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Biomedical subjects

G Peltz

Publications and source records attributed to G Peltz.

At least 19 recordsLinked to original sources
PubMed2005

Tumor necrosis factor-alpha polymorphism, bone strength phenotypes, and the risk of fracture in older women.

TNFalpha is a proinflammatory cytokine that promotes osteoclastic bone resorption. We evaluated the association between a G-308A polymorphism (rs1800629) at the TNFA locus and osteoporosis phenotypes in 4306 older women participating in the Study of Osteoporotic Fractures. Femoral neck bone mineral density (BMD) and structural geometry were measured using dual-energy x-ray absorptiometry and hip structural analysis. Incident fractures were confirmed by physician adjudication of radiology reports. Despite similar femoral neck BMD, women with the A/A genotype had greater subperiosteal width (P = 0.01) and endocortical diameter (P = 0.03) than those with the G/G genotype. The net result of these structural differences was that there was a greater distribution of bone mass away from the neutral axis of the femoral neck in women with the A/A genotype, resulting in greater indices of bone bending strength (cross-sectional moment of inertia: P = 0.004; section modulus: P = 0.003). Among 376 incident hip fractures during 12.1 yr of follow-up, a 22% decrease in the risk of hip fracture was seen per copy of the A allele (relative risk 0.78; 95% confidence interval 0.63, 0.96), which was not influenced by adjustments for potential confounding factors, BMD, or bone strength indices. The G-308A polymorphism was not associated with a reduced risk of other fractures. These results suggest a potential role of genetic variation in TNFalpha in the etiology of osteoporosis.

Absorptiometry, Photon↗
PubMed2001

In silico mapping of complex disease-related traits in mice.

Experimental murine genetic models of complex human disease show great potential for understanding human disease pathogenesis. To reduce the time required for analysis of such models from many months down to milliseconds, a computational method for predicting chromosomal regions regulating phenotypic traits and a murine database of single nucleotide polymorphisms were developed. After entry of phenotypic information obtained from inbred mouse strains, the phenotypic and genotypic information is analyzed in silico to predict the chromosomal regions regulating the phenotypic trait.

Algorithms↗
PubMed2001

Evidence for an interferon-inducible gene, Ifi202, in the susceptibility to systemic lupus.

The Nba2 locus is a major genetic contribution to disease susceptibility in the (NZB x NZW)F(1) mouse model of systemic lupus. We generated C57BL/6 mice congenic for this NZB locus, and these mice produced antinuclear autoantibodies characteristic of lupus. F(1) offspring of congenic and NZW mice developed high autoantibody levels and severe lupus nephritis similar to (NZB x NZW)F(1) mice. Expression profiling with oligonucleotide microarrays revealed only two differentially expressed genes, interferon-inducible genes Ifi202 and Ifi203, in congenic versus control mice, and both were within the Nba2 interval. Quantitative PCR localized increased Ifi202 expression to splenic B cells and non-T/non-B cells. These results, together with analyses of promoter region polymorphisms, strain distribution of expression, and effects on cell proliferation and apoptosis, implicate Ifi202 as a candidate gene for lupus.

Animals↗
PubMed2000

Identification of complement factor 5 as a susceptibility locus for experimental allergic asthma.

The prevalence and severity of allergic asthma continue to rise, lending urgency to the search for environmental triggers and genetic substrates. Using microarray analysis of pulmonary gene expression and single nucleotide polymorphism-based genotyping, combined with quantitative trait locus analysis, we identified the gene encoding complement factor 5 (C5) as a susceptibility locus for allergen-induced airway hyperresponsiveness in a murine model of asthma. A deletion in the coding sequence of C5 leads to C5-deficiency and susceptibility. Interleukin 12 (IL-12) is able to prevent or reverse experimental allergic asthma. Blockade of the C5a receptor rendered human monocytes unable to produce IL-12, mimicking blunted IL-12 production by macrophages from C5-deficient mice and providing a mechanism for the regulation of susceptibility to asthma by C5. The role of complement in modulating susceptibility to asthma highlights the importance of immunoregulatory events at the interface of innate and adaptive immunity in disease pathogenesis.

Animals↗
PubMed2000

Quantitative trait loci controlling allergen-induced airway hyperresponsiveness in inbred mice.

