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R J Moots

Publications and source records attributed to R J Moots.

At least 37 records · Page 2Linked to original sources
PubMed1999

Old drug, new tricks: haloperidol inhibits secretion of proinflammatory cytokines.

OBJECTIVES: It was noted that treatment of a patient with acute mania by haloperidol was associated with marked improvement in activity of rheumatoid arthritis. The objective of this study was to examine the effects of haloperidol on inflammatory cytokine release in vitro, as a potential mechanism to explain the in vivo anti-inflammatory effects of haloperidol. METHODS: The effect of haloperidol on the production of inflammatory cytokines interleukin 1beta (IL1beta) and tumour necrosis factor alpha (TNFalpha) was measured in bacterial lipopolysaccharide stimulated whole blood cultures and on the promonocyte cell line THP-1, using commercial and in house enzyme linked immunosorbent assays to measure cytokine concentrations. RESULTS: Haloperidol inhibited lipopolysaccharide stimulated production of both IL1beta and TNFalpha in vitro in a dose dependent manner and over a prolonged time period. Marked inhibition was seen over a range of concentrations of haloperidol from 0.5 microgram/ml to 50 microgram/ml, including those predicted to occur in the patient's blood. CONCLUSIONS: Haloperidol treatment seemed to alleviate inflammation in rheumatoid arthritis. In vitro experiments would suggest that the mechanism is by direct inhibition of proinflammatory cytokine release. This phenomenon requires further investigation and may potentially lead to the development of novel treatment.

Adult↗
PubMed1998

A fistful of T cells.

Evidence incriminating T cells in rheumatoid arthritis (RA) is strong but circumstantial--like a smoking gun at the scene of a crime. To investigate this, T lymphocytes were studied in health and disease. The effect of mutations in the groove of HLA-A2 on peptide presentation to T cells was studied to investigate normal T cell function. This allowed a detailed description of the interactions between individual MHC residues and antigens. Subsequently, T cells in the autoimmune disease, multiple sclerosis, were studied, to investigate the mechanisms for breakdown in peripheral tolerance. T-cell clones that recognized both autoantigens and viral proteins were isolated, suggesting that infection may trigger disease. Autoantigens would need to be defined to use this strategy in RA. T-cell responses to type II collagen, a candidate auto-antigen, were therefore studied in RA and an epitope successfully defined. The search for microbial 'mimics' triggering RA, and novel forms of immunotherapy are now possible--with potential rehabilitation of T cells.

Antigen Presentation↗
PubMed1995

Genetic evidence for difference between intracellular and extracellular peptides in influenza A matrix peptide-specific CTL recognition.

During the course of extensive mutagenesis of HLA-A2.1, we examined influenza A matrix peptide (FMP)-specific CTL recognition of HMy2.C1R (C1R) cells expressing mutant HLA-A2.1 molecules, sensitized with synthetic peptide, FMP 58-66, (exogenous peptide), or infected with influenza A virus (endogenous peptide). Most mutants showed equivalent presentation of exogenous and endogenous peptides to FMP-specific CTL. However, five of the mutants differed in this property. Two of the five mutants, F9L and T134K, present exogenous peptide to FMP-specific CTL, but fail to present endogenous peptide to CTL. Western blot analysis using anti-matrix protein Ab indicates that the matrix protein is expressed in these mutants after infection with virus. Interestingly, transfection of these two mutants with a minigene encoding FMP 58-66 results in efficient lysis by FMP-specific CTL. Peptide-binding assays demonstrate that the two mutations dramatically decrease the binding of FMP. However, these mutants bind FMP as well as wild type in the presence of exogenously added human beta 2-m, suggesting that the lower affinity for beta 2-m leads to the inability to present endogenous peptide. The remaining three mutants, Y27N, Q32K, and S132C, fail to present exogenous peptide, but present endogenous peptide to FMP-specific CTL. Pulse-chase analyses followed by endoglycosidase-H treatment show that the rate of maturation and processing of the five mutant HLA-A2 molecules in C1R cells is identical to that of wild type. Overall, this study suggests that the assembly and subsequent recognition of endogenous peptide differs from that of exogenous peptide.

Amino Acid Sequence↗
PubMed1994

Significance of the six peptide-binding pockets of HLA-A2.1 in influenza A matrix peptide-specific cytotoxic T-lymphocyte reactivity.

To evaluate the roles of the six peptide-binding pockets of HLA-A2.1 in FMP-specific CTL recognition, we have constructed an extensive library of HMy2.C1R cell lines expressing mutant HLA-A2.1 molecules with different amino acid substitutions in each of the six pockets. These cell lines were tested for their ability to present synthetic FMP 58-66 to FMP-specific, HLA-A2.1-restricted human CTL lines. Six of 12 mutants with amino acid changes in pocket B significantly affect the FMP-specific CTL recognition, suggesting that pocket B plays a critical role in FMP-specific CTL recognition. Surprisingly, mutations in all other pockets, except for pocket F, also have significant effects on the CTL recognition. These results suggest that even the shallow pockets, which are likely to be less critical for peptide binding than the deep pockets, play a crucial role in FMP-specific CTL recognition.

Antigen Presentation↗
PubMed1994

Corticosteroids: do they damage the cardiovascular system?

