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F H Bach

Publications and source records attributed to F H Bach.

At least 127 records · Page 7Linked to original sources
PubMed1994

Selective inhibition of E-selectin, ICAM-1, and VCAM in endothelial cells.

Endothelial cells, as they normally exist in the vasculature as quiescent cells, perform several functions. In an inflammatory response, endothelial cells are activated to up-regulate a number of genes, including E-selectin (ELAM-1), VCAM-1, ICAM-1, interleukin (IL)-1, IL-8 and plasminogen activator inhibitor-1 (PAI-1). Very little is known about factors that regulate the activation process. We describe here that a heat-stable protein, normally present in the alpha-globulin fraction of serum, inhibits induced expression of E-selectin, ICAM-1, and VCAM-1 in vitro and also impedes the accumulation of mRNA for these molecules. Inhibition of E-selectin, the only gene tested in this respect, is at the level of transcription. At the same time, the alpha-globulins do not, under the same conditions, repress mRNA accumulation for IL-1, IL-8, or PAI-1. The effect of the inhibitor does not relate to constraints on function of nuclear-factor kappa B, the induced activity of which is not interfered with at the early time points at which the suppression of these three genes is seen.

Alpha-Globulins↗
PubMed1994

Molecular analysis of the immune response to human cytomegalovirus glycoprotein B (gB). II. Low gB-specific T and B cell responses are associated with expression of certain HLA-DR alleles.

Human cytomegalovirus (HCMV) is a common cause of congenital infection leading to birth defects and a leading cause of serious illness in patients with immunodeficiencies. Studies in this laboratory have focused on a molecular analysis of the immune response to glycoprotein B (gB) of HCMV. This protein has been shown to elicit B cell, helper T cell (Th), and cytotoxic T cell responses, suggesting that it may be useful as a subunit HCMV vaccine. However, previous studies showed that although peripheral blood mononuclear cells (PBMC) from all HCMV-seropositive donors proliferate in response to stimulation with whole HCMV, not all donors respond to purified recombinant gB. In the present study, PBMC from HCMV-seropositive donors homozygous for HLA-DR were tested for proliferative responses to whole HCMV and to purified gB expressed in vaccinia virus. PBMC from all donors proliferated in response to HCMV, but those from multiple donors expressing the HLA-DR3Dw3 and -DR4Dw4 specificities, and single donors expressing the -DR15Dw2, -DR13Dw19 and -DR14Dw9 specificities, failed to respond to gB. These results suggested a possible HLA-DR association with low proliferative responses to gB. In further studies, PBMC from donors expressing both putative gB-high responder and low responder HLA-DR alleles were stimulated multiple times with gB to generate gB-specific T cell lines. These cells were then tested for proliferative responses to gB presented by irradiated PBMC sharing only one DR allele with the responder cells. Cells from the gB-specific lines proliferated only when antigen was presented in the context of a responder DR allele but not when presented in the context of a low responder DR allele. Analysis of immune sera revealed that those from donors with PBMC proliferative responses always contained antibodies reactive with B cell epitopes on both the N-terminal gp93 and C-terminal gp55 portions of gB. In contrast, many of the sera from donors with low gB-specific proliferative responses had gp55-specific antibodies but lacked antibodies to gp93. These results suggest that immunogenetic differences in Th responsiveness to gB may lead to lack of antigen-specific help for antibody responses to gp93 in some cases. The prevalence of these low responder HLA alleles in the population, and the central importance of the T cell response to the generation of antibodies suggest that native gB alone may not be an attractive candidate for an HCMV subunit vaccine.

Adult↗
PubMed1994

Depletion of IgM xenoreactive natural antibodies by injection of anti-mu monoclonal antibodies.