Identification of the genetic loci underlying asthma in humans has been hampered by variability in clinical phenotype, uncontrolled environmental influences, and genetic heterogeneity. To circumvent these complications, the genetic regulation of asthma-associated phenotypes was studied in a murine model. We characterized the strain distribution patterns for the asthma-related phenotypes airway hyperresponsiveness (AHR), lung eosinophils, and ovalbumin (OVA)-specific serum immunoglobulin (Ig) E induced by allergen exposure protocols in A/J, AKR/J, BALB/cJ, C3H/HeJ, and C57BL/6J inbred strains and in (C3H/HeJ x A/J)F1 mice. Expression of AHR differed between strains and was sometimes discordant with lung eosinophils or serum IgE. Furthermore, we identified two distinct quantitative trait loci (QTL) for susceptibility to allergen-induced AHR, Abhr1 (allergen-induced bronchial hyperresponsiveness) (lod = 4. 2) and Abhr2 (lod = 3.7), on chromosome 2 in backcross progeny from A/J and C3H/HeJ mice. In addition, a QTL on chromosome 7 was suggestive of linkage to this trait. These QTL differ from those we have previously found to control noninflammatory AHR in the same crosses. Elucidation of the genes underlying these QTL will facilitate the identification of biochemical pathways regulating AHR in animal models of asthma and may provide insights into the pathogenesis of human disease.

Allergens↗
PubMed1999

Tpm1, a locus controlling IL-12 responsiveness, acts by a cell-autonomous mechanism.

Th phenotype development is controlled not only by cytokines but also by other parameters including genetic background. One site of genetic variation between murine strains that has direct impact on Th development is the expression of the IL-12 receptor. T cells from B10.D2 and BALB/c mice show distinct control of IL-12 receptor expression. When activated by Ag, B10.D2 T cells express functional IL-12 receptors and maintain IL-12 responsiveness. In contrast, under the same conditions, BALB/c T cells fail to express IL-12 receptors and become unresponsive to IL-12, precluding any Th1-inducing effects if subsequently exposed to IL-12. Previously, we identified a locus, which we termed T cell phenotype modifier 1 (Tpm1), on murine chromosome 11 that controls this differential maintenance of IL-12 responsiveness. In this study, we have produced a higher resolution map around Tpm1. We produced and analyzed a series of recombinants from a first-generation backcross that significantly narrows the genetic boundaries of Tpm1. This allowed us to exclude from consideration certain previous candidates for Tpm1, including IFN-regulatory factor-1. Also, cellular analysis of F1(B10.D2 x BALB/c) T cells demonstrates that Tpm1 exerts its effect on IL-12 receptor expression in a cell-autonomous manner, rather than through influencing the extracellular milieu. This result strongly implies that despite the proximity of our locus to the IL-13/IL-4 gene cluster, these cytokines are not candidates for Tpm1.

Alleles↗
PubMed1998

GATA-3-dependent enhancer activity in IL-4 gene regulation.

Previously, we analyzed the proximal IL-4 promoter in directing Th2-specific activity. An 800-base pair proximal promoter conferred some Th2-selective expression in transgenic mice. However, this region directed extremely low reporter mRNA levels relative to endogenous IL-4 mRNA, suggesting that full gene activity requires additional enhancer elements. Here, we analyzed large genomic IL-4 regions for enhancer activity and interaction with transcription factors. The proximal IL-4 promoter is only moderately augmented by GATA-3, but certain genomic regions significantly enhanced GATA-3 promoter transactivation. Some enhancing regions contained consensus, GATA sites that bound Th2-specific complexes. However, retroviral transduction of GATA-3 into developing T cells induced IL-5 to full Th2 levels, but only partially restored IL-4 production. Thus, we propose that GATA-3 is permissive, but not sufficient, for full IL-4 enhancement and may act through GATA elements surrounding the IL-13/IL-4 gene locus.

Animals↗
PubMed1997

Induction of alloantigen-specific T cell tolerance through the treatment of human T lymphocytes with wortmannin.

Signaling through the CD28 molecule on T cells by its natural ligand, B7, on APCs has recently been shown to require the presence of an active phosphatidylinositol 3-kinase pathway to mediate some of its costimulatory activities (1-7). Using the phosphatidylinositol 3-kinase inhibitor, wortmannin (WN) (8), on human and murine T cells, we have inhibited B7-1-mediated T cell activation and induced Ag-specific tolerance. The addition of WN and/or the B7-1 antagonist, CTLA4Ig, to primary human T cell cultures stimulated with B7-1-transfected allogeneic melanoma cell lines inhibited the generation of alloantigen-specific proliferative and cytolytic responses in vitro. Subsequent examination of these WN- and CTLA4Ig-treated primary T cell cultures revealed that these lymphocyte populations were tolerized to rechallenge with the priming alloantigens in secondary cultures in the absence of additional inhibitor(s). However, reactivity to a third party allogeneic stimulator remained intact. This WN-induced tolerance was reversed by the addition of high dose IL-2, but not IL-4 or IL-7, to the primary cultures, indicating that T cell anergy, not deletion, was responsible for this phenomenon. In vivo studies using a murine graft-vs-host disease (GVHD) model demonstrated that WN treatment of allogeneic donor lymphocytes in vitro failed to generate a significant GVHD in irradiated mouse recipients compared with control allogeneic donor lymphocytes. These findings suggest potentially novel therapeutic strategies for the prevention of GVHD.

