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G Kingsley

Publications and source records attributed to G Kingsley.

At least 37 records · Page 2Linked to original sources
PubMed1993

T cells are responsible for the enhanced synovial cellular immune response to triggering antigen in reactive arthritis.

In reactive arthritis (ReA) there is specific proliferation of synovial fluid (SF) mononuclear cells (MNC) to the triggering bacterial antigen; comparatively little or no response is seen in peripheral blood (PB). To investigate the mechanism of this elevated local immune response, we examined patients with typical ReA who showed an enhanced antigen-specific synovial immune response in bulk culture. Using separated fractions of T cells and antigen-presenting cells (APC) from PB and SF we showed that the synovial T cells rather than SF APC are responsible for the specific proliferation. By limiting dilution analysis, the frequency of T cells responding to the specific antigen was found to be significantly increased compared with the frequency of irrelevant antigen-specific T cells. Furthermore, the frequency of T cells responding to the specific antigen was higher in SF (between 1/619 and 1/4846, mean 1/2389) than in PB (between 1/1286 and 1/16,279, mean 1/7350). We conclude that the specific synovial cellular immune response in ReA is mainly due to an expansion of antigen-specific T cells within the joint. However, the non-specific hyper-reactivity of SF T cells and differences between SF and PB APC may make a more minor contribution.

Adult↗
PubMed1993

The immunopathogenesis and immunotherapy of autoimmune disease.

A conference entitled 'The Immunopathogenesis and Immunotherapy of Autoimmune Disease' was held at the Royal College of Physicians on 20 May 1992. Its aim was to consider advances in pathogenesis and their translation into therapeutic targets.

Autoimmune Diseases↗
PubMed1992

Enumeration of interleukin-1 alpha and beta producing cells by flow cytometry.

A technique for intracytoplasmic immunofluorescence staining to detect and quantify human interleukin-1 alpha (IL-1 alpha) and beta (IL-1 beta) in CD4, CD8, and CD14 positive lymphoid cells is described. Mononuclear cells stimulated in vitro with PHA to produce IL-1, were fixed and made permeable to antibodies by sequential exposure to paraformaldehyde and the detergent n-octyl-glucoside. Cytoplasmic and surface staining of both forms of IL-1 were demonstrated by indirect fluorescence using IL-1 beta and IL-1 alpha specific mouse monoclonal antibodies and quantified with flow cytometry.

Antigens, CD↗
PubMed1992

Defective hypothalamic response to immune and inflammatory stimuli in patients with rheumatoid arthritis.

OBJECTIVE: To determine the integrity of the hypothalamic-pituitary-adrenal (HPA) axis responses to immune/inflammatory stimuli in patients with rheumatoid arthritis (RA). METHODS: Diurnal secretion of cortisol and the cytokine and cortisol responses to surgery were studied in subjects with active RA, in subjects with chronic osteomyelitis (OM), and in subjects with noninflammatory arthritis, who served as controls. RESULTS: Patients with RA had a defective HPA response, as evidenced by a diurnal cortisol rhythm of secretion which was at the lower limit of normal in contrast to those with OM, and a failure to increase cortisol secretion following surgery, despite high levels of interleukin-1 beta (IL-1 beta) and IL-6. The corticotropin-releasing hormone stimulation test in the RA patients showed normal results, thus suggesting a hypothalamic defect, but normal pituitary and adrenal function. CONCLUSION: These findings suggest that RA patients have an abnormality of the HPA axis response to immune/inflammatory stimuli which may reside in the hypothalamus. This hypothalamic abnormality may be an additional, and hitherto unrecognized, factor in the pathogenesis of RA.

Adult↗
PubMed1992

Management of early inflammatory arthritis. Intervention with immunomodulatory agents: T cell vaccination.

