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Biomedical subjects

G H Kingsley

Publications and source records attributed to G H Kingsley.

At least 37 records · Page 2Linked to original sources
PubMed1995

Innovative treatment approaches for rheumatoid arthritis. T-cell regulation.

There is considerable evidence to implicate T cells in the pathogenesis of rheumatoid arthritis (RA). They initiate and sustain inflammation and therefore are attractive targets for immunotherapy. Several strategies targeting T cells have been tried in RA. The use of monoclonal antibodies to deplete T cells have been used extensively but with little success. Studies have shown that T cell depleting antibodies produce profound peripheral blood lymphopenia but they are less effective in depleting lymphocytes in the joint. Since clinical efficacy is likely to depend on depleting almost all synovial lymphocytes, high doses of monoclonal antibodies would have to be given. However, the invariably severe peripheral blood lymphopenia induced by such a regimen is likely to result in profound immunosuppression. Therefore, this strategy has been abandoned and recent attempts have been made to induce tolerance in RA. In animal models of RA, treatment with high dose non-depleting anti-CD4 monoclonal antibody protects them from arthritis induced by injection of streptococcal cell wall. In addition, it leads to a state of anergy which protects the animals from arthritis induction without further treatment with anti-CD4 monoclonal antibody. This is currently being used in clinical trials of RA. Other tolerance inducing treatment strategies include T cell or T cell receptor vaccination and oral tolerance. The former is particularly difficult since the rheumatoid arthritogenic antigen and the pathogenic T cell remain unknown. The latter has shown promise in placebo controlled trials although the ideal dosage remains unknown. The mechanism of action of oral tolerance involves either immunosuppressive T cell cytokines, T cell anergy or depletion.

Animals↗
PubMed1995

The therapeutic effects of an engineered human anti-tumour necrosis factor alpha antibody (CDP571) in rheumatoid arthritis.

Pro-inflammatory cytokines such as tumour necrosis factor alpha (TNF alpha) have been implicated in the pathogenesis of rheumatoid arthritis (RA), and have therefore become therapeutic targets. An engineered human antibody, CDP571, that neutralizes human TNF alpha was administered intravenously in single doses of 0.1, 1.0 or 10 mg/kg to patients with active RA (n = 24). The effects of the antibody were compared in a double-blind fashion with those of placebo (n = 12). In an open continuation phase patients were given either 1.0 or 10 mg/kg. We found that CDP571 was well tolerated and caused reductions in markers of disease activity such as erythrocyte sedimentation rate (ESR) and serum C-reactive protein (CRP): this was confirmed by a reduction in the disease activity score (DAS). There was a reduction in the number of tender joints, maximal in degree and duration after 10 mg/kg. Patients also documented a reduction of pain and relief of arthritis symptoms. The effects of 10 mg/kg CDP571 on ESR, CRP, tender joints, pain and symptom relief compared to placebo were statistically significant at weeks 1 or 2. The continuation phase, although open, confirmed both the safety and the beneficial effects of CDP571 in active RA. In conclusion CDP571, an engineered human anti-TNF alpha antibody, is well tolerated and, after a single dose of 10 mg/kg, provides improvements in symptoms, signs and serological markers of disease activity in patients with active RA.

Adolescent↗
PubMed1995

Diltiazem induces remission of calcinosis in scleroderma.

There is no widely accepted treatment for the calcinosis which occurs in scleroderma and dermatomyositis. We report a case of a 62-yr-old woman with active scleroderma complicated by tuberose calcinosis. The calcinosis, which had previously been unchanged for several years, regressed over a 2-yr period during which diltiazem was used to treat hypertension. This effect could not be explained by altered disease activity or renal function but, we suggest, may be due to inhibition of calcium influx into cells. This treatment merits further evaluation.

Calcinosis↗
PubMed1995

Therapeutic monoclonal antibodies.