Abatacept↗
PubMed1997

Transcription factors in immune-mediated disease.

A large amount of detailed information about the intracellular proteins regulating NF-kappa B activation and the cellular response to NF-kappa B activation has emerged recently. Several small molecules, an antisense oligonucleotide, and gene therapeutic agents that inhibit NF-kappa b activation have been described. Despite this, there are still significant gaps in our understanding of this process and its consequences. In contrast, the characterization of transcription factors selectively regulating cytokine production by CD4+ T cell subsets is at a very early stage. Three interacting proteins have recently been shown to contribute to subset-restricted expression of the IL-4 gene. There are other elements regulating IL-4 gene expression, however, and the relative importance of these recently identified proteins has yet to be determined.

Animals↗
PubMed1996

CD45 isoforms on human CD4+ T-cell subsets.

We have examined the level of surface expression and functional properties of leukocyte function associated antigen-1, very late antigen-4, and CD45 isoforms on a panel of human CD4+ T-cell clones representative of TH0, TH1, and TH2 cells. There were no qualitative differences in the expression of these antigens among the three types of CD4+ T-cell clones. However, CD45RB was the only CD45 isoform that provided a costimulatory signal in a solid-phase antibody-induced cellular proliferation assay. Additionally, the antigen-induced proliferative response of T-cell clones was inhibited by soluble anti-CD45RO and anti-CD45RB antibodies. Our results suggest that CD45 isoforms differentially provide costimulatory signals to T cells. However, the ability of each CD45 isoform to provide a costimulatory signal does not differ among the TH0, TH1, or TH2 T-cell populations.

CD4-Positive T-Lymphocytes↗
PubMed1995

Modulation of the Grb2-associated protein complex in human CD4+ T cells by receptor activation.

A panel of human CD4+ T cell clones was utilized to dissect and analyze the biochemical consequences of activation of CD3 or CD28. To molecularly characterize receptor-activated proximal signaling events, tyrosine-phosphorylated proteins co-precipitating with a Grb2 fusion protein after receptor activation were analyzed. Ligation of CD28, but not other costimulatory molecules, induced the tyrosine phosphorylation of two previously identified Grb2 binding proteins (pp76 and pp116). A third Grb2 binding protein (pp36) was extensively tyrosine phosphophorylated in response to combined CD3 and CD28 activation, but not in response to ligation of either receptor alone. cAMP and co-ligation of CD45 affected the receptor-activated tyrosine phosphorylation of Grb2-associated proteins. Furthermore, we demonstrated that two signaling molecules, Vav and phosphatidylinositol 3'-kinase (PI(3)K), also interacted with the Grb2 protein complex. The activity of PI(3)K was required for T cell activation, because wortmannin, a PI(3)K inhibitor, blocked T cell proliferation and cytokine production induced by ligation of CD3 and CD28. In conclusion, we demonstrate that in activated human T cell clones, the composition of Grb2 protein complex is modulated by costimulatory signals and cAMP, which may be important for the regulation of intracellular signal transduction.

Adaptor Proteins, Signal Transducing↗
PubMed1995

Costimulatory signals can selectively modulate cytokine production by subsets of CD4+ T cells.

Analysis of experimental animal models and human clinical samples has indicated that the selective activation of CD4+ T cell subsets with distinct profiles of cytokine production plays an important role in the pathogenesis of human inflammatory and allergic diseases. The possibility that differential activation of costimulatory pathways is a mechanism for selectively modulating cytokine production by CD4+ T cells was tested. The proliferative response and cytokines secreted by a panel of human CD4+ T cell clones, representative of Th1 or Th2/0 cells, in response to activation of different costimulatory pathways was measured. CD28-mediated costimulatory signals induced proliferation and IFN-gamma secretion by Th1 cells. Although CD28-ligation induced Th2/0 cells to proliferate, it did not trigger IL-4 production. Ligation of LFA-1 and CD45 isoforms also generated costimulatory signals activating cytokine secretion by the different types of T cell clones. Th1 cells secreted the same profile of cytokines, irrespective of which costimulatory pathway was engaged. However, the cytokine secreted by a subset of Th2/0 cells varied, depending upon which costimulatory pathways were activated. These results suggest that the costimulatory pathways activated by APCs can selectively influence cytokine production by CD4+ T cell subsets.

Animals↗
PubMed1995

CD28:B7 interactions promote T cell adhesion.

