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T W Redford

Publications and source records attributed to T W Redford.

7 recordsLinked to original sources
PubMed2001

Lipopolysaccharide and CpG DNA synergize for tumor necrosis factor-alpha production through activation of NF-kappaB.

Unmethylated CpG motifs in bacterial DNA (CpG DNA) activate host innate immune responses synergistically with some other microbial products, such as endotoxins, and may contribute to disease pathogenesis through excessive production of proinflammatory cytokines. Because monocyte-derived tumor necrosis factor (TNF)-alpha is an important mediator of disease, we investigated whether CpG DNA and lipopolysaccharide (LPS) synergize for inducing TNF-alpha biosynthesis. CpG DNA and LPS synergistically induce TNF-alpha production in RAW264.7 cells and J774 cells through activation of NF-kappaB. Furthermore, transient transfection with a super-repressive mutant of IkappaBalpha (IkappaBalpha-AA) demonstrated that NF-kappaB plays a critical role in CpG DNA-mediated TNF-alpha expression. Like NF-kappaB activation, CpG DNA-induced activation of mitogen-activated protein kinases (MAPK) regulates TNF-alpha production. Both extracellular receptor kinase (ERK) and p38 can regulate TNF-alpha gene transcription induced by CpG DNA. Although CpG DNA at the higher concentration slightly enhanced LPS-mediated phosphorylation of ERK, it did not alter the LPS-mediated activation of c-Jun N-terminal kinase and p38. In addition, CpG DNA showed little or no enhancement of LPS-mediated AP-1 activation. These results suggest that CpG DNA- and LPS-mediated signals converge at or above the level of NF-kappaB and ERK, and that there are distinct, as well as common, signaling pathways which are utilized by both CpG DNA and LPS for activating various transcription factors and MAPK.

Animals↗
PubMed1999

HLA-DRB1 genotype influences risk for and severity of rheumatoid arthritis.

OBJECTIVE: To examine how HLA-DRB1 genotypes influence rheumatoid arthritis (RA) risk and clinical severity. METHODS: We performed polymerase chain reaction based DRB1 and tumor necrosis factor (TNF) genotyping of 309 Caucasian RA and 283 Caucasian control subjects. For risk analyses, we grouped the DRB1 alleles encoding each specific shared epitope: *0401 alone, *0404 with *0102, *0405 with *0408 and *0101, and *1001 alone. For estimates of RA outcome, we retrospectively obtained data regarding ARA classification criteria, age of disease onset and disease duration, number of slow acting antirheumatic drugs (SAARD) used, and rheumatoid factor (RF). RESULTS: Homozygous shared-epitope DRB1 genotypes, compound heterozygous genotypes, and simple heterozygous genotypes all conferred elevated relative risk (RR) for RA (RR 4.3, 11.7, and 3.5, respectively). However, compound heterozygous genotypes conferred more risk than either simple heterozygous genotype (RR 3.3, p = 0.004) or homozygous genotype (RR 2.8, p = 0.036). There was a trend toward more compound heterozygous genotypes in the male RA group than in the female RA group (p < 0.1), and male sex was associated with higher frequency of rheumatoid nodules (56 vs 35% for female RA). RA outcome was estimated by number of SAARD used; mean SAARD used was higher in male than in female RA (p < 0.01) and higher in genotypes containing one or 2 shared epitope DRB1 alleles than in those negative for shared epitope DRB1 alleles (p < 0.05). Analyses also suggested that shared epitope DRB1 genotype significantly influenced the occurrence of seropositive RA. Seropositive RA fraction was related to either number of shared epitope alleles (0, 1, or 2) represented in the DRB1 genotype, or, alternatively, to the combination of sex with shared epitope DRB1 genotype. The presence of one or 2 shared epitope DRB alleles influenced the occurrence of high titer seropositive RA as defined by sheep cell agglutination test (p < 0.01). TNFab microsatellite markers and TNF promoter polymorphisms did not influence SAARD number, seropositive RA, or high titer seropositive RA. CONCLUSION: Not all shared epitope DRB1 genotypes conferred the same relative risk, and the male RA group tended to have more compound heterozygous genotypes and more severe RA as indicated by rheumatoid nodules and SAARD usage. DRB1 genotypes with one or 2 shared epitope DRB1 alleles influenced the RA outcome as estimated by numbers of SAARD used and RF.

Alleles↗
PubMed1999

Tumor necrosis factor microsatellite markers TNFa5b5 and TNFa6b5 influence adverse reactions to parenteral gold in Caucasians.

