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Biomedical subjects

D E Trentham

Publications and source records attributed to D E Trentham.

At least 55 records · Page 3Linked to original sources
PubMed1988

Detection of arthritogenic factor in adjuvant arthritis.

An evocation of arthritis by an Ag-specific lymphokine has recently been considered with the description of arthritogenic factor (AF) in rats with collagen arthritis. Because rats with CFA-induced arthritis also exhibit T cell reactivity to native type II collagen, T cell lines specific for this protein were established from CFA-injected rats. Supernatant material from these lines contained a type II collagen-binding lymphokine with functional and biochemical attributes identical with those described for AF, i.e., it was a 65-kDa species cross-reacting immunoprotein possessing the ability to incite an erosive, proliferative synovitis when injected into the knee joint of naive recipients. Similarities were also observed with HPLC and on two-dimensional gels. Lymph node cells from rats with arthritis created by injection of the synthetic adjuvant, CP-20,961 failed to produce AF, suggesting that this material is not a ubiquitous concomitant of inflammatory arthritis in the rat. Test injections into sites contiguous with the ear cartilage plate and into fibroblast-lined s.c. pouches suggested that cartilage was a requisite for the induction of inflammation by AF. These data identify a potentially shared effector pathway in the collagen and adjuvant models. The presence of AF in two frequently used models further supports the hypothesis that Ag-specific lymphokines can create autoimmune disease.

Animals↗
PubMed1988

Long-term prospective trial of low-dose methotrexate in rheumatoid arthritis.

Twenty-six patients with severe rheumatoid arthritis who had completed a randomized crossover trial of methotrexate elected to continue to receive the drug in a long-term prospective study. At 36 months, 16 patients remained in the study. Over this period of time, significant improvement was noted in the number of painful and swollen joints, physician and patient global assessments, erythrocyte sedimentation rate, and prednisone dose. Adverse reactions occurred in 16 patients (62%), including nausea, alopecia, headache, stomatitis, herpes zoster, and diarrhea. Mild leukopenia (3 patients), thrombocytopenia (3 patients), and elevated transaminase levels (8 patients) resolved with temporary drug discontinuation. No patient withdrew due to drug toxicity. Liver biopsy specimens in 17 patients after 24 months of treatment showed no evidence of fibrosis or cirrhosis. A significant increase in the percentage of T3 and T4 blood cells and increases in lymphocyte proliferation to concanavalin A and purified protein derivative of tuberculin were found after 2 years of therapy. Our findings indicate that methotrexate has remained effective over 36 months of therapy, with acceptable toxicity levels and no evidence of systemic immunosuppression.

Aged↗
PubMed1988

Activation of rat synovium by iron.

We observed a consistent sequence of activation changes in rat knee synovia following a single intravenous injection of sterile ferric citrate at a dosage sufficient to cause a transient saturation of transferrin. The initial alteration, appreciated 2 hours postinjection, consisted of an expansion in the lumen of synovial lining and subsynovial tissue due to the hypervascularity and increased cellularity was noted, along with peaks in the mitotic activity of synovial cells (fourfold over baseline) and pinocytosis by endothelial cells. During the period of 8-24 hours, mature collagen appeared in the space between pericyte layers and between pericytes and endothelial cells, and 2-9-fold increases in ferritin +, W3/13+, W3/25+, Ox8+, and Ox26+ mononuclear cells occurred. In contrast to the action on synovial fibroblasts, iron injection did not affect the mitotic activity of fibroblasts within the serosa of the small intestine. These findings demonstrate that, under experimental conditions, iron can readily induce changes in the synovium that are reminiscent of early events occurring in response to antigen.

Animals↗
PubMed1988

Collagen arthritis in rats, arthritogenic lymphokines and other aspects.

This review will mainly highlight data from selected, independent studies which collectively implicate a primary role for T cells in the pathogenesis of collagen arthritis in rats. Conferring insusceptibility to this experimental disease with the use of polyclonal, T cell specific antiserum provided direct initial evidence for this conclusion. Substantiation for the theory of a dominant T cell role in collagen arthritis was afforded by T cell line vaccination; scrutiny showed that the mechanism accounting for this protection was a specific down-regulation of the cellular response to collagen. Additional support came from experiments which showed that as few as 10(3) type II collagen specific T line cells were capable of provoking a sustained proliferative synovitis when instilled into the knee joint cavity of syngeneic naive rats. Further analysis of this phenomenon revealed that the arthritogenic capacity of various collagen-reactive line cells correlated with their ability to release a 65-Kd, collagen-binding lymphokine. This antigen-specific lymphokine was designated arthritogenic factor, based on an arthritogenic activity in the knee joint bioassay similar to that of the cells. A functional and physicochemically identical rat arthritogenic factor has also been identified in the adjuvant model of arthritis. These data support the premise that a major effector mechanism in experimental rat arthritis is the release of arthritogenic factor by expanded clones of autoreactive T cells; they also indicate that substantive efforts should be undertaken to seek to identify arthritogenic factor-like lymphokines in patients with chronic inflammatory synovial disease. As an equally plausible alternative hypothesis, the review will close with a brief discussion of recent findings supporting the possible involvement of cartilage-binding, complement-fixing anti-type II collagen antibodies in the pathogenesis of rheumatoid arthritis.

Animals↗
PubMed1988

Intraarticular injection of arthritogenic factor causes mast cell degranulation, inflammation, fat necrosis, and synovial hyperplasia.

