Biomedical subjects

T J Smeets

Publications and source records attributed to T J Smeets.

At least 19 recordsLinked to original sources

PubMed2000

The effects of interferon-beta treatment of synovial inflammation and expression of metalloproteinases in patients with rheumatoid arthritis.

OBJECTIVE: Interferon-beta (IFNbeta) treatment is emerging as a potentially effective form of therapy in various immune-mediated conditions. This study evaluated the effects of IFNbeta therapy on the cell infiltrate, cytokine profile, and expression of metalloproteinase 1 (MMP-1) in synovial tissue from patients with rheumatoid arthritis (RA). To further assess the mechanism of action, in vitro experiments were conducted to determine the effects of IFNbeta on the production of MMP-1, MMP-3, tissue inhibitor of metalloproteinases 1 (TIMP-1), and prostaglandin E2 (PGE2) by human fibroblast-like synoviocytes (FLS). METHODS: Eleven patients were treated for 12 weeks with purified natural fibroblast IFNbeta (Frone; Ares-Serono, Geneva, Switzerland) subcutaneously 3 times weekly with the following dosages: 6 million IU (n = 4), 12 million IU (n = 3), and 18 million IU (n = 4). Synovial biopsy specimens were obtained by needle arthroscopy at 3 time points: directly before and at 1 month and 3 months after initiation of treatment. Immunohistologic analysis was performed using monoclonal antibodies specific for the following phenotypic markers and mediators of joint inflammation and destruction: CD3, CD38, CD68, CD55, tumor necrosis factor alpha (TNFalpha), interleukin-1beta (IL-1beta), IL-6, MMP-1, and TIMP-1. In addition, we measured the production of MMP-1, MMP-3, TIMP-1, and PGE2 by RA FLS and dermal fibroblasts in the presence and absence of IFNbeta. RESULTS: A statistically significant reduction in the mean immunohistologic scores for CD3+ T cells and the expression of MMP-1 and TIMP-1 at 1 month, CD38+ plasma cells and the expression of IL-6 at 3 months, and the expression of IL-1beta at both 1 and 3 months was observed in synovial tissue after IFNbeta treatment. The scores for CD68+ macrophages and TNFalpha expression also tended to decrease, but the differences did not reach statistical significance. The in vitro experiments revealed inhibition of MMP-1, MMP-3, and PGE2 production by RA FLS, whereas TIMP-1 production was only slightly decreased. These effects were more consistent in RA FLS than in dermal fibroblasts. CONCLUSION: The changes in synovial tissue after IFNbeta treatment and the in vitro data support the view that IFNbeta therapy has immunomodulating effects on rheumatoid synovium and might help to diminish both joint inflammation and destruction. Larger well-controlled studies are warranted to show the efficacy of IFNbeta treatment for RA.

Adjuvants, Immunologic↗

PubMed2000

Modulation of inflammation and metalloproteinase expression in synovial tissue by leflunomide and methotrexate in patients with active rheumatoid arthritis. Findings in a prospective, randomized, double-blind, parallel-design clinical trial in thirty-nine patients at two centers.

OBJECTIVE: Leflunomide and methotrexate have proven to be efficacious in reducing joint inflammation and slowing destruction in clinical trials of patients with rheumatoid arthritis (RA). This study was conducted to provide more insight into the mechanism of action of these agents in synovial tissue. METHODS: In a 2-center, prospective, randomized, double-blind clinical trial, we compared leflunomide (20 mg/day, after a 3-day 100 mg/day loading dose) and methotrexate (increased stepwise to 15 mg/week) treatment in patients with active RA. Paired synovial tissue biopsy samples were obtained by knee arthroscopy at baseline and after 4 months of treatment. Frozen synovial tissue sections were stained for macrophages (CD68), T cells (CD3), adhesion molecules (intercellular adhesion molecule 1 [ICAM-1], vascular cell adhesion molecule 1 [VCAM-1]), cytokines (tumor necrosis factor alpha, interleukin-1beta [IL-1beta]), matrix metalloproteinase 1 (MMP-1), and tissue inhibitor of metalloproteinases 1 (TIMP-1). RESULTS: Paired synovial tissue sections were available in 35 patients (16 taking leflunomide, 19 taking methotrexate). Both drugs displayed equal clinical efficacy, with 8 leflunomide-treated patients (50%) and 10 methotrexate-treated patients (53%) fulfilling the American College of Rheumatology 20% response criteria. Both compounds showed similar effects on synovial tissue: reduced numbers of macrophages and reduced ICAM-1 and VCAM-1 expression were noted after 4 months of treatment. Both leflunomide- and methotrexate-treated patients exhibited a decreased MMP-1:TIMP-1 ratio in the synovial tissue. In the subset of patients fulfilling the 20% response criteria of the American College of Rheumatology, a more pronounced reduction in the expression of ICAM-1, VCAM-1, IL-1beta, and MMP-1 was found compared with the nonresponders. CONCLUSION: Leflunomide and methotrexate are clinically efficacious drugs that interfere with mechanisms involved in joint inflammation and destruction of joint integrity.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed2000

