline-naphthaline-8-sulfonate and pyrene) and 14C-uridine inclusion into immuno-competent cells were used to investigate T-lymphocyte membrane E-receptor activity, mobility of the surface and deep parts of lymphocytic membrane lipid bilayer, and membrane transport, respectively. A total of 16 patients with conservatively curable and 31 patients with a terminal stage of chronic renal failure (CRF) were examined. The lymphocytic membranes were found unstable: E-receptor activity of RFC changed, microviscosity of the surface and deep lipid bilayer diminished, the transport function got disturbed. These phenomena significantly progress with deterioration of renal function. It is evident that morphofunctional damage to lymphocytic membranes may be a reason of lymphocytopenia and secondary immunodeficiency in CRF patients.
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PMID:[The morphofunctional instability of the lymphocyte membranes in patients with chronic kidney failure]. 839 46

To determine the effect of various stereoisomers of benzo[a]pyrene-7,8-dihydrodiol 9,10-epoxide (BPDE) on translesion bypass by human immunodeficiency virus-1 reverse transcriptase and its alpha-helix H mutants, six 33-mer templates were constructed bearing site- and stereospecific adducts. This in vitro model system was chosen to understand the structure-function relationships between the polymerase and damaged DNA during replication. Comparison of the replication pattern between wild type human immunodeficiency virus-1 reverse transcriptase and its mutants, using primers which were 3' to the lesion, revealed essentially similar patterns. While these primers terminated with all three of the C10R and two of the C10S BPDE-adducted templates 1 base 5' and 1 base 3' to the damaged site respectively, (+)-anti-trans-(C10S) BPDE-adducted DNA alone permitted the formation of full-length products. Utilization of a primer with its 3'-hydroxyl 1 base beyond the lesion resulted in full-length products with all the C10S BPDE-adducted templates and the (-)-syn-trans-(C10R)-BPDE-adducted template, following replication with either the wild type or mutant enzymes. However, the other two C10R BPDE-adducted templates failed to allow any primer extension, even with the wild type enzyme. Although T.P depletion studies further confirmed the differential primer extension abilities using the C10R and C10S adducted templates, their binding affinities were similar, yet distinct from the unadducted template.
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PMID:Differential tolerance to DNA polymerization by HIV-1 reverse transcriptase on N6 adenine C10R and C10S benzo[a]pyrene-7,8-dihydrodiol 9,10-epoxide-adducted templates. 903 95

Childhood cancer has been increasing significantly over the past two decades in the United States, suggesting that environmental exposures may be playing a causative role. One such cause may be maternal smoking during pregnancy. Suspected carcinogens in cigarette smoke and environmental pollution include N-nitrosamines and polycyclic aromatic hydrocarbons, which may be several micrograms per exposure. Previously, we have shown that mouse progeny of mothers exposed to benzo[a]pyrene (B[a]P) during midpregnancy had abnormalities in their humoral and cell-mediated immune response. Immunodeficiency was detectable during gestation, at one week after birth and persisted for 18 months. Tumor incidences in progeny were eight to 10-fold higher than in controls. The present study compared frequencies of CD4+, CD8+, V gamma 2+, and V beta 8+ T cells in progeny following in utero exposure to B[a]P. The significant reduction in newborn CD4+CD8+, CD4+CD8+V beta 8+ thymocytes and CD4+ splenocytes from 1-week-old progeny, suggests that B[a]P induces abnormal changes in developing T cells. These early alterations may lead to postnatal T cell suppression, thus providing a more suitable environment for the growth of tumors later in life. These results suggest that developmental immunosuppression mediated by B[a]P may play a critical role in the relationship between maternal exposures and childhood carcinogenesis.
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PMID:Maternal exposure to benzo[a]pyrene alters development of T lymphocytes in offspring. 1031 87

Phospholipid conjugates of 3'-azido-3'-deoxythymidine (AZT) show activity against human immunodeficiency virus (HIV) in vitro. Here we report on the synthesis and characterization of two pyrene containing conjugates: 2-N-(4-(pyren-1-yl)butanoyl)ceramide 5'-phosphothymidine (Pbs-Cer-P-T) (XII) and 2-N-(10-(pyren-1-yl)decanoyl)ceramide 5'-phosphothymidine (Pds-Cer-P-T) (XIII). These fluorescent labelled conjugates served as model compounds to study incorporation of sphingoliponucleotides into membranes. The complex compounds were prepared by condensation of 3'-acetylthymidine and labelled ceramides using the phosphite triester coupling procedure. UV absorption, fluorimetry as well as 1H-, 31P-, 13C-NMR analyses were used for structure confirmation of the synthesized substances. When incorporated into small unilamellar 1-palmitoyl-2-oleoyl-glycerophosphatidyl-choline (POPC) vesicles and incubated with unlabelled acceptor POPC vesicles, the compounds (XII) and (XIII) exhibited spontaneous transfer. Kinetic data suggest that transfer from donor to acceptor vesicles occurred via the intervening aqueous phase. The non-specific lipid transfer protein from bovine liver stimulated the transfer of Pds-Cer-P-T between phospholipid vesicles in a concentration dependent manner.
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PMID:Synthesis and intermembrane transfer of pyrene-labelled liponucleotides: ceramide phosphothymidines. 1037 64

Integration of the viral cDNA into host chromosomes is required for viral replication. Human immunodeficiency virus integrase catalyzes two sequential reactions, 3'-processing (3'-P) and strand transfer (ST). The first integrase inhibitors are undergoing clinical trial, but interactions of inhibitors with integrase and DNA are not well understood in the absence of a co-crystal structure. To increase our understanding of integrase interactions with DNA, we examined integrase catalysis with oligonucleotides containing DNA backbone, base, and groove modifications placed at unique positions surrounding the 3'-processing site. 3'-Processing was blocked with substrates containing constrained sugars and alpha-anomeric residues, suggesting that integrase requires flexibility of the phosphodiester backbone at the 3'-P site. Of several benzo[a]pyrene 7,8-diol 9,10-epoxide (BaP DE) adducts tested, only the adduct in the minor groove at the 3'-P site inhibited 3'-P, suggesting the importance of the minor groove contacts for 3'-P. ST occurred in the presence of bulky BaP DE DNA adducts attached to the end of the viral DNA suggesting opening of the active site for ST. Position-specific effects of these BaP DE DNA adducts were found for inhibition of integrase by diketo acids. Together, these results demonstrate the importance of DNA structure and specific contacts with the viral DNA processing site for inhibition by integrase inhibitors.
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PMID:Effect of DNA modifications on DNA processing by HIV-1 integrase and inhibitor binding: role of DNA backbone flexibility and an open catalytic site. 1694 99


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