Monoclonal antibodies have been used extensively over the last few years in clinical trials of rheumatoid arthritis (RA). Not only are they potential therapeutic agents, but they are also useful probes into the immunopathogenesis of RA. Anti-tumour necrosis factor alpha (TNF alpha) monoclonal antibodies have been shown to be clinically efficacious. Although they produced rapid disease amelioration, the duration of clinical improvement was limited to 4-6 weeks. Re-treatments were again effective but long-term studies are required to assess their therapeutic role in RA. So far, the therapeutic effects of lymphocyte-depleting antibodies have been disappointing. From the data, it is clear that synovial lymphocytes are more difficult to eliminate than peripheral blood lymphocytes and it is likely that in order to delete all synovial lymphocytes, high doses of depleting antibodies will be required which could lead to severe immunosuppression. Hence, lymphocyte depletion may not be a feasible therapeutic strategy. However, there are a number of clinical trials currently underway attempting to inhibit CD4 lymphocyte function by non-depleting antibodies. In animal models of RA, such antibodies have been shown to induce long-term disease remission. Another possibility is to combine several monoclonal antibodies in order to induce disease remission in RA. This strategy has been used in murine collagen-induced arthritis in which a combination of anti-CD4 and anti-TNF alpha monoclonal antibodies was shown to be synergistic.

Antibodies, Monoclonal↗
PubMed1995

Reactive arthritis-associated bacteria can stimulate lymphocyte proliferation in non-exposed individuals and newborns.

In reactive arthritis (ReA) a specific T cell response to the triggering bacterial antigen is present in the synovial fluid, while in paired peripheral blood T cells the response is markedly reduced. The proliferative response to ReA-associated bacteria in the peripheral blood of ReA patients was compared with that seen in the blood of healthy adults, who denied exposure to these microbes, and in the umbilical cord blood of newborns, who have clearly not been exposed to bacterial antigen. Peripheral blood mononuclear cells (PBMC) from non-exposed adults and those from umbilical cord blood proliferated to ReA-associated bacteria, whilst little response was seen in ReA PBMC. The response was MHC class II-restricted, required processing of the bacterial antigen, was seen in both CD45RO+ and CD45RA+ subsets, and was not oligoclonal. These T cell responses are similar to those previously demonstrated in non-exposed individuals to malaria, leishmania and trypanosoma antigen, and may reflect the existence of 'natural' T cell immunity to ReA-associated bacteria. The lack of such responses in ReA peripheral blood may suggest that such 'natural' responses may restrict the dissemination or progression of infection.

Adult↗
PubMed1994

Evidence for the continuous recruitment and activation of T cells into the joints of patients with rheumatoid arthritis.

Rheumatoid arthritis (RA) synovial fluid (SF) T cells express the activation markers CD69, HLA-DR and very late antigen (VLA)-1, but surprisingly few bear interleukin-2 receptors (CD25). This unusual activation state is commonly assumed to be due to stimulation by local antigen, yet T cells activated in vitro express activation antigens in the clearly defined sequence: CD69, CD25, HLA-DR and finally VLA-1. Two possible explanations for the activation state of SF cells are: first, they comprise several subpopulations each expressing different activation antigens or, second, activation markers are up-regulated by mechanisms other than antigen stimulation. To examine these hypotheses, double- and triple-color immunofluorescence techniques were applied to four T cell populations: normal peripheral blood T cells activated in vitro, RA SF T cells, T cells from an in vivo model of migration [tuberculin purified protein derivative (PPD)-induced skin blisters] and T cells co-cultured with endothelial cells (EC). The results confirmed that in vitro activated T cells expressed activation markers in the sequence described above, with significant CD25 expression and few cells co-expressing CD69 with HLA-DR or VLA-1. In contrast, almost half the SF T cells were CD69+HLA-DR+ but CD25-; a significant minority were CD69+VLA-1+. T cells from PPD-induced skin blisters were already HLA-DR+ and VLA-1+ at 24 h, although, in vitro, PPD-activated T cells up-regulated HLA-DR and VLA-1 only after 1 week, suggesting that pre-activated T cells were preferentially recruited into the blisters. Finally, T cells were found to up-regulate CD69 and, to a lesser extent, HLA-DR after adhering to EC in vitro. In summary, the paradoxical activation state of SF T cells cannot be explained solely by single or multiple rounds of activation in situ. At least two other mechanisms, the preferential recruitment of pre-activated T cells and the induction of HLA-DR and especially CD69 by endothelial contact during migration, may also play a role.

