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Biomedical subjects

J M Stuart

Publications and source records attributed to J M Stuart.

At least 73 records · Page 4Linked to original sources
PubMed1995

Vaccination with a recombinant V alpha domain of a TCR prevents the development of collagen-induced arthritis.

A recombinant TCR domain, derived from a T cell hybridoma that recognizes an immunodominant type II collagen epitope, was used to vaccinate against collagen-induced arthritis in DBA/1 (H-2q) mice. The recombinant TCR domain comprises VA11.1-JA17 gene segments and is representative of the V alpha domains expressed by oligoclonal T cells in this disease model. Vaccination of mice 28 days before type II collagen (CII) immunization with this V alpha 11.1 domain resulted in a significantly decreased incidence of arthritis in DBA/1 mice, in contrast to vaccination with a V alpha 4-J alpha 40 domain derived from an encephalitogenic T cell hybridoma specific for MBP. Disease blockade is accompanied by a reduction in T and B cell responses to both the immunogen bovine CII and the autoantigen murine CII. V alpha 4 and V alpha 11.1 domains were found to be highly immunogenic in DBA/1 mice, inducing both T cell proliferation and the production of V alpha specific Abs, indicating that the vaccination effect of V alpha 11.1 is specific. This is the first report of V alpha-directed immunotherapy in an autoimmune disease model and demonstrates the potential use of recombinant TCR vaccines in the treatment of autoimmune diseases that involve oligoclonal autoreactive T cells.

Amino Acid Sequence↗
PubMed1995

Identification and characterization of a tolerogenic T cell determinant within residues 181-209 of chick type II collagen.

The murine model of collagen-induced arthritis is characterized by the development of an immune response against joint cartilage. Arthritis can be significantly suppressed by the administration of type II collagen (CII) or one of the CNBr peptides, CB11 (CII 124-402) as a tolerogen prior to immunization. We have previously shown that two synthetic peptides, representing sequences CII 260-270 and CII 181-209, are effective tolerogens. In this paper, we now characterize the T cell determinant with CII 181-209. A series of synthetic peptides overlapping CII 181-209 and analogs of chick CII 181-209 containing site-directed amino acid substitutions was developed and cultured with T cells from DBA/1 mice immunized with CII. Supernatants were collected and analyzed for the presence of the T cell lymphokine IFN-gamma. These data indicate the critical T cell determinant to be located within CII 190-200. This conclusion is further supported by the observation that an unodecapeptide representing CII 190-200 was just as effective as CII 181-209 in suppressing arthritis and anti-CII antibody response when tested as a tolerogen. Analogs containing single amino acid substitutions at residues 191, 194, 197, 198, or 200 were significantly less effective in inducing T cell responses. Each of these peptide analogs was then given as neonatal tolerogens to DBA/1 mice. Mice were subsequently immunized and observed for the development of arthritis. These studies identified residues 194, 197, 198, and 200, and probably residue 191, as critical for tolerance and the suppression of arthritis. Elucidation of the fine structures of T cell determinants which are critical for suppression of arthritis should allow these techniques to be used for developing specific immunotherapeutic approaches to autoimmune arthritis.

Amino Acid Sequence↗
PubMed1995

Collagen-induced arthritis in B10.RIII mice (H-2r): identification of an arthritogenic T-cell determinant.

Susceptibility to collagen-induced arthritis (CIA), a murine model of autoimmune arthritis, is strongly linked to only two major histocompatibility complex (MHC) haplotypes, H-2q and H-2r. In order to identify the determinants of type II collagen (CII) required to induce arthritis in H-2r-bearing mice, B10.RIII mice were immunized with bovine, chick or human CII. Only bovine CII induced significant arthritis and autoantibodies. When the major CNBr peptides of bovine collagen were isolated and used for immunization, only mice immunized with CB8, representing CII 403-551, developed arthritis. To identify immunogenic epitope(s) within CB8, a panel of synthetic peptides representing overlapping sequences of the bovine peptide was generated. When each peptide was cultured with T cells from B10.RIII mice immunized with CII, one peptide, representing CII 430-466, contained a major T-cell epitope. By using an in vitro lymphokine production assay, the T-cell epitope was further narrowed to CII 442-456. These findings suggest that a T-cell determinant important for the initiation of arthritis in B10.RIII (H-2r) mice is located within a 15 amino acid sequence, residues 442-456 of bovine CII.