CD28 activation by antibody-mediated ligation has been shown to provide an important co-stimulatory signal for T cell adhesion to purified protein ligands. However, the effect of CD28 ligation by one of its natural ligands, B7.1, on T cell adhesion to other cells has not been studied. Therefore, in the present manuscript, we characterized the adhesive interactions between human T cells and B7.1-transfected major histocompatibility complex class II+ and class II- melanoma cells. In our studies, human T cells and T cell clones adhered to B7.1-transfected melanoma cells, but not to untransfected parental cells. The adhesive reaction in this model was rapid, occurring within 15 min, and was inhibited by anti-B7.1 antibody and soluble CTLA-4 immunoglobulin. Antibody inhibition studies demonstrated that adhesion between T cells and B7.1-transfected melanoma cells was mediated by interactions between LFA-1:ICAM-1 and CD2:LFA-3. Inhibition by pharmacological agents demonstrated that the CD28-induced adhesion required specific intracellular signaling events. A protein kinase C inhibitor, staurosporin, significantly inhibited T cell binding to transfected melanoma cells, while cyclosporin A and wortmannin, an inhibitor of phosphatidylinositol-3-kinase, did not. These results suggest that the presence of B7 on various cell populations may activate lymphocytes to adhere better, thus promoting activation, cytolysis, and migration.

Abatacept↗
PubMed1995

Pathogen antigen- and superantigen-reactive synovial fluid T cells in reactive arthritis.

Analysis of pathogen-reactive T cell clones (CD3+4+8-TCR alpha beta +), isolated from the synovial fluid of 2 HLA-B27-positive patients with Yersinia enterocolitica-triggered reactive arthritis, has provided important information about the cellular immune response to this disease-inciting pathogen. This study demonstrates that the proteins secreted by Y. enterocolitica, including a protein with tyrosine phosphatase activity (YopH), are potent immunogens stimulating CD4+ cells within the inflamed joint. The pathogen-reactive T cell clones preferentially utilized a limited set of T cell receptor variable region gene segments. A purified Yersinia superantigen triggered a proliferative response in most of the antigen-reactive T cell clones tested. These results suggest that the activity of this pathogen's superantigen influences the cellular immune response to its antigens.

Adult↗
PubMed1994

Genes within the HLA class II region confer both predisposition and resistance to primary biliary cirrhosis.

Nonradioactive sequence-specific oligonucleotide probes for the polymorphic HLA class II genes have been used to type samples from 51 Caucasian patients with the autoimmune liver disease, primary biliary cirrhosis, and 240 Caucasian controls. Although the allelic distribution at the DPB1 locus showed no significant variation between patients and controls, there was heterogeneity in the distribution of DR-DQ haplotypes where the frequency of the DRB1*0801-DQA1*0401/0601-DQB1*04 haplotype was significantly increased in the patients, suggesting it confers susceptibility to this disease. Two other haplotypes, DRB1*1501-DQA1*0102-DQB1*0602 and DRB1*1302-DQA1*0102-DQB1*0604, were significantly reduced in the patients, suggesting they confer protection. Tests of the individual loci show that resistance to this disease is most strongly associated with the DQA1*0102 allele shared by both protective haplotypes. Due to linkage disequilibrium it is unclear whether multiple genes or a single locus on the susceptible DR8 haplotype are needed for predisposition. These data show that distinct HLA class II alleles confer both predisposition and resistance to PBC and provide insight into the role that these genes may play in the immunopathogenesis of this disease.

Causality↗
PubMed1993

Preferential usage of T cell antigen receptor V region gene segment V beta 5.1 by Borrelia burgdorferi antigen-reactive T cell clones isolated from a patient with Lyme disease.

Forty-three CD3+4+8- TCR alpha beta+ Borrelia burgdorferi-reactive T cell clones isolated from the peripheral blood of a single patient with clinically active chronic Lyme arthritis were characterized. The spirochetal Ag recognized by 16 of these T cell clones was determined by reactivity with a panel of recombinant spirochetal Ag, which included the OspA, OspB, flagellin, Hsp60 and Hsp70 proteins. All three T cell clones reactive with heat shock proteins recognized a non-cross-reactive epitope unique to the spirochetal Ag. Analysis of the TCR V regions revealed preferential usage of V beta 5.1; 5 of 15 T cell clones that recognized an unidentified spirochetal Ag utilized this V beta gene segment. Most of the T cell clones recognized a given spirochetal Ag exclusively within the context of one HLA class II allele. However, two T cell clones, which recognized an unidentified Ag in the spirochetal lysate within the context of different HLA class II alleles, were both TCR V beta 5.1+, although each displayed a distinct alpha-chain. Moreover, in vitro incubation of this patient's PBMC with B. burgdorferi Ag resulted in a specific increase in the percentage of T cells expressing TCR V beta 5.1. These results indicate that B. burgdorferi has a V beta-selective factor influencing the cellular immune response in a patient with clinically active Lyme disease.

Adolescent↗