PubMed Health⌕ Search

Biomedical subjects

N A Mitchison

Publications and source records attributed to N A Mitchison.

At least 37 records · Page 2Linked to original sources
PubMed1998

The distribution of variation in regulatory gene segments, as present in MHC class II promoters.

Diversity in the antigen-binding receptors of the immune system has long been a primary interest of biologists. Recently it has been suggested that polymorphism in regulatory (noncoding) gene segments is of substantial importance as well. Here, we survey the level of variation in MHC class II gene promoters in man and mouse using extensive collections of published sequences together with unpublished sequences recently deposited by us in the EMBL gene bank using the Shannon entropy to quantify diversity. For comparison, we also apply our analysis to distantly related MHC class II promoters, as well as to class I promoters and to class II coding regions. We observe a high level of intraspecies variability, which in mouse but not in man is localized to a significant extent near the binding sites of transcription factors-sites that are conserved over longer evolutionary distances. This localization may both indicate and enhance heterozygote advantage, as the presence of two functionally different promoters would be expected to confer flexibility in the immune response.

Animals↗
PubMed1997

Type II collagen serology: a guide to clinical responsiveness to oral tolerance?

A double-blind placebo-controlled randomized trial of oral collagen type II (CII) treatment in rheumatoid arthritis was completed in Berlin. Anti-CII antibody titres were measured before and after the treatment. They showed that: (1) the titre prior to treatment did not identify a responder subgroup, (2) the treatment reduced CII antibody titres, but only in those patients making a clinical response and (3) administration of 10 mg CII per day reduced the titre in these subsets more effectively than 1 mg per day. Although the data are limited, they suggest that a titre drop may be useful for identifying those patients who respond to this form of treatment and that the drop may be a valid parameter for detecting the impact of the treatment on the immune system.

Administration, Oral↗
PubMed1997

Thalidomide therapy of established collagen-induced arthritis (CIA) not accompanied by an evident Th2 shift.

Thalidomide, a drug likely to affect the cytokine pattern, was administered orally to mice at various stages of CIA. Treatment (150 mg/kg per day by gavage, 5 days/week), started 6 weeks post-immunization, i.e. at the height of the disease, significantly reduced arthritis, and appeared also to reduce the level of inflammation as judged by neutrophil chemiluminescence. With treatment started 9 weeks post-immunization the effect on arthritis was no longer statistically significant, and when started at 14 weeks was lost. Over a dose range of up to 150 mg/kg per day the treatment had no effect on either interferon-gamma (IFN-gamma) or IL-4 mRNA levels. The treatment is therefore not likely to have operated via a shift in the Th1/Th2 balance.

Animals↗
PubMed1997

T cell response of I-Aq mice to self type II collagen: meshing of the binding motif of the I-Aq molecule with repetitive sequences results in autoreactivity to multiple epitopes.

Type II collagen (CII) is of immunological interest because of its repetitive structure and properties as an autoantigen. The mouse gene has recently been cloned, thus enabling T cell-defined epitopes to be identified. Multiple novel epitopes on mouse CII are here detected in the autoreactive T cell response. The major response is directed to an epitope with residues 707-721 located on the CB10 fragment. Some 25 other epitopes are also recognized, including the autologous homologue of the 256-270 epitope which dominates in the response to foreign collagen. The cells reactive with mouse collagen peptides were of Th1 type, as judged by release of IFN-gamma. No significant reactivity was detected to mouse CII peptides during ongoing disease. Alignment of the mouse epitopes revealed a sequence motif with characteristic side chains at residues P1, P4 and P7, and to a lesser extent at P5, within a nonamer core sequence. Binding of these epitopes was simulated in a computer model of the I-Aq molecule, where peptides with anchor residues at P1, P4 and P7 were indeed found to fit the binding groove best. The spacing of pockets and the fine structure of the binding surface of the I-Aq molecule meshes with the repetitive structure of the collagen (X-Y-Gly), thus providing a likely explanation for the occurrence of multiple epitopes. Comparison with human DR binding motifs showed that the I-Aq motif resembles most closely that of the DR4 subtypes which predispose for rheumatoid arthritis.

Amino Acid Sequence↗
PubMed1996

Oral type II collagen treatment in early rheumatoid arthritis. A double-blind, placebo-controlled, randomized trial.

OBJECTIVE: To investigate the efficacy of oral type II collagen in the treatment of early rheumatoid arthritis (RA). METHODS: Ninety patients with RA (disease duration < or = 3 years) were treated for 12 weeks with oral bovine type II collagen at 1 mg/day (n = 30) or 10 mg/day (n = 30) or with placebo (n = 30), in a double-blind randomized study. RESULTS: There were no significant difference between the 3 groups in terms of response to treatment. However, we observed a higher prevalence of responders in the type II collagen-treated groups: 7 responders in the 10-mg type II collagen group and 6 in the 1-mg group, versus 4 in the placebo group. Furthermore, 3 patients in the 10-mg type II collagen group and 1 patient in the 1-mg type II group, but no patients in the placebo group, had very good response. A total of 14 patients had to be withdrawn from the study: 2 because of side effects (nausea) and 12 because of lack of efficacy. CONCLUSION: Only a minority of patients responded to treatment with oral type II collagen. These results justify further efforts to identify which patients will have good response to such therapy.