Current theories of the aetiology of RA point to a central role for the trimolecular complex comprising the MHC class II molecule on the surface of the APC, the antigenic peptide and the TCR on the disease-inducing T cell. Thus the arthritogenic T cell is an important target for new therapy. However, it cannot be directly identified because the causative antigen is unknown, so indirect techniques such as TCV and TCR peptide vaccination are required. In TCV, T cells thought to mediate the disease, in an activated and attenuated form, are injected into the patient, who then develops a specific immune response against these pathogenic T cells. TCV has been shown to be effective in protecting against and treating a variety of animal models of autoimmune disease, including AA, EAE and IDDM in NOD mice. The vaccines initially comprised clones and lines of T cells shown to be capable of transferring the disease, but later unseparated LN cells were also shown to be effective, paralleling more closely the human situation. Interestingly, it has become clear that TCV does not create its own regulatory network but amplifies a natural immunoregulatory network which forms as the disease develops. The major stimulating moiety on the vaccinating T cell is its receptor (anti-idiotypic response), although there is also an anti-ergotypic (anti-activated T cell) response. For this reason the technique of TCR peptide vaccination was developed, which utilizes only a short peptide from the TCR of the disease-causing cells to stimulate an immune response against them. This is effective in the prevention and treatment of EAE, where there is a preferential usage of TCR-V beta 8 by encephalitogenic T cells. The application of both these techniques to human autoimmune disease is in its infancy. Studies of TCV in MS and RA have not shown clear-cut clinical benefit, although immunological changes have been observed; comparison of methodology with the animal work and assessment of results are complex and further studies are in progress. Studies of TCR peptide vaccination in MS and RA are handicapped by the lack of a consensus on TCR usage in these conditions, but a limited study is underway in MS.

Adjuvants, Immunologic↗
PubMed1992

Cellular responses to human chondrocytes: absence of allogeneic responses in the presence of HLA-DR and ICAM-1.

To assess the accessory cell function of human articular chondrocytes, we assessed the ability of human chondrocytes to stimulate allogeneic peripheral blood mononuclear cells (PBMC) and to support phytohaemagglutinin (PHA)-induced proliferation of highly purified T cells. We also examined the surface expression of HLA-DR and ICAM-1 on the chondrocytes both unstimulated and stimulated with cytokines in vitro. Chondrocytes failed to stimulate allogeneic PBMC despite the constitutive expression of MHC class I molecules and the cytokine-induced expression of class II molecules but were able to support T cell proliferation to PHA, IFN-gamma and to a limited extent, IL-1 beta, induced class II expression on chondrocytes. ICAM-1 was present on 94-99% of freshly isolated cells; this declined with culture (17-59%; P < 0.005) but was readily induced by IFN-gamma, IL-1 beta, and tumour necrosis factor-alpha. Alloreactivity and, presumably, autoreactivity to chondrocytes requires factors in addition to the surface expression of DR and ICAM-1. However the presence of these molecules suggests a capacity for cell-cell interactions in inflammatory sites such as the cartilage pannus junction.

Antigen-Presenting Cells↗
PubMed1992

Alteration in T cell/macrophage ratio may reveal lymphocyte proliferation specific for the triggering antigen in reactive arthritis.

It has previously been shown that synovial fluid (SF) mononuclear cells (MNC) from patients with reactive arthritis (ReA) and some patients with undifferentiated oligoarthritis (UOA) respond specifically to the triggering bacterium (specific responders). However, in some patients there is a response to two or more bacteria (non-specific responders) and in a third group no response is found (non-responders). We assessed whether the proportion of synovial MNC which were macrophage-monocyte (MaMo) differed among the specific responder, non-specific responder and non-responder groups. There was no difference between the specific (33 +/- 9) and the non-specific (32 +/- 26) groups; non-responders had a higher percentage of MaMo (61.3 +/- 31%) although the difference was not significant. We also investigated whether the specificity of the response to antigen in ReA or UOA SF was altered by changing the T-cell/MaMo ratio. In all five specific responders the immune response remained specific whatever the ratio tested. However, four of the five non-specific responders, but none of the non-responders, developed a specific response to one of the tested antigens by increasing the T cell/MaMo ratio. We conclude that in some patients with a non-specific response, alteration of the T cell/MaMo ratio uncovers a specific response which may identify the triggering antigen.