Increased cellularity and expression of adhesion molecules in muscle biopsy specimens from patients with rheumatoid arthritis with clinical suspicion of vasculitis, but negative routine histology.

OBJECTIVE: Histological analysis of random quadriceps muscle biopsy specimens can be used to detect vasculitis in patients with rheumatoid arthritis (RA). This study aimed at determining the immunohistological features in patients with clinical suspicion of rheumatoid vasculitis, but without a transmural infiltrate or fibrinoid necrosis of the vessel wall on routine histology. METHODS: Three groups of patients with RA were studied: (a) without clinical signs of vasculitis (n=6); (b) with recent onset of extra-articular features and a clinical suspicion of vasculitis but normal routine histology (n=11); and (c) with recent onset of extra-articular features and vasculitis, histologically proved either in muscle or other biopsy specimens (n=14). A control group of patients with osteoarthritis was also included (n=5). Frozen sections from quadriceps muscle biopsy specimens were analysed with monoclonal antibodies to detect CD3, CD4, CD8, CD68, ICAM-1, VCAM-1, and HLA-DR. The slides were evaluated using a semiquantitative scoring system (0-4). RESULTS: The mean scores gradually increased from group 1 to 3, leading to significant differences between groups 1 and 2, but not between groups 2 and 3 for most markers (p< 0.05). Thus the pathological changes were similar for the two groups with clinical signs of vasculitis, even when the conventional histological evaluation was negative. Higher immunohistological scores were associated with perivascular infiltrates on routine histology. CONCLUSION: The pathophysiological events leading to vasculitis are reflected by the changes in the quadriceps muscle biopsy specimens. The data indicate that the sensitivity of examination of muscle biopsy specimens for the diagnosis of rheumatoid vasculitis can be increased by the use of new criteria.

Aged↗

PubMed1999

Anti-CD25 therapy reveals the redundancy of the intragraft cytokine network after clinical heart transplantation.

BACKGROUND: Despite blockade of the interleukin-2/interleukin 2 receptor (IL-2/IL-2R) pathway by the murine anti-CD25 (i.e., IL-2R alpha chain) monoclonal antibody BT563, cardiac rejection can still occur. In these cases, growth factors other than IL-2 may contribute to allograft rejection. We studied the expression of IL-15, a macrophage-derived cytokine associated with T-cell activation, which interacts with the beta and gamma chains of the IL-2R during rejection episodes under anti-CD25 therapy. METHODS: We measured intragraft IL-15 mRNA expression and the number of IL-15- and CD68-positive cells in posttransplantation endomyocardial biopsies (EMBs; n=45) and in nontransplanted, donor-heart specimens (n=11) by competitive template reverse transcription-polymerase chain reaction and immunohistochemistry, respectively. RESULTS: IL-15 mRNA expression was present in the majority of posttransplantation EMB specimens (91%, 41/45) and in nontransplanted donor-heart specimens (91%, 10/11). Relative IL-15 mRNA levels were neither associated with transplantation nor with rejection status. After transplantation, the number of IL-15- and CD68-positive cells significantly increased (P<0.001), but IL-15-positive cell counts did not reflect the histological rejection grade. Anti-CD25 treatment, in contrast to its effects on the IL-2/IL-2R complex, had no influence on intragraft IL-15 mRNA and protein production. In rejection EMB specimens, during (n=5) and after (n=8) anti-CD25 therapy, no differences in relative IL-15 mRNA levels, or in IL-15- and CD68-positive cell counts, were measured. CONCLUSIONS: After heart transplantation, high numbers of IL-15- and CD68-positive cells infiltrate the graft. This phenomenon is independent of the rejection status. IL-15 remains present during blockade of the IL-2/IL-2R pathway by anti-CD25 monoclonal antibodies, and it may participate in T cell-dependent donor-directed immune responses, thereby explaining the occurrence of rejection in the absence of IL-2.