Administration, Oral↗
PubMed1996

Regulation by non-major histocompatibility complex genes of the allo-4-hydroxy-phenylpyruvate dioxygenase (F liver protein) response.

Although rapid progress is being made in the quantitative genetics of multifactorial disease, no response to a simple antigen has yet been subjected to full genomic analysis. The well-characterized antigen allo-HPPD (4-hydroxy-phenylpyruvate dioxygenase, previously known as F liver antigen) is a good candidate for such treatment. Old and new data bearing on this possibility are here assembled. In respect of antibody production and an early burst of interleukin-4 (IL-4) transcription, introduction of the non-major histocompatibility complex (MHC) background from A/J strain mice into F1 hybrids with C57BL10 strains up-regulates the response. These findings can be aligned with previous quantitative genetics carried out on airway hyper-responsiveness in related strains, and to a lesser extent with the genetics of autoimmune diabetes in the mouse. Taken together, the findings suggest that regulation of the pro-inflammatory cytokines are largely responsible for the variation. Additional data indicate that these non-MHC genes are are to a variable extent (depending on the response parameter) epistatic to the down-regulatory MHC allele H-2Ab.

4-Hydroxyphenylpyruvate Dioxygenase↗
PubMed1996

Functional significance of polymorphism among MHC class II gene promoters.

The functional significance of polymorphism among MHC class II promoters in man and mouse is here reviewed, mainly in terms of the hypothesis of differential expression. The hypothesis proposes that differences between antigen-presenting cells in MHC class II expression exert a co-dominant effect on the Th1-Th2 cytokine balance, such that class II molecules of one type come to control to a greater extent the production of one group of cytokines, and those of another type the production of the alternative group. The survey deals with the influence of signal strength and antigen-presenting cell type on T-cell subset differentiation; functional differences between MHC class II molecules not obviously related to determinant selection; disease protection mediated by HLA alleles; mechanisms possibly responsible for allotypic and isotypic bias; overdominance (heterozygous advantage) in selection for expression of class II alleles; MHC class II promoter structure and function; inter-locus and inter-allele variability within human MHC class II gene upstream regulatory regions; a comparison of these polymorphisms in mouse and man; read-out of class II promoter function; and a comparison with expression of MHC class I. We conclude that the evidence that this variation is functionally active (i.e. controls expression) is increasing, but is not yet compelling. The crucial test still to come, we suggest, is whether or not the biological effects attributable to this polymorphism will line up with molecular studies on expression.

Alleles↗
PubMed1995

Self-reactive T cell hybridomas and tolerance. Same range of antigen dose dependence but higher numbers of self-reactive T cell hybridomas from mice in which self-tolerance has been broken by antiserum treatment.

Mechanisms of self-tolerance of 4-hydroxyphenylpyruvate dioxygenase (HPPD) are explored. It is well established that negative selection based on TCR affinity occurs in the thymus. We have investigated the frequency with which self-reactive T cell hybridomas can be obtained in relation to self-tolerance. Mice immunized with the self-form of HPPD gave rise to T cell hybridomas that were able to recognize self-protein and a synthetic peptide representing the T cell epitope, at higher Ag concentration than was necessary for recognition of allo-protein. The efficiency of negative selection was then reduced by treating neonatal mice with anti-HPPD antiserum. This reduced T cell tolerance of the self-protein, as judged by in vitro proliferation, and enabled self-reactive T cell hybridomas to be generated at a higher frequency. However, the Ag concentration requirements of these hybridomas for the self-protein and the self-peptide remained unaltered. The possibility that these findings reflect an auxiliary mechanism of self-tolerance based on frequencies of self-reactive T cells is discussed.

4-Hydroxyphenylpyruvate Dioxygenase↗
PubMed1995

Association of H2Ab with resistance to collagen-induced arthritis in H2-recombinant mouse strains: an allele associated with reduction of several apparently unrelated responses.

HLA class II alleles can protect against immunological diseases. Seeking an animal model for a naturally occurring protective allele, we screened a panel of H2-congenic and recombinant mouse strains for ability to protect against collagen-induced arthritis. The strains were crossed with the susceptible strain DBA/1, and the F1 hybrids immunized with cattle and chicken type II collagen. Hybrids having the H2Ab allele displayed a reduced incidence and duration of the disease. They also had a reduced level of pre-disease inflammation, but not of anti-collagen antibodies. The allele is already known to be associated with reduction of other apparently unrelated immune responses, suggesting that some form of functional differentiation may operate that is not exclusively related to epitope-binding. It is suggested that this may reflect allelic variation in the class II major histocompatibility complex promoter region.