It is believed that IgM xenoreactive natural antibodies (XNA) and activation of complement are the two main effectors involved in the hyperacute rejection (HAR) of discordant xenografts, such as pig-to-primate kidney, liver or heart transplants. We have hypothesized that long-term depletion of circulating IgM XNA might be able to overcome HAR and induce the "accommodation" of pig-to-primate vascular discordant xenografts. Several techniques have been described to eliminate circulating XNA in primates but, up to now, none has been able to totally deplete these antibodies for a sufficiently long period of time in order to test the hypothesis of discordant xenograft "accommodation". Previous reports from our laboratory have shown that, in rodents, B-cell immunosuppression could be achieved by neonatal administration of anti-mu antibodies. Recently we have shown that administration of an anti-mu mAb, in adult rats, was able to totally deplete circulating IgM and IgM XNA, without immune complex disease. Furthermore, we have used different methods such as splenectomy, plasma exchange and an anti-B cell immunosuppressive agent mycophenylate mophetil (RS61443, Syntex, Palo Alto, USA) to pre-deplete circulating IgM before administration of anti-mu mAb (MARM-7) and showed that the effectiveness of anti-mu mAb to deplete circulating IgM was increased by 100-fold. Depletion of circulating IgM in adult rats by anti-mu mAb (MARM-7) was used as an experimental model to study the role of IgM XNA in the pathogenesis of HAR in guinea pig-to-rat cardiac xenografts. Our data show that IgM XNA play a major role in HAR, even if in this discordant combination direct activation of complement, probably through the alternative pathway, seems to be the main effector involved in HAR. We have analyzed the mechanisms of anti-mu depletion of circulating IgM in adult animals and shown that, besides anti-mu/IgM immune complex formation, depletion of circulating IgM results from the very significant inhibition of B-cell differentiation and secretion of IgM following in vivo crosslinking and internalization of surface IgM on B cells. As well, we provide evidence demonstrating that anti-mu mAb blocks B cells at an early stage of maturation, probably in the bone marrow. Furthermore, we have developed several rat anti-human and anti-baboon IgM mAb and tested their ability to deplete circulating IgM and IgM XNA in baboons, after splenectomy or splenectomy and plasma exchange.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1993

Cytokine-inducible expression in endothelial cells of an I kappa B alpha-like gene is regulated by NF kappa B.

The transient expression of many different genes is mediated by the inducible transcription factor p50-p65 NF kappa B, which in turn is regulated by complex formation with its inhibitor I kappa B alpha. We describe here that in porcine aortic endothelial cells, either IL-1 alpha, TNF alpha or LPS upregulates an inhibitor of NF kappa B which we refer to as ECI-6. ECI-6 is by structural and functional criteria an I kappa B alpha protein, the porcine homologue of MAD-3, pp40 and RL/IF-1. We have studied the promoter of the ECI-6/I kappa B alpha gene and provide three lines of evidence that its expression is directly regulated by NF kappa B. First, the 5' regulatory region of ECI-6/I kappa B alpha contains two sites that bind NF kappa B in electrophoretic mobility shift assays. Second, expression following transfection of an ECI-6/I kappa B alpha promoter-luciferase reporter construct is dependent on a co-transfected NF kappa B-p65 subunit. Third, pretreatment of endothelial cells with antioxidants, agents that inhibit activation of NF kappa B, inhibit the expression of ECI-6/I kappa B alpha. We conclude that the regulated expression of ECI-6/I kappa B alpha could represent a novel feedback mechanism by which NF kappa B downregulates its own activity after transient activation of target genes has been achieved.

Amino Acid Sequence↗
PubMed1993

Genomic structure of NKG5, a human NK and T cell-specific activation gene.

We reported previously the isolation of a cDNA clone, designated NKG5, encoding a secreted protein that is expressed only in natural killer and T cells and is strongly upregulated upon cell activation. In this report we have isolated the NKG5 gene from a human placental genomic library and sequenced the gene and two kilobases of 5'-flanking DNA. Comparison with the cDNA sequence reveals that the NKG5 gene consists of five exons and four introns. Intron 1 contains a DNA segment that was reported to occur as an exon in 519, a closely related cDNA clone that was isolated from a T-cell library. This result indicates that NKG5 and 519 are alternative splicing products of a single gene. The 5'-flanking region of the NKG5 gene was analyzed for homology with the promoter regions of cytokines and other activation-induced genes showing lymphocyte-specific expression. Several segments displaying sequence similarity were identified. We also identified numerous sequence elements that have strong similarity to known binding sites for transcriptional regulatory proteins including T cell-specific and activation-specific regulatory factors. These findings are consistent with the cell-specific expression and the tight regulatory control that is observed for the NKG5 gene.

Alternative Splicing↗