Antibodies, Monoclonal↗

PubMed1999

Expression of the activation antigen CD97 and its ligand CD55 in rheumatoid synovial tissue.

OBJECTIVE: Fibroblast-like synoviocytes (FLS) express decay-accelerating factor (CD55) at high levels. Recently, it was found that CD55 is a specific cellular ligand for the 7-span transmembrane receptor CD97. The objective of this study was to define the expression of this receptor-ligand pair in synovial tissue (ST) to provide more insight into the interaction between FLS and surrounding cells. METHODS: Antibodies against CD97 and CD55 were used for immunohistologic analysis of synovial biopsy specimens from 16 patients with rheumatoid arthritis (RA) and 15 patients with osteoarthritis (OA). In addition, an enzyme-linked immunosorbent assay system was used to determine the expression of soluble CD97 (sCD97) in synovial fluid (SF) from 30 patients with RA, 13 with OA, and 10 with reactive arthritis (ReA). RESULTS: In both RA and OA ST sections, strong expression of CD55 was confirmed on FLS in the intimal lining layer, where it was also found that all macrophages expressed CD97. The percentage of macrophages that expressed CD97 was lower in the synovial sublining (P = 0.005). The mean levels of sCD97 in SF were significantly higher in RA patients than in patients with OA or ReA (P < 0.0001). CONCLUSION: These results suggest that FLS are able to interact with macrophages via the CD97/CD55 receptor-ligand system. In this respect, the CD97/CD55 pair may account for the specific architecture of the intimal lining layer and may be of primary importance in maintaining and amplifying synovial inflammation. The specific increase in sCD97 levels in RA SF might be related to the presence of activated proteolytic systems or to the increase in synovial mass, rather than a consequence of local receptor-ligand interaction.

Adult↗

PubMed1999

p53 overexpression in synovial tissue from patients with early and longstanding rheumatoid arthritis compared with patients with reactive arthritis and osteoarthritis.

OBJECTIVE: The p53 tumor suppressor gene is overexpressed in synovial tissue (ST) from patients with longstanding rheumatoid arthritis (RA), and may contain somatic mutations. The aim of this study was to determine p53 expression in ST from RA patients in different stages of the disease, compared with disease controls. METHODS: ST biopsy specimens were obtained from the knee joints of 31 RA patients in varying disease phases, 8 patients with reactive arthritis (ReA), 10 patients with inflammatory osteoarthritis (OA), and 6 control patients (4 with meniscus pathology, 2 with vascular insufficiency). ST was also obtained from the clinically uninvolved knee joints of 9 RA patients. Expression of p53 was determined by immunohistology with DO1 monoclonal antibody (mAb) in all patients and by Western blot analysis with DO7 mAb in a subgroup of the patients. RESULTS: The p53 protein was detected by immunohistology in 10 of the 13 patients with early RA (duration <6 months) and in 12 of the 14 patients with longstanding RA (duration >5 years). The p53 protein was also demonstrated in clinically uninvolved knee joints. Western blots revealed immunoreactive p53 in ST extracts from all RA patients. Expression of p53 was about twice as high in ST from patients with longstanding RA as in early RA samples, but the difference did not reach statistical significance. Small amounts of p53 were also detected in ST from ReA and OA patients, although the expression in RA synovium was significantly higher. Immunohistologic analysis of normal ST gave negative results for p53. CONCLUSION: This study shows that p53 overexpression is specific for RA, compared with OA and ReA. This phenomenon is probably secondary to increased production of wild-type p53 protein in response to DNA damage and secondary to somatic mutations caused by the genotoxic local environment in inflamed ST. Of interest, p53 overexpression can also be found in the earliest stages of RA and in clinically uninvolved joints.