Amino Acid Sequence↗
PubMed1995

Identification and characterization of a major tolerogenic T-cell epitope of type II collagen that suppresses arthritis in B10.RIII mice.

Tolerization of B10.RIII mice (H-2r) with intravenously injected type II collagen (CII) renders the animals resistant to induction of collagen-induced arthritis (CIA). In order to clarify H-2r-restricted T-cell responses that modulate CIA, we have analysed the T-cell proliferative response of B10.RIII mice against cyanogen bromide (CB) peptides of CII, and detected the strongest response to alpha 1(II)-CB10 (CII 552-897). A panel of chemically synthesized overlapping peptide homologues was used to deduce the minimum structure of this determinant which was found to be CII 610-618. A 15-residue synthetic peptide flanking this region, CII 607-621, was found to effectively suppress arthritis when administered as a tolerogen. Collectively, these data identify the structural component within alpha 1(II)-CB10 which is capable of inducing tolerance in B10.RIII mice. A similar approach to the treatment of autoimmune arthritis, involving the institution of self-tolerance, has potential applicability to human rheumatoid arthritis.

Amino Acid Sequence↗
PubMed1994

Characterization of the T cell determinants in the induction of autoimmune arthritis by bovine alpha 1(II)-CB11 in H-2q mice.

Collagen-induced arthritis (CIA) is an experimental autoimmune disease elicited in genetically susceptible strains of mice by immunization with heterologous type II collagen. This experimental disease is mediated by the immune response of both T and B cells, and susceptibility is restricted by the class II molecules of the MHC. To study the T cell determinants of bovine type II collagen (CII) that mediate the autoimmune response in H-2q mice, we have identified a cyanogen bromide fragment of bovine CII, CII(124-402), that induces arthritis in DBA/1 mice. Using an overlapping set of peptides to map the T cell response to CII(124-402), we have determined that the I-Aq-restricted T cell response to this collagen fragment is mediated by a single immunodominant antigenic determinant. Consequently, this determinant plays a central role in promoting the production of the collagen-specific Abs and the induction of CIA in H-2q mice. Characterization of this immunodominant determinant revealed that the core residues required for T cell stimulation consists of only eight amino acids and is located at amino acids 260 through 267 of bovine CII. The systematic analysis of the contribution of each of these amino acids, in conjunction with sequences of other peptides known to bind to I-Aq, have allowed us to propose a peptide binding motif for the collagen arthritis susceptibility allele, I-Aq.

Amino Acid Sequence↗
PubMed1994

Smoking, the environment and meningococcal disease: a case control study.

This case control study investigated environmental factors in 74 confirmed cases of meningococcal disease (MD). In children aged under 5, passive smoking in the home (30 or more cigarettes daily) was associated with an odds ratio (OR) of 7.5 (95% confidence interval (CI) 1.46-38.66). ORs increased both with the numbers of cigarettes smoked and with the number of smokers in the household, suggesting a dose-response relationship. MD in this age group was also significantly associated with household overcrowding (more than 1.5 persons per room) (OR 6.0, 95% CI 1.10-32.8), with kisses on the mouth with 4 or more contacts in the previous 2 weeks (OR 2.46, 95% CI 1.09-5.56), with exposure to dust from plaster, brick or stone in the previous 2 weeks (OR 2.24, 95% CI 1.07-4.65); and with changes in residence (OR 3.0, 95% CI 1.0-8.99), marital arguments (OR 3.0, 95% CI 1.26-7.17) and legal disputes in the previous 6 months (OR 3.10, 95% CI 1.24-7.78). These associations were independent of social class. Public health measures to lower the prevalence of cigarette smoking by parents of young children may reduce the incidence of MD. The influence of building dust and stressful life events merits further investigation.