Since their introduction for the treatment of rheumatoid arthritis, corticosteroids have become widely used as effective agents in the control of inflammatory diseases. Although there have been undoubted benefits upon mortality in diseases such as systemic lupus erythematosus, many patients survive only to suffer a high incidence of premature atherosclerosis. There is also evidence of increased rates of vascular mortality in other corticosteroid-treated diseases, such as rheumatoid arthritis, reversible airways obstruction and transplant recipients. Possible mechanisms of damage include elevated blood pressure, impaired glucose tolerance, dyslipidaemia, and imbalances in thrombosis and fibrinolysis. This paper reviews the clinical evidence supporting the contention that there is an excess cardiovascular mortality in steroid-treated patients and the underlying mechanisms, and points to further areas of research.

Adrenal Cortex Hormones↗
PubMed1994

Birmingham Vasculitis Activity Score (BVAS) in systemic necrotizing vasculitis.

The continuing morbidity of patients with vasculitis, despite the improved prognosis with aggressive therapy, underlines the need for accurate disease assessment. We have devised a clinical index of disease activity, and evaluated its use in several forms of necrotizing vasculitis. The weighted score is based on symptoms and signs in nine separate organ systems. Disease features are only scored if they are attributable to active vasculitis. The Birmingham Vasculitis Activity Score (BVAS) was compared with two other published vasculitis activity scores, with the physician's global assessment (PGA), with outcome, and with serological markers of disease activity. In a cross-sectional study of 213 consecutive patients with different forms of vasculitis, all 107 vasculitis patients who were judged completely well on clinical assessment had a BVAS score of 0. Twenty-two patients with active vasculitis prior to treatment had a median score of 7.5 (range 4-30) and 69 with active disease on treatment had a median score of 10 (1-29). Of the 12 who died, median score immediately prior to death was 20.5 (9-30). In a serial prospective study, 30 cases had documented episodes of active disease. During periods of disease activity, the median BVAS values were significantly higher than in remission (15 [range 3-32] vs. 0 [0-2], p < 0.001); the same was true for CRP values (80 [9-361] vs. 13.5 [5-68], p < 0.001). This was not true for erythrocyte sedimentation rate (ESR), haemoglobin (Hb) or von Willebrand factor (VWF).(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗
PubMed1993

In the groove: the fine detail of antigen presentation to cytotoxic T lymphocytes.

1. A panel of cells designed to express normal or mutated human HLA-A0201 was constructed and used to investigate the interactions between the peptide antigen, class I major histocompatibility complex, CD8 and cytotoxic T lymphocyte antigen receptor. 2. Analysis of the extensive data generated has revealed that the optimum peptide presented to cytotoxic T lymphocytes by HLA-A0201 contains nine amino acids. It lies in the peptide-binding groove of the class I molecule, orientated from N- to C-termini, and its detailed position within the groove has been deduced. The roles of individual residues in the class I molecule in antigen presentation are described, and the site of the ligand on target cells for interaction with CD8 on cytotoxic T lymphocytes is located.

Amino Acid Sequence↗
PubMed1992

A cross-species functional interaction between the murine major histocompatibility complex class I alpha 3 domain and human CD8 revealed by peptide-specific cytotoxic T lymphocytes.

The monomorphic cell surface glycoprotein CD8 acts as co-receptor in the recognition of peptide-major histocompatibility complex (MHC) class I complexes by cytotoxic lymphocytes (CTL) by binding to the monomorphic alpha 3 domain of the class I molecule. Positions 227 and 245 in the class I alpha 3 domain appear to be especially important for this interaction. Recent reports suggest there is no interspecies recognition between CD8 and MHC class I. In this study, hybrid genes from human class I HLA-A0201 and murine class I H-2Kb were transfected into human and mouse cells and tested in Cr-release assays using HLA-A0201-restricted influenza A matrix peptide-specific CTL as effectors. Transfected cells expressing chimeric genes comprising the alpha 1 and alpha 2 domains from HLA-A0201 together with the H-2Kb alpha 3 domain were lysed as effectively as wild-type HLA-A0201 and in both cases, killing was blocked by anti-CD8 antibody equally well. These results indicate that human CD8 can interact with the alpha 3 domain of murine class I to the same level as human class I.

Animals↗
PubMed1991

Extensive conservation of alpha and beta chains of the human T-cell antigen receptor recognizing HLA-A2 and influenza A matrix peptide.

The major histocompatibility complex class I molecule HLA-A2.1 presents the influenza A virus matrix peptide 57-68 to cytotoxic T lymphocytes in all individuals with this common HLA type and is among the most thoroughly studied immune responses in humans. We have studied the T-cell receptor (TCR) heterogeneity of T cells specific for HLA-A2 and influenza A matrix peptide using the polymerase chain reaction. The usage of V alpha and V beta sequences seen on these T cells is remarkably conserved as are certain junctional sequences associated with alpha and beta chains. Furthermore, two unrelated HLA-A2 individuals have a similar pattern of TCR usage, implying that this is a predominant response in HLA-A2 populations. Analysis in one individual showed that the conserved TCR V alpha and V beta genes are minor members of the peripheral blood TCR repertoire. The sequences provide important information on the TCR necessary for the final structural analysis of this ternary complex.

Amino Acid Sequence↗