Aged↗

PubMed1999

The effects of interferon beta treatment on arthritis.

OBJECTIVE: To determine whether interferon beta (IFN-beta) therapy might have a beneficial effect on arthritis, we evaluated the effect of IFN-beta on collagen type II-induced arthritis (CIA) in rhesus monkeys and conducted a pilot study in patients with rheumatoid arthritis (RA). METHODS: Four rhesus monkeys with CIA were treated with 10 x 10(6) U (MIU)/kg mammalian cell-derived recombinant IFN-beta (Rebif; Ares-Serono) s.c. daily for 1 week. Subsequently, 12 patients with active RA were treated for 12 weeks with purified natural fibroblast IFN-beta (Frone, Ares-Serono) s.c. 3 times weekly at the following dosages: 6 MIU (n = 4), 12 MIU (n = 4) and 18 MIU (n = 4). RESULTS: Rapid clinical improvement during IFN-beta therapy was observed in three of the four rhesus monkeys with CIA. There was also a marked decrease in serum C-reactive protein (CRP) levels with a subsequent increase after discontinuation of the treatment in all monkeys. The 10 RA patients who completed the study exhibited on average gradual improvement of tender and swollen joint counts, patient's assessment of pain, and patient's and doctor's global assessment (all P < 0.05). The health assessment questionnaire and serum CRP levels also tended to decrease, but this was not statistically significant; 40% of the patients fulfilled the ACR criteria for 20%, improvement, whereas none fulfilled the ACR criteria for 50% improvement 12 weeks after initiation of treatment. There was no clear dose response relationship. CONCLUSION: The data suggest that IFN-beta treatment has a beneficial effect on arthritis.

Adjuvants, Immunologic↗

PubMed1999

Analysis of serial synovial biopsies in patients with rheumatoid arthritis: description of a control group without clinical improvement after treatment with interleukin 10 or placebo.

OBJECTIVE: Analysis of serial synovial biopsy specimens is increasingly used as an outcome measure for the evaluation of therapeutic interventions. However, observations in placebo treated groups are scarce. We describe the immunohistologic features of the synovium in placebo treated patients with RA and in those who received interleukin 10 (IL-10). METHODS: Ten patients with active RA received dosages of either placebo (n = 7) or 5 microg/kg (n = 1) or 10 microg/kg (n = 2) of recombinant human IL-10 (rhIL-10; SCH 52000, Schering-Plough, Kenilworth, NJ, USA) daily for 28 consecutive days. Synovial biopsy specimens from the knee joint were obtained by needle arthroscopy before and 4 weeks after initiation of treatment. Immunohistochemistry was performed using monoclonal antibodies specific for the following surface markers and cytokines: CD3, CD4, CD8, CD38, CD68, CD55, IL-1beta, IL-6, and tumor necrosis factor-alpha. RESULTS: No patient exhibited clinical improvement after treatment with placebo or any rhIL-10 dosage. Microscopic analysis of synovial tissue revealed no significant change in the scores for infiltration by inflammatory cells or in the scores for the expression of cytokines after treatment. CONCLUSION: Studies of serial synovial biopsies from patients treated with placebo or IL-10 revealed no changes in immunohistologic scores. This suggests that the biopsy procedure itself has no effect on the features of the synovium.

Adult↗

PubMed1998

Analysis of the cellular infiltrates and expression of cytokines in synovial tissue from patients with rheumatoid arthritis and reactive arthritis.

The cellular infiltrates and cytokine patterns in synovial tissue (ST) from patients with rheumatoid arthritis (RA) and reactive arthritis (ReA) were compared in order to determine the mechanisms responsible for the chronic and destructive course of RA. Since the results could be influenced by differences in disease duration, ST was studied from patients in both early and late stages of the disease. Ten patients had early RA (< 1 year), ten long-standing RA (> 1 year), six early ReA (< 1 year), and five long-standing ReA (> 1 year). Histological analysis demonstrated that the scores for infiltration by lymphocytes and plasma cells, and the scores for inflammation, were significantly higher in RA than in ReA. Immunolabelling studies showed that in particular, the scores for infiltration by CD38+ plasma cells, granzyme B+ cells, and interferon-gamma (IFN gamma)+ cells were significantly higher in RA than in ReA. The results were independent of the disease duration. The increased number of lymphocytes, plasma cells, and granzyme B+ cells in rheumatoid synovial tissue supports the paradigm that RA is the result of specific immune recognition in the joint and that granzyme B+ cells play an important role in joint destruction.