Adult↗
PubMed1992

Aetiological role of bacteria associated with reactive arthritis in pauciarticular juvenile chronic arthritis.

BACKGROUND: The cause of juvenile chronic arthritis (JCA) is unknown. Pauciarticular JCA is the most common subtype and can be subdivided into early (type I) and late onset (type II) forms, the latter clinically resembling reactive arthritis. METHODS: The cellular immune responses to bacteria associated with reactive arthritis in blood and synovial fluid from 39 children with pauciarticular JCA, three children with classical reactive arthritis, and two children with psoriatic arthritis were examined. Specific titres of antibodies to bacteria in serum samples were measured in all patients. RESULTS: A bacteria specific synovial cellular immune response was found in two of three (67%) patients with reactive arthritis and 14 of 28 (50%) patients with pauciarticular JCA type II but only in one of 11 (9%) patients with pauciarticular JCA type I and none in patients with psoriatic arthritis. Six patients responded specifically to Chlamydia trachomatis and 11 to Yersinia enterocolitica. Antigen specific lymphocyte proliferation correlated poorly with the specific antibody response. CONCLUSIONS: These findings suggest that bacteria with associated reactive arthritis may have a causative role in pauciarticular JCA type II but not in JCA type I.

Adolescent↗
PubMed1992

Pathogenetic role of Chlamydia, Yersinia and Borrelia in undifferentiated oligoarthritis.

We studied the cellular and humoral immune response to Chlamydia trachomatis, Yersinia enterocolitica and Borrelia burgdorferi in paired samples of peripheral blood and synovial fluid (SF) in undifferentiated oligoarthritis, reactive arthritis (ReA) and rheumatoid arthritis. Antigen specific lymphocyte proliferation was found in SF of 43% of patients with ReA and 34% of patients with undifferentiated oligoarthritis. C. trachomatis was the most frequent single agent. HLA-B27 was positive in 83% of patients with ReA and in 62% of patients with undifferentiated oligoarthritis with antigen specific lymphocyte proliferation. Antigen specific lymphocyte proliferation correlated poorly with the specific antibody response. Only chlamydial antigen was detected in SF cells using monoclonal antibodies. We conclude that some patients with undifferentiated oligoarthritis may have a forme fruste of ReA. This finding is important in view of recent evidence supporting the efficacy of antibiotic therapy in ReA.

Adult↗
PubMed1992

Antigenic responses in reactive arthritis.

In this article, the mechanisms by which infection at a distant site could lead to ReA and whether they could explain the association of ReA with HLA-B27 have been discussed. We propose that ReA synovitis is primarily due to specific synovial T-cell proliferation to fragments of the triggering bacterial found in the joint. Nonspecific T cells amplify synovitis with antibodies playing only a secondary role. First, we have shown that the triggering bacterial antigen is present in a nonviable form in ReA synovium and that this, not cross-reactive joint autoantigen, stimulates the specific synovial immune response. Second, the studies of the humoral immune response in ReA have been reviewed. Further evidence of bacterial persistence in the joint comes from work demonstrating intrasynovial bacteria-specific antibody synthesis. Continuing maturation of the antibody response also points to persisting antigen. In enteric but not genitourinary ReA, the humoral response is mainly IgA, implying chronic stimulation of the gut mucosa. Analysis of the molecules against which the humoral response is directed has shown no difference between yersinia arthritis and yersiniosis, but in CTA, the response to the 57kD and 59kD antigens differs from CT urethritis suggesting they may be arthritogenic. Finally, the antibody response may be absent in ReA patients rendering antibody titres diagnostically less useful and confirming their secondary role in the pathogenesis of synovitis. Third, studies of cellular response in ReA have been analyzed. We show there is a specific synovial MNC proliferative response to fragments of the triggering bacteria found in the joint, which is potentially of diagnostic use. The proliferation is due to CD4+ and CD8+ T cells and restricted by MHC class I and II antigens. This antigen-specific T-cell response is accompanied by an antigen-independent recruitment of nonspecific T cells, which may contribute to the amplification of synovitis. The importance of the synovial APC in determining the synovial immune response is unarguable but the exact mechanisms are unclear. Further details on the possible role of HLA-B27 in the presentation of arthritogenic peptides and on the exact identity of the antigenic epitopes recognized in ReA must await analysis of a large panel of T-cell clones. Finally, it is hoped that advances in this field will lead to specific and effective immunologic therapies or vaccines for this currently untreatable disease.