Alleles↗
PubMed1995

Immunology of reactive arthritides.

Reactive arthritis (ReA) and Lyme arthritis together comprise a pair of chronic inflammatory diseases of the joints. Although differing in detail, these relatively rare diseases are related in their immunopathology to the much commoner rheumatoid arthritis (RA), for which they serve as both model and control. The trigger for rheumatoid arthritis is unknown, but for these rarer diseases triggering occurs by certain well-defined bacterial infections. Arthritis is an uncommon outcome of these infections, for reasons unknown, and the development of chronic, as distinct from brief, arthritis is even rarer; again, the reasons are unknown. Not only does knowing the trigger greatly assist us in understanding these diseases, so also does knowing the contrasting pattern of Th1 versus Th2 cytokines observed in RA and ReA. ReA and Lyme arthritis are here considered in the wider setting of infections where chronic morbidity arises first from hypersensitivity, and perhaps finally from autoimmunity, such as occurs in some of the major tropical diseases. The immunology of ReA and Lyme disease is surveyed in detail, concentrating on T cells and including an update on the Lyme vaccine(s). Additional sections deal with the enigma of HLA B27, with epidemiological findings relevant to the chronicity of ReA and to the need for enlarged prospective studies of ReA in the setting of a developing country.

Arthritis, Reactive↗
PubMed1995

Variable response to a candidate cancer vaccine antigen: MHC control of the antibody response in the rat to avian erythroblastosis virus (AEV)-encoded epithelial growth factor receptor but not AEV-encoded thyroid hormones receptor.

BACKGROUND: A problem likely to be encountered in any cancer immunotherapy based on vaccination with a single protein or peptide is variation in the host response. A particularly informative example is provided by the two oncogenic proteins, one intracellular and the other extracellular, encoded by the avian erythroblastosis virus (AEV), homologs of the thyroid hormones receptor (THsR) and the epithelial growth factor receptor (EGFR), respectively. MATERIALS AND METHODS: Antibodies to these two proteins were assayed by radioimmune precipitation (RIP) in sera from MHC-congenic rats immunized by virally induced tumors. RESULTS: Among the four haplotypes tested, RT1(1) rats exhibited a significantly lower response to the EGFR homolog than the high responders RT1c and RT1u, while RT1a rat strains had an intermediate response. Analysis of the recombinant haplotype RT1ac indicated that the response is controlled, as expected, by the class II locus of the MHC. In contrast, these rat strains responded uniformly to the intracellular THsR homolog. CONCLUSIONS: These results support the hypothesis that MHC restriction of the response to self-related proteins reflects mainly a tolerance mechanism. They sound a note of warning for cancer vaccine development, and also one of positive advice. The likelihood of MHC restriction suggests that a widely applicable polyvalent vaccine should be the final aim in cancer immunotherapy. Yet, paradoxically, evidence of MHC restriction can help establish that a candidate vaccine is likely to prove effective.

Alpharetrovirus↗
PubMed1994

Primed lymphocytes are boosted by type II collagen of their hosts after adoptive transfer.

A central question in understanding autoimmunity is whether an endogenous self-antigen can drive an immune response initially triggered by a foreign one. This possibility is here tested by adoptive transfer, in which T and B cells from mice primed with foreign type II collagen were transferred into irradiated syngeneic hosts. Previous work with other protein antigens has established that primed cells normally respond only if boosted after transfer with antigen. In the present case, and in respect only to that portion of the antibody response able to bind to endogenous type II collagen, that requirement did not hold. This indicates that the anti-self component is indeed driven by endogenous antigen, which the transferred lymphocytes presumably obtain from their adoptive hosts. The transfers were carried out in C57BL10.A x DBA/1 mice using donors primed with either chick or bovine collagen, and the non-boosted responses, presumably driven by endogenous antigen, could be followed in a proportion of the recipients for as long as 45 days.

Animals↗
PubMed1994

Assessment of collagen type II induced arthritis in mice by whole blood chemiluminescence.

Lucigenin-enhanced chemiluminescence can be measured in 100 microliters samples of whole, unseparated mouse blood. A procedure for doing so is here described in detail, using a standard clinical luminometer. The assay measures the TPA-induced oxidative burst from granulocytes and macrophages, which is believed to depend on the overall level of inflammation in the body. It is here applied to mice suffering from type II collagen-induced arthritis, and its relation to overt disease symptoms (the arthritis score) is characterised during the course of the disease. A correlation between the assay and the arthritis score is found at the height of the disease (r = 0.42, p = .039), but not at early or very late time points, although there is a strong hint that the results of an early assay may predict the subsequent disease course. The assay provides a rapid, convenient, quantitative and economical method of assessing disease activity, which can be carried out repeatedly on the same individual. It should be applicable in other mouse models of chronic inflammatory disease. It may find application for rapid screening of novel anti-rheumatic drugs and treatments.

Acridines↗
PubMed1993

The Concorde trial.

Explore the source record for details and available documents.

Antigen-Presenting Cells↗