Adult↗
PubMed1993

Chimaeric anti-CD4 monoclonal antibody cross-linked by monocyte Fc gamma receptor mediates apoptosis of human CD4 lymphocytes.

Previous studies have shown that murine anti-CD4 monoclonal antibody, cross-linked by rabbit anti-mouse immunoglobulin, could mediate apoptosis of murine CD4+ lymphocytes when they were stimulated by T cell receptor antibody. In this study, we have shown that the murine anti-CD4 monoclonal antibody, OKT4, can induce apoptosis in human CD4+ T cells stimulated by the recall antigen tuberculin purified protein derivative (PPD) only when cross-linked by rabbit anti-mouse immunoglobulin. The chimeric anti-CD4 monoclonal antibody, cM-T412 whose Fc fragment is human, was able to cause apoptosis without cross-linking by a second antibody. Similarly, abolition of PPD-induced proliferation of peripheral blood mononuclear cells by cM-T412 did not require cross-linking with rabbit anti-human immunoglobulin. Inhibition of proliferation by cM-T412 could be reduced by pre-treating monocytes with heat-aggregated human IgG. This suggested that monocyte Fc gamma receptors might be cross-linking the human Fc of cM-T412. Propidium iodide staining together with immunofluorescence showed that the apoptotic cells were indeed CD4+ lymphocytes. It is proposed that during treatment with cM-T412 in autoimmune disease such as rheumatoid arthritis, cM-T412-coated CD4 T cells, when they are subsequently stimulated by the unknown arthritogenic antigen, may undergo apoptotic cell death through cross-linking of cM-T412 on Fc gamma receptor-positive cells within the joint.

Animals↗
PubMed1993

Intramuscular methylprednisolone is superior to pulse oral methylprednisolone during the induction phase of chrysotherapy.

In a randomized double-blinded placebo-controlled trial, 41 patients with RA starting on i.m. sodium aurothiomalate (SAT) therapy were randomized to receive three doses of either 500 mg methylprednisolone (MP) orally and a placebo injection or 120 mg of i.m. depot methylprednisolone acetate (MPA) and oral placebo tablets at 4-weekly intervals. Disease activity was assessed by visual analogue scale (VAS) of pain, grip strength (GS), tender joint count (JC), and Health Assessment Questionnaire (HAQ). Laboratory assessment was by haemoglobin concentration (Hb) and ESR. A composite index of Disease Activity score (IDA) was constructed using all six measurements. The group receiving i.m. MPA showed greater improvement when compared with the group receiving oral MPA. These changes were statistically significant (P < 0.05) for ESR (weeks 2, 6, 8, 10, 12), VAS (week 4, 6, 8), JC (weeks 2, 4, 6, 8, 10) and HAQ (weeks 2, 8, 10). Statistically significantly (P < 0.05) greater improvement in Hb was seen throughout all time points in favour of the group treated with i.m. MPA. Using the IDA score to summarize the results, patients treated with i.m. MPA had better disease remission from weeks 2-12. In all measures, except Hb, no statistically significant difference between the two groups was seen by 16 weeks. We conclude that 120 mg i.m. depot MPA is more effective at inducing improvement in disease activity than 500 mg of oral MPA in RA patients starting on SAT therapy.

Administration, Oral↗
PubMed1993

HLA-B27 subtypes in the spondarthropathies.

The spondarthropathy (Sp)-associated HLA-B27 antigen includes at least seven subtypes, B*2701-07, of which 01, 02, 05 and 07 occur in Caucasians. This study examined the B27 subtype distribution in British patients with Sp. The 133 HLA-B27+ subjects comprised 94 European Caucasian Sp (58 ankylosing spondylitis (AS), 22 reactive arthritis (ReA; 11 sexually acquired (SARA), 11 enteric (EReA)), eight undifferentiated Sp (USp), and six pauciarticular juvenile-onset chronic arthritis (pJCA)) patients, and 34 healthy Caucasian controls, together with four Asian Indian and one Chinese. 35S-labelled B27 was immunoprecipitated with anti-B27 MoAbs, and subtyped according to isoelectric point (pI) following isoelectric focussing. The use of B27 MoAb permitted subtype assignment without full class I HLA typing. The vast majority (95%) were B*2705 (Caucasian controls 31/34; AS 55/58; ReA 21/22; USp 8/8, and pJCA 6/6; Indian control 1/1 and AS 2/3; Chinese pJCA 1/1), and the remainder B*2702. No B*2701 or 07 subjects were identified. AS occurs in both B*2702 and 05 subjects, and we extend this observation to small numbers of ReA and of Indian AS subjects. This implicates molecular features shared between B27 subtypes, rather than subtype-determining regions of the antigen, in Sp pathogenesis.

Antibodies, Monoclonal↗
PubMed1992

The importance of the T cell in initiating and maintaining the chronic synovitis of rheumatoid arthritis.

We hope that this short review has produced convincing, although indirect, evidence that in the case of rheumatoid synovitis, the T cell is the conductor of an orchestra playing a tune written by an antigen-presenting cell. The tune develops and becomes modified with time, so that it is difficult to discern with clarity much of the original melody. We believe that it may be possible to substitute a new score that will bring this symphony to a harmonious end. We also strongly believe that this is preferable to augmenting the string section or suppressing the percussion section of the orchestra in the vain hope that in the end harmony can be achieved. The final musical analogy must be the hope that the first page of the score can be found, so that we may discover the main theme, the leitmotif, of the rheumatoid-specific antigenic peptide.

Animals↗
PubMed1992

Activation of gold-reactive T lymphocytes in rheumatoid arthritis patients treated with gold.

OBJECTIVE: To assess the role of T lymphocyte sensitization in the etiology of side effects of gold therapy in patients with rheumatoid arthritis (RA). METHODS: Lymphocyte proliferation induced by gold(III) and gold(I) salts was measured in 53 subjects: 30 RA patients with gold-induced side effects (17 with dermatitis, 9 with proteinuria, 3 with hematologic complications, and 1 with colitis), 9 RA patients without side effects despite prolonged chrysotherapy, 4 RA patients who had never received gold, and 10 healthy controls. Peripheral blood lymphocytes were cultured with the different gold salts and proliferation was measured by 3H-thymidine incorporation. RESULTS: Thirteen of the 17 RA patients who developed gold-induced dermatitis showed significant T lymphocyte proliferation in response to gold(III) salts, and this proliferation could be completely blocked by monoclonal antibodies directed at the HLA-DR molecule. Such proliferative responses were not seen in patients with other gold-induced side effects, in patients who had never received gold, or in healthy controls. Only 1 of 9 patients who had not developed side effects despite long-term maintenance chrysotherapy showed significant lymphocyte activation with gold(III) salts. Lymphocyte proliferation could not be induced with gold(I) salts or with other metal salts. CONCLUSION: Patients with RA who develop dermatitis following treatment with sodium aurothiomalate [gold(I)] have T cells which proliferate in an HLA-DR-restricted manner in response to HAuCl4 [gold(III)]. We believe this observation can lead to more accurate diagnosis and treatment of side effects, which currently limit the use of one of the most effective antirheumatic drugs.

Adult↗
PubMed1992

Inhibition of synovial fluid T cell proliferation by anti-CD5 monoclonal antibodies. A potential mechanism for their immunotherapeutic action in vivo.