Adolescent↗
PubMed1993

T cell epitopes of type II collagen that regulate murine collagen-induced arthritis.

Chick type II collagen (CII), a protein commonly found in joint cartilage, induces an autoimmune arthritis when administered to susceptible strains of mice. A cyanogen bromide fragment of CII, CB11, contains the requisite epitopes critical for inducing collagen-induced arthritis. If administered as a tolerogen, however, before immunization, CB11 prevents the onset of disease. Therefore, delineation of structural elements of CB11 that can regulate autoreactive T cells became the goal of this study. To delineate the structural elements of CB11 antigenic to T cells, 14 peptides containing overlapping sequences of CB11 were generated. Mononuclear cells from CII-immunized DBA/1 mice were cultured with these peptides and the resulting supernatants examined for the production of IFN-gamma. Two peptides, CII 181-209 and CII 245-270, generated the greatest responses. The ability of these two peptides to regulate arthritis was tested by administering them to neonatal DBA/1 mice as tolerogens before immunization with CII. Both peptides suppressed the incidence of arthritis whereas no other peptide used as a tolerogen significantly altered the course of the disease. T cells from four arthritis-resistant murine strains did not recognize either peptide when immunized with CII, whereas cells from the disease-susceptible B10.Q mice responded well to both. Thus, the coincidence of T cell responses to CII 181-209 and CII 245-270 in CIA-susceptible mice and the lack of response in disease-resistant strains or CII-tolerized mice identify these two peptides as containing important T cell epitopes that regulate CIA.

Amino Acid Sequence↗
PubMed1993

A synthetic peptide analogue of a determinant of type II collagen prevents the onset of collagen-induced arthritis.

The immunization of genetically susceptible strains of mice with type II collagen (CII) elicits a collagen-induced arthritis that resembles rheumatoid arthritis. Our laboratory previously identified a region of CII, CII-245-270, that contains a T cell epitope that is prominent in the immune response to CII. Residues critical to the I-Aq-restricted presentation of this determinant have been characterized. To produce synthetic peptides with the potential of disrupting I-Aq-restricted Ag presentation, synthetic analogue peptides were developed that contain site-directed substitutions in critical positions. One analogue peptide was found to be an efficient competitor for binding to I-Aq and to be capable of inhibiting T cell responses in vitro. When DBA/1 mice were coimmunized with CII and the analogue peptide, the incidence and severity of arthritis were greatly reduced, concordant with the humoral immune responses to CII.

Amino Acid Sequence↗
PubMed1993

Audit of near patient cholesterol testing in occupational health clinics.

An audit of near patient cholesterol testing was carried out in occupational health clinics. The aims were to examine the statistical agreement between Reflotron and laboratory measurements of blood cholesterol and to formulate a policy for the use of Reflotrons in cholesterol testing. Three hundred and fifty-two staff members attending occupational health clinics over a period of 10 months had blood taken for both Reflotron and laboratory measurements. The correlation between the two methods was 0.95. The Reflotron had a negative bias compared to the laboratory, with the mean difference between the two methods of measurement being -0.21 mmol/l (95 per cent confidence interval -0.18 to -0.25 mmol/l). Despite the high correlation coefficient and small mean difference, the scatter of Reflotron-laboratory differences was broad, with 95 per cent of the differences lying in the range of 0.95 mmol/l below to 0.52 mmol/l above the laboratory result. For Reflotron results of 5.50 mmol/l and greater, the sensitivity and specificity of the Reflotron in detecting subjects with laboratory cholesterol levels greater than 6.5 mmol/l were 100 per cent and 70 per cent respectively. The laboratory participated in two external quality assessment schemes for cholesterol testing during the course of the audit and all the results of these fell within the acceptable limits. The audit demonstrated that the Reflotron was too imprecise to be used to give accurate measurements of blood cholesterol. However, providing a suitable Reflotron result above which patients were sent for confirmatory laboratory testing was selected, it was an acceptable screening device in the detection of hypercholesterolaemia. Other Reflotron users should consider carrying out similar audits.