Adolescent↗

PubMed1998

Poor expression of T cell-derived cytokines and activation and proliferation markers in early rheumatoid synovial tissue.

We compared the state of activation and proliferation of T cells in synovial tissue (ST) from rheumatoid arthritis (RA) patients in early and late stages of the disease to find out whether T-cell-driven immune responses vary during the course of the disease. ST was obtained from 12 patients with early RA (< 1 year) and 12 patients with longstanding RA (> 5 years). T cells and interferon-gamma (IFN-gamma)-positive cells were detected in ST using immunohistologic methods. To determine the percentage of T cells expressing the interleukin-2 receptor, IFN-gamma, or the proliferation associated antigen Ki-67, immunofluorescence double-staining techniques were used. The scores for the number of T cells and for the expression of IFN-gamma as well as the percentages of T cells expressing CD25, IFN-gamma, or Ki-67 in rheumatoid synovium were not dependent on disease duration. These results do not support the assumption that the responsiveness of T cells in ST of RA patients differs between early and late stages of the disease. The data indicate that at present no arguments exist that the effect of T-cell-directed interventions on synovial inflammation might vary in different stages of the disease.

Adult↗

PubMed1998

Microscopic measurement of cellular infiltration in the rheumatoid arthritis synovial membrane: a comparison of semiquantitative and quantitative analysis.

Microscopic measurement of inflammation in synovial tissue may be important in studies of clinical status, prognosis and response to treatment. The aim of this study was to compare quantitative microscopic analysis of inflammation with a semiquantitative grading system in rheumatoid arthritis (RA) synovial membrane. Knee synovial membrane samples from 16 patients with RA, including paired samples taken before and after treatment in nine patients, were immunostained with anti-CD68 and anti-CD3 monoclonal antibodies using standard techniques. The intensity of macrophage and T-lymphocyte infiltration was measured both by quantitative and semiquantitative techniques, and the results were compared. In a cross-sectional comparison, both methods correlated significantly for lining layer macrophage infiltration, as well as sublining layer macrophage and T-cell infiltration. However, in some patients demonstrating a clinical response to treatment, semiquantitative analysis lacked sensitivity to biologically relevant changes in mononuclear cell infiltration. These observations have important implications for future studies of therapeutic modalities.

Antibodies, Monoclonal↗

PubMed1997

Increased expression of IL-15 in the synovium of patients with rheumatoid arthritis compared with patients with Yersinia-induced arthritis and osteoarthritis.

Recently, a new player in the cytokine network has been described that is produced by monocytes and can be detected in the rheumatoid synovium: interleukin-15 (IL-15). Since this cytokine may play a role in the accumulation and activation of T-cells, B-cells, and natural killer (NK) cells characteristic of synovial tissue (ST) from patients with rheumatoid arthritis (RA), the expression of IL-15 was studied in ST from RA patients in comparison with ST from patients with reactive arthritis (ReA) and osteoarthritis (OA) and the phenotype of IL-15-positive cells was determined. IL-15 expression was investigated by immunohistochemical analysis of ST from ten patients with RA, ten patients with Yersinia enterocolitica-induced ReA, and nine patients with OA. The immunohistological findings were quantified and the results obtained in the different patient groups were compared. To determine the phenotype of IL-15-expressing cells, double-labelling immunofluorescence was performed. The expression of IL-15 was significantly higher in ST from patients with RA than in ST from patients with ReA or OA. In double-label experiments, co-expression was observed with markers for macrophages, T-cells, and NK cells. The composition of the cellular infiltrate in the synovium of patients with RA might be partly explained by the specific increase in expression of IL-15 in rheumatoid ST. It can be speculated that IL-15 production by inflammatory cells other than macrophages may occur in the rheumatoid synovium.