Arthritis resembling human rheumatoid arthritis is produced in rats either by immunization with type II collagen or injection of complete Freund's adjuvant. The development of arthritis in both models may be mediated by a T cell-derived, type II collagen-specific protein that has been termed arthritogenic factor. Here, the morphologic changes produced after intraarticular injection of this factor were determined. T cell lines were derived from type II collagen-immunized rats. Arthritogenic factor was isolated from culture supernatants by affinity chromatography on type II collagen-conjugated Sepharose and injected into rat knees. The synovium covering the infrapatellar fat pad was examined by light and electron microscopy at 6 hours to 7 days after injection. By 6 hours, the synovium and fat pad were edematous and heavily infiltrated with neutrophils and a few mononuclear cells. Fibrin was present in the synovium and joint space. Most mast cells had partially degranulated. By 24 hours, the infiltrate became primarily mononuclear and fewer neutrophils were seen. Fat necrosis and edema occurred in the subsynovium. By 48 hours and 7 days, the synovium was hyperplastic, some fibrin persisted, and macrophages were present. Control knees, injected with material obtained from T cell lines established with the antigen, ovalbumin, and subjected to type II collagen affinity chromatography, had less fibrin deposition, milder cellular infiltrates, and less mast cell degranulation than knees injected with arthritogenic factor. These studies suggest that arthritogenic factor stimulates acute cellular infiltration and mast cell secretion which is followed by fat necrosis, synovial hyperplasia, and mononuclear cell infiltration.

Adipose Tissue↗
PubMed1987

Attenuation of collagen arthritis and modulation of delayed-type hypersensitivity by type II collagen reactive T-cell lines.

T-cell lines were established from the lymph node cells of syngeneic Louvain (LOU) rats previously immunized with native chick type II collagen (CII) emulsified in incomplete Freund's adjuvant. The CII lines proliferated in vitro to type II collagen but not to type I collagen, ovalbumin (OV), or PPD. Control lines, developed from LOU rats immunized with OV emulsified in complete Freund's adjuvant, were OV specific because they did not respond to other antigens in vitro. CII line cells could adoptively transfer delayed-type hypersensitivity (DTH) but did not induce IgG antibody production to collagen. Moreover, the intravenous administration of 2 X 10(7) CII line cells prevented the subsequent induction of collagen arthritis following immunization and suppressed DTH to collagen without affecting antibody responses in the recipients. Spleen cells, but not sera, from these resistant rats decreased CII line reactivity in vitro. OV or irradiated CII lines had no effect on clinical or immunologic parameters in this model. These findings demonstrate protection from arthritis afforded by T-cell line transfer and suggest that the phenomenon results from down-regulation of the recipients' cellular immunity to collagen.

Animals↗
PubMed1987

Cyclosporin A treatment of refractory rheumatoid arthritis.

Ten patients with rheumatoid arthritis were entered into a 24-week pilot study of oral cyclosporin A at a starting dosage of 6 mg/kg/day, followed by a 12-week washout period. Significant improvement in clinical parameters was observed at 12 weeks and 24 weeks (P less than 0.02 versus baseline for joint pain and joint swelling indexes and patient and physician assessments; P less than 0.04 versus baseline in the numbers of painful/tender joints and swollen joints). Adverse reactions were varied: renal impairment occurred in all patients and hypertension occurred in 7. All patients demonstrated an increase in defined disease activity at cessation of treatment and through the washout period. Cyclosporin A is clinically effective in the treatment of patients with refractory rheumatoid arthritis, but its value as an intervention therapy is limited by its toxicity.

Arthritis, Rheumatoid↗
PubMed1987

2,000-centiGray total lymphoid irradiation for refractory rheumatoid arthritis.

Because toxicity with the use of 3,000 centiGray (cGy) of total lymphoid irradiation (TLI) was observed in an earlier study, 2,000-cGy treatments were delivered in a 2-portal format to 7 patients and in a modified 3-portal fashion to 6 patients, as part of a randomized, investigator-blinded trial of TLI treatment for refractory rheumatoid arthritis. Analysis of combined data from the 13 patients revealed statistically significant improvement in 5 clinical indicators of disease activity at the end of TLI and 6 and 12 months later, accompanied by T4-specific immunosuppression. Management considerations resulted in the introduction of prednisone therapy in 5 patients, methotrexate in 4, and azathioprine in 1 during the interval of 8-12 months post-TLI. Herpes zoster occurred in 5 patients prior to the initiation of this additional therapy. These data indicate that, in patients with rheumatoid arthritis, a TLI dose of 2,000 cGy is sufficient to produce measurable benefit that lasts for 6 months, and that the improvement can be maintained at 12 months by the use of prednisone and methotrexate.

Adult↗
PubMed1987

Clues provided by animal models of arthritis.

All the findings discussed support the premise that animal experimentation is a pertinent endeavor for understanding chronic inflammatory synovitis in humans. Whether any of these data actually identify processes operative in RA or can be used to predict outcomes in the human disease is currently unclear. The review closes with an illustration of an area of controversy existing, in part, because of an absence of animal model research. The rationale for the use of gamma-interferon (IFN) in RA has been aptly described by S. H. Pincus as "curious". Evidence of deficient gamma-IFN production within the rheumatoid synovium has been acquired by several laboratories, suggesting that administration of this lymphokine might be helpful. This conclusion has been supported by news of short-term success in uncontrolled pilot trials. However, gamma-IFN is perhaps the most vigorous of the interleukins in terms of diversely activating the immune system. Thus, it would seem logical to envision that gamma-IFN would accelerate any process attributable to autoimmunity. The use of animal models to probe this dilemma, and others arising in the future, could provide a more convincing scientific cornerstone for clinical trials in RA. One caveat, however--animal