Ambulatory Care Facilities↗
PubMed1992

Characterization of a tolerogenic T cell epitope of type II collagen and its relevance to collagen-induced arthritis.

A synthetic peptide representing sequences of type II collagen, (CII 245-270), has previously been used to induce tolerance and suppress arthritis in DBA/1 mice. To determine important residues, a series of peptides, each containing one or two site-directed substitutions, was generated. Mononuclear cells from DBA/1 mice immunized with CII were cultured in the presence of each peptide and the T cell response determined by measuring IFN-gamma in culture supernatant fluids. Substitutions within the region CII 260-270 led to significant decreases in IFN-gamma responses, identifying this sequence as a T cell epitope. To determine the effects of substitutions within this epitope on arthritis, substituted peptides were administered to neonatal mice as tolerogens. Five site-directed substitutions, four of which included the insertion of a residue found in type I collagen to replace its type II counterpart, abrogated the ability of the peptides to induce tolerance and suppress arthritis. These substitutions were located at residues 260, 261, 263, 264, and 266. Two patterns of T cell reactivity were observed. Peptides containing individual substitutions at positions 261, 264, or 266 were capable of generating a significant T lymphokine response, although those containing substitutions at residues 260 or 263 were ineffective Ag. Systematic analysis of the fine structures of T cell determinants important for autoimmune arthritis can lead to strategies for therapeutic intervention.

Amino Acid Sequence↗
PubMed1992

Induction of arthritis with monoclonal antibodies to collagen.

mAb were developed from DBA/1 mice immunized with chick type II collagen. A total of 69 IgG antibodies was isolated and characterized. The majority (36%) reacted with a CNBr-derived peptide CB11 previously identified as containing a major immunogenic and arthritogenic epitope(s). Seven of the antibodies reactive with CB11 crossreacted strongly with mouse type II collagen. These were administered to DBA/1 mice in an attempt to induce arthritis. Individual antibodies were able to induce mild lesions consisting of minimal synovial proliferation but not overt arthritis. However, a combination of antibodies induced severe arthritis with marked destruction of articular cartilage. The minimal effective combination consisted of three antibodies. Arthritis developed within 48 to 72 h after injection of the antibodies and persisted for the duration of the observation period of 3 wk. Antibody levels were measured at intervals and persisted for the 3 wk observation period although at diminishing levels. Competitive binding assays demonstrated that each of the effective antibodies bound independently suggesting that some spatial or quantitative relationship was important possibly related to their ability to activate complement.

Animals↗
PubMed1992

Salivary antibody testing in a school outbreak of hepatitis A.

During a community-wide outbreak of hepatitis A in Gloucester, UK there was a high attack rate in children attending two city primary schools and a pre-school centre sharing the same site. In September 1990, saliva specimens were collected from 478 (85%) of the 562 children. The prevalence of antibody to hepatitis A virus (anti-HAV), as determined by saliva testing, was 29.6%; highest prevalences were seen in 5-6-year-olds and in children from that area of the city at the centre of the community-wide outbreak. The proportion of immune children with a history of clinical hepatitis varied with age from 1 in 42.7 of under-5-year-olds to 1 in 4.7 of 8-10-year-olds. Six children who received prophylaxis with human normal immune globulin (HNIG) because they were household contacts of cases subsequently became infected. Since there was evidence of transmission outside the school environment it is unlikely that a policy of universal prophylaxis within the schools would have stopped the outbreak. Mass prophylaxis in school outbreaks is only likely to be effective if most transmission is occurring at school and if the target population can be clearly defined. Salivary antibody testing is a simple, practical and acceptable procedure in young children. Salivary antibody surveys in conjunction with vaccination against hepatitis A should provide a cost-effective method for control of future outbreaks.

Age Factors↗
PubMed1992

An outbreak of hepatitis A in Gloucester, UK.