Antibody Formation↗
PubMed1991

Synovial T lymphocyte-specific immune response to Chlamydia trachomatis in Reiter's disease.

We studied the lymphocyte proliferative response to Chlamydia trachomatis in Reiter's syndrome (RS) compared with that in other rheumatic diseases. RS patients showed significantly increased C trachomatis-specific synovial fluid (SF) T cell proliferation. Proliferating cells were found in both CD4+ and CD8+ T cell subsets. The SF lymphocyte proliferative response to C trachomatis in RS was inhibited by anti-class I and class II major histocompatibility complex monoclonal antibodies, while the response to tuberculin purified protein derivative was inhibited only by anti-class II monoclonal antibodies. T cell receptor gamma/delta-bearing T cells were not consistently increased in RS SF compared with peripheral blood, nor did such cells consistently expand upon in vitro culture with C trachomatis. Finally, there was no correlation between the cellular immune response and levels of antibody to C trachomatis antigens. Our results indicate that a specific T cell response to C trachomatis within the joint plays a role in the pathogenesis of RS.

Adult↗
PubMed1991

Immunotherapy of rheumatic diseases--practice and prospects.

Present treatments for rheumatic diseases are both toxic to patients and largely ineffective in modifying the disease process. This report, based on a meeting recently held in London, investigates how far recent molecular and immunological advances can be converted into more effective, less toxic and, above all, more specific therapies.

Cytokines↗
PubMed1991

Inhibition of lymphocyte proliferation by a monoclonal antibody (RFT2) against CD7.

The effect of the monoclonal antibody RFT2, directed against CD7, on T cell proliferation in unseparated peripheral blood mononuclear cell populations induced by various stimulants was investigated. The addition of RFT2 to cell cultures inhibited the T cell proliferation induced by tuberculin PPD and OKT3 but not by phytohaemagglutinin, concanavalin A or phorbol myristic acid; RFT2 had to be present during the first 24 h of culture in order to elicit inhibition; inhibition of proliferation was not due to down regulation of interleukin-2 receptor on the surface of T cells; and suppressive effects could be transferred by mononuclear cells pre-treated with RFT2. These results are of particular relevance in view of the known in vivo suppressive effect of RFT2 in humans.

Antibodies, Monoclonal↗
PubMed1990

Monocyte activation in rheumatoid arthritis: evidence for in situ activation and differentiation in joints.

Monocytes, defined by staining with the Mo-2 and Leu-M3 monoclonal antibodies which both detect the CD14 antigen, were studied in peripheral blood of control subjects and patients with rheumatoid arthritis as well as in rheumatoid synovial fluid of the latter for expression of activation/differentiation markers. The monocytes in the rheumatoid synovial fluids showed increased expression of class II major histocompatibility antigens (HLA-DR and -DQ) and decreased positivity for the peanut agglutinin receptor as compared with those from patient and control peripheral blood. There were no differences in phenotype between the control and patient peripheral blood monocytes. These findings are consistent with the hypothesis that monocytes are activated and differentiate into more mature macrophage-like cells after entry into the rheumatoid joint.

Adult↗