OBJECTIVE: To investigate which HLA haplotypes identified by DRB1 or tumor necrosis factor (TNF) microsatellite markers are associated with adverse reactions to parenteral gold injections. METHODS: We retrospectively studied 193 Caucasian subjects with rheumatoid arthritis (RA) who had received parenteral gold injections from a university faculty outpatient practice (n = 163) and outpatient clinics at a Department of Veterans Affairs Medical Center (n = 30). DRB1 typing was done by several DNA based techniques. TNF microsatellite genotypes were derived by polymerase chain reaction amplification, sequencing-type gel electrophoresis, and silver staining. RESULTS: Seventy-six subjects had experienced adverse reactions to gold injections (other than nitritoid reactions), 18 of whom had 2 concurrent toxicities. The numbers with adverse reactions included: mucocutaneous (57), proteinuria (25), hematuria without proteinuria (5), thrombocytopenia (3), and miscellaneous (11). By frequency comparisons, no DR was associated with adverse reactions to parenteral gold (chi-squared 4.7, 6 df, NS). Specifically, there was no increased risk of proteinuria or mucocutaneous side effects in the DR3 positive RA group, almost all of whom had the DRB1 allele *0301. By logistic regression modeling controlling for sex and onset age, DR12 and the TNF microsatellite markers a5b5 and a6b5 were associated with mucocutaneous reactions (p < 0.05 for each). The odds ratios favoring mucocutaneous adverse reactions were 3.72 with TNFa5b5 and 2.03 with TNFa6b5. TNFa5b5 was commonly found on the HLA haplotypes bearing DRB1*0101, and TNFa6b5 was on the ones bearing DRB1 alleles of the DR1, DR2, DR3, DR5, or DR6 groups or the DRB1*0401 allele. CONCLUSION: HLA haplotypes conferring risk of gold induced mucocutaneous reactions were better identified by certain HLA class III markers, namely TNFa5b5 and TNFa6b5, than by any previously associated DR groups.

Antirheumatic Agents↗
PubMed1998

Cyclosporin A enhances IL-12 production by CpG motifs in bacterial DNA and synthetic oligodeoxynucleotides.

Certain sequences of nucleotides (CpG motifs) in bacterial DNA or synthetic oligonucleotides (CpG DNA) promote the production of proinflammatory cytokines, including TNF-alpha, IFN-gamma, IL-6, and IL-12. Here we demonstrate that the immunosuppressant cyclosporin A (CsA) unexpectedly enhanced CpG DNA-induced IL-12 production in murine splenocytes. CsA did not inhibit CpG DNA-induced TNF-alpha or IL-6 production, but decreased the production of IFN-gamma by CpG DNA. Upon examining mechanisms by which CsA increases IL-12 production, we found that CpG DNA can also induce IL-10 production in B cells and that this production was sensitive to CsA. IL-10 has anti-inflammatory effects and can reduce the production of IL-12. To determine the possible role of CsA-modulated IL-10 production in mediating the increased IL-12 levels, splenocytes from IL-10 gene-disrupted mice (IL-10 -/-) and splenocytes cultured in anti-IL-10 Ab were studied. CpG DNA-stimulated IL-10 (-/-) splenocytes demonstrated no increase in IL-12 levels in the presence of CsA. Anti-IL-10 Ab treatment of normal splenocytes increased the magnitude of CpG DNA-induced IL-12 production to that seen with CsA. These results suggest that CpG DNA induces CsA-sensitive IL-10 production in B cells and that IL-10 acts as a negative feedback regulator of CpG DNA-induced IL-12 production.

Animals↗
PubMed1995

Update on pharmacotherapy of systemic lupus erythematosus.

Established and novel approaches to the pharmacologic management of systemic lupus erythematosus (SLE) are described. SLE is a chronic, multiple-organ-system inflammatory disorder associated with immune system dysfunction. Autoantibodies are produced that react with self-antigens, notably cell membranes and nuclear and cytoplasmic constituents. There are many clinical manifestations, including arthritis, arthralgia, myalgia, skin changes, photosensitivity reactions, fever, anemia, thrombocytopenia, proteinuria, and renal, CNS, and cardiopulmonary involvement. The disease characteristically fluctuates between remission and relapse. Survival has been improving because of new drug treatments and better diagnostic and serologic tests. Minor manifestations can be treated with less toxic agents, such as nonsteroidal anti-inflammatory drugs, sunscreens, topical and intralesional corticosteroids, and antimalarials. Aggressive therapy with high-dose corticosteroids or immunosuppressants is necessary in patients with worsening renal function (lupus nephritis). CNS lupus has responded to various degrees to dexamethasone, methylprednisolone, and cyclophosphamide. Other therapeutic options include methotrexate in corticosteroid-resistant SLE and cyclosporine. The use of monoclonal antibodies is under intensive study. As mortality due to SLE decreases, complications like cardiovascular problems are becoming more prominent; patients may require antihypertensives, cholesterol-lowering drugs, and hypoglycemic agents. The complexity and chronicity of SLE have led to diverse pharmacotherapeutic strategies based on the organ systems involved. Immunologic research may ultimately bring patients greater relief.

Female↗