During an outbreak of hepatitis A that occurred in Gloucester, UK between September 1989 and January 1991, 162 clinical cases were identified through notifications and laboratory reports, a monthly attack rate of 1.05 per 10,000 residents. The highest attack rate was seen in 5-14-year-olds. There were significant correlations between hepatitis A attack rates in the electoral wards of Gloucester and with the Jarman UPA 8 scores for the wards and with overcrowding, unemployment, under 5-year-olds and ethnic minority. The use of human normal immune globulin prophylaxis (HNIG) for household contacts was unsuccessful in ending the outbreak, partly because only one third of cases reported a household contact with recent hepatitis A. Our experience does not support the use of HNIG in stopping community-wide outbreaks of hepatitis A. Two public health campaigns were mounted during the outbreak; both were followed by a fall in the number of cases. Greater priority should be given to the implementation and evaluation of public health campaigns in future community-wide outbreaks of hepatitis A.

Adolescent↗
PubMed1991

Influenza A and meningococcal disease.

There are several anecdotal accounts of the association between outbreaks of influenza and meningococcal disease. The exceptional increase in the number of cases of meningococcal infection 2 weeks after an influenza A outbreak in England and Wales during November and December, 1989, provided an opportunity to investigate the relation between the two events. Patients with meningococcal disease in December, 1989, were more likely than age-matched controls to show serological evidence of recent influenza A infection (odds ratio 3.9, 95% Cl 1.2-13.9). The most likely explanation for the association is immune suppression induced by influenza A, though a lowering of mucosal resistance to meningococcal invasion may also be a factor. Public health authorities should be aware of the association and should be prepared to alert medical practitioners and the public to the increased risk of meningococcal disease when influenza A outbreaks occur.

Adult↗
PubMed1991

SWR mice are resistant to collagen-induced arthritis but produce potentially arthritogenic antibodies.

SWR mice are resistant to collagen-induced arthritis but produce antibodies to type II collagen. To determine if these antibodies have arthritogenic potential, serum from collagen-immunized mice was concentrated and passively transferred to DBA/1 mice. The recipients developed severe arthritis within 72 hours. To evaluate the role of complement, SWR mice were bred with congenic inbred B10.D2/oSn (complement deficient) and B10.D2/nSn (complement normal) mice. Collagen-immunized (SWR x B10.D2/nSn)F1 mice had high levels of C5 and were susceptible to arthritis, while (SWR x B10.D2/oSn)F1 mice were deficient in C5 and were resistant to arthritis.

Animals↗
PubMed1991

The role of C5 and T-cell receptor Vb genes in susceptibility to collagen-induced arthritis.

Collagen-induced arthritis (CIA) is a rodent arthritis model in which immunization with heterologous type II collagen induces an inflammatory polyarthritis. Susceptibility to the disease is mediated by major histocompatibility complex (MHC) genes as well as genes at other loci. Previous studies of the SWR/J mouse strain, which is resistant to CIA despite bearing the susceptible H-2q haplotype, have suggested that this resistance is the result of a deletion of T-cell receptor (Tcr) Vb gene segments which is carried by this strain. Other studies have implicated a deficiency in complement component C5 as the cause for the resistance. In order to assess the relative importance of these two genes in susceptibility to CIA, and to provide an estimate of the number of independent genes involved in the disease, we analyzed 196 F2 progeny of a (DBA/1 x SWR/J) cross for arthritis susceptibility, and expression of both C5 and Tcr genes. Thirty of the F2 progeny developed arthritis. All of the arthritic mice had at least one copy of the wild-type C5 allele, while the Tcr-Vb haplotypes were distributed in Mendelian fashion. These results demonstrate that C5 sufficiency is an absolute requirement for CIA, but that Tcr-Vb genes located within the SWR deletion have little influence. Genetic analysis of the incidence rate suggests that there is polygenic control of susceptibility to CIA and that in addition to H-2, 5-6 other independent loci (including C5) may be involved.

Analysis of Variance↗