Adult↗

PubMed1997

Analysis of the synovial cell infiltrate in early rheumatoid synovial tissue in relation to local disease activity.

OBJECTIVE: To define variations in the cellular infiltrate and in the expression of monokines in synovial tissue (ST) from rheumatoid arthritis (RA) patients with different durations of disease and different levels of disease activity. METHODS: The immunohistologic features of synovial biopsy specimens from 31 patients with early RA (< 1 year) and 35 patients with longstanding RA (> 5 years) were compared. The possible associations between these features and local disease activity, as measured by the score for pain in the biopsied knee joint were also evaluated. RESULTS: The immunohistologic features were not dependent on disease duration. We found a positive correlation between the scores for knee pain and the semiquantitative scores for the number of macrophages, as well as the expression of interleukin-6 and tumor necrosis factor alpha, whereas the correlation with the scores for CD4+ T cells was negative. Multivariate analysis showed that these correlations were highly statistically significant (P < 0.003). CONCLUSION: The results do not support the view that inflammatory mechanisms in the synovial tissues of RA patients differ between early and late stages of the disease. The findings presented here are consistent with the concept that early RA is the result of a synovitis process of longer duration and that macrophage-derived cytokines play an important role in maintaining the clinical signs of inflammation.

Adult↗

PubMed1996

Decrease in cellularity and expression of adhesion molecules by anti-tumor necrosis factor alpha monoclonal antibody treatment in patients with rheumatoid arthritis.

OBJECTIVE: The effect of chimeric anti-tumor necrosis factor alpha (TNF alpha) monoclonal antibody (MAb) therapy on synovial inflammation was studied in order to address the hypothesis that anti-TNF alpha therapy leads to down-regulation of adhesion molecules and a decrease in inflammatory cell influx in synovial tissue (ST). METHODS: The immunohistologic features of synovial biopsy specimens, both before and 4 weeks after anti-TNF alpha MAb (cA2) therapy, were studied in 14 patients with rheumatoid arthritis (RA). The patients either received a placebo (n = 2), or were given intravenous doses of cA2 at 10 mg/kg (n = 5) or 20 mg/kg (n = 7). RESULTS: A significant (P < 0.03) reduction in the mean scores for T cells and for the adhesion molecules, vascular cell adhesion molecule 1 and E-selectin, was observed after therapy with 10 mg/kg or 20 mg/kg of cA2 in RA patients. CONCLUSION: The reduced expression of adhesion molecules, and the decrease in cellularity of rheumatoid ST after cA2 administration support the hypothesis that the antiinflammatory effect of anti-TNF alpha therapy might be partly explained by down-regulation of cytokine-inducible vascular adhesion molecules in ST, with a consequent reduction of cell traffic into joints.

Antibodies, Monoclonal↗

PubMed1996

Expression of the activation antigen CD27 in rheumatoid arthritis.

Differentiation of CD4+ T-cells is reflected by the change from the CD45RA+CD27+ phenotype via CD45RO+CD27+ to the CD45RO+CD27- phenotype. To provide insight into the migration and activation of T-cells at the site of inflammation in rheumatoid arthritis (RA), CD27 expression by T-cells in peripheral blood (PB), synovial fluid (SF), and synovial tissue (ST) as well as the levels of the soluble form of CD27 (sCD27) in plasma and SF were studied in patients with RA. Since CD4+CD27+ T-cells are involved in providing helper activity for B-cells, we also investigated the levels of rheumatoid factors in serum and SF in relation to CD27 expression. The mean level of sCD27, which is produced by CD27+ cells, and the mean percentage of CD27 T-cells within the CD4+CD45RA- subset were higher in SF than in PB. SF sCD27 levels were higher in the patients with RA than in the patients with osteoarthritis, who served as controls. In ST infiltration by CD4+CD45RO+CD27+ T-cells, could be demonstrated in the rheumatoid perivascular lymphocytic aggregates with a relative increase in the percentage of CD27- T-cells in the diffuse lymphocytic infiltrate. The sCD27 levels and the percentages of CD4+CD27+ cells in SF correlated positively with the levels of rheumatoid factors in serum and SF. The findings presented in this study suggest a continuous influx of preactivated CD4+CD45RO+CD27+ cells from the PB into the rheumatoid ST and further activation and differentiation to CD4+CD45RO+CD27- cells in situ, followed by migration to the SF. These activated T-cells are likely to play a role in synovial inflammation.