OBJECTIVE: Monoclonal antibodies (MAb) directed against the T cell surface molecule CD5 are able to provide accessory stimulatory signals to resting T cells. The potential role of CD5 as an immunoregulatory molecule in inflammatory synovitis was examined. METHODS: Synovial fluid and peripheral blood T cells of patients with active rheumatoid arthritis (RA) were purified and stimulated with interleukin-2 (IL-2), and the effect of MAb directed against CD5 on IL-2 responsiveness was examined. RESULTS: IL-2-induced proliferation of synovial fluid T cells was strongly inhibited by anti-CD5 MAb, but not by anti-CD28 or anti-CD3 MAb. In RA peripheral blood T cells, MAb directed against CD5, CD3, and CD28 induced IL-2-dependent T cell growth, similar to findings in healthy controls. The difference in activity of anti-CD5 MAb on synovial fluid T cells compared with peripheral blood T cells was not due to different surface expression of CD5. CONCLUSION: Anti-CD5 has an inhibitory effect on in vivo-activated synovial fluid T cells. The disease-ameliorative effects of anti-CD5 immunotoxin treatment of RA may be partly due to "switching-off" of T cell activation in the joints.

Adult↗
PubMed1992

T lymphocyte adhesion to fibronectin (FN): a possible mechanism for T cell accumulation in the rheumatoid joint.

The accumulation of T cells within the joint is responsible for the perpetuation of synovitis. This process is partly regulated by selective binding to endothelium. However, adhesion to extra-cellular matrix proteins, like FN, may also be important. FN binding is mediated by certain members of the VLA (beta 1 integrin) family of proteins. To investigate the role of Tc-FN interactions in synovitis the binding of synovial fluid (SF) and peripheral blood (PB) T cells to FN-coated wells, and the expression of cell surface VLA molecules on these cells by double label immunofluorescence, were studied. SF T cells bound better to FN than PB T cells. VLA alpha 4 and VLA beta 1 but not VLA alpha 5 were up-regulated on SF compared with PB T cells. Anti-VLA alpha 4, VLA beta 1 and VLA alpha 5 MoAbs inhibited the binding of SF T cells to FN. The increased binding of SF T cells to FN could have been related to activation and/or to their predominantly memory phenotype. Purified resting memory or naive T cells bound poorly to FN. In contrast, compared with SF T cells, concanavalin A-activated T cells showed a very similar level of binding to FN, comparable expression of VLA molecules and the same pattern of inhibition of binding to FN by MoAbs. Thus, VLA molecules may play an important role in the retention of T cells in the joint and since T cells can be activated via VLA-FN interactions, this mechanism may perpetuate chronic inflammation.

Arthritis, Rheumatoid↗
PubMed1992

Treatment of rheumatoid arthritis with single dose or weekly pulses of chimaeric anti-CD4 monoclonal antibody.

The aetiology of rheumatoid arthritis is unknown but CD4+ T cells are known to be involved in its pathogenesis. Because of this, anti-CD4 monoclonal antibody has been used in open studies with clinical benefit in up to 60% of patients. We have used a chimaeric anti-CD4 monoclonal antibody (cM-T412, Centocor) in a randomized, double-blinded, placebo controlled trial as treatment for rheumatoid arthritis. Nine patients with active rheumatoid arthritis resistant to traditional disease-modifying drugs were recruited. Four received an intravenous 50 mg bolus of antibody, and three received 50 mg weekly for four consecutive weeks. Two patients received placebo. Despite a marked reduction (P less than 0.001) in peripheral blood CD4+ lymphocytes, there was no significant clinical improvement in any of these patients. The decrease in CD4+ lymphocyte number lasted one week after a single 50 mg dose of cM-T412 but was more prolonged in the patients who received four infusions. CD8+ T cells, CD16+ cytotoxic cells and CD14+ monocytes showed only a transient reduction. It may be concluded that the therapeutic efficacy of anti-CD4 therapy is not directly related to CD4+ T-cell lymphopenia.

Adult↗