Adult↗

PubMed1995

Reduction of synovial inflammation after anti-CD4 monoclonal antibody treatment in early rheumatoid arthritis.

OBJECTIVE: To study the effect of chimeric anti-CD4 monoclonal antibody (MAb) therapy on synovial inflammation, in order to interpret the clinical experience with anti-CD4 treatment. METHODS: The immunohistologic features of synovial biopsy specimens before and 4 weeks after anti-CD4 MAb (cM-T412) therapy were studied in patients with rheumatoid arthritis. The patients received intravenous doses of either placebo (n = 1) or 10 mg (n = 4), 25 mg (n = 2), or 50 mg (n = 1) of cM-T412 daily for 5 consecutive days. RESULTS: Although the patients did not experience clinical improvement, significant decreases in the number of circulating CD4+ cells, the degree of synovial inflammatory infiltration, and the mean scores for expression of adhesion molecules were found in the 7 patients 4 weeks after receiving cM-T412. The scores for infiltration with CD4+ and other inflammatory cells were particularly reduced following treatment with either 25 mg or 50 mg cM-T412. Cytokines, such as interleukin-1 beta and tumor necrosis factor alpha, could still be detected in the synovial tissue after treatment. CONCLUSION: The decline in the numbers of inflammatory cells and adhesion molecules in synovial tissue after CD4+ cell depletion supports the view that CD4+ T cells orchestrate local cellular infiltration. The lack of clinical effect of anti-CD4 therapy might be explained by an insufficient decrease in the number of synovial CD4+ cells and by the persistence of cytokines. Determination of whether more adequate dosing would lead to a clinical improvement must await further study.

Adult↗

PubMed1995

Expression of adhesion molecules in early rheumatoid synovial tissue.

The objective of this paper is to define the expression of adhesion molecules in synovial tissue (ST) from patients with rheumatoid arthritis (RA) with respect to disease duration. Antibodies against adhesion molecules were used for immunohistochemistry to examine ST sections from 11 patients with early RA ( < 1 year), 14 patients with long-standing RA ( > 5 years), and 15 patients with osteoarthritis (OA). Increased cellular infiltration and increased expression of E-selectin, ICAM-1, VCAM-1, PECAM-1, VLA-4, and Mac-1 were found in ST from patients with RA compared to ST from patients with OA. The immunohistological findings were similar for the different stages of RA. The upregulation of adhesion molecules in ST of patients with RA of < 1 year's duration suggests the activation of chronic inflammatory processes in these patients. Therefore, the mechanisms by which therapies directed toward these adhesion molecules exert their effects are likely to be similar for patients with so-called early RA and patients with long-standing RA.

Aged↗

PubMed1994

Granzyme-positive cytotoxic cells are specifically increased in early rheumatoid synovial tissue.

OBJECTIVE: To define the expression and the phenotype of granzyme (Gran) A and B positive cytotoxic cells in synovial tissue (ST) from patients with rheumatoid arthritis (RA) with respect to disease duration and activity. METHODS: Using antibodies against GranA and GranB, which serve as markers of activated natural killer (NK) cells and cytotoxic T lymphocytes, ST sections from 10 patients with early RA, 10 patients with longstanding RA, and 10 patients with osteoarthritis were examined. The phenotype of Gran+ cells was determined with double-labeling techniques. RESULTS: Gran+ cells, the majority of which were NK cells, were found in ST from patients in all groups. Several of these cells did not express the surface markers CD16, CD56, and CD57. The highest ST expression of GranB was found in patients with early RA. In RA patients, there was a positive correlation of GranB expression with serum levels of acute-phase reactants, but not with histologic scores for inflammation. CONCLUSION: Gran+ cells are mainly NK cells, a substantial proportion of which do not express conventional NK cell surface markers. GranB expression is specifically increased in the synovial tissues of patients with RA of short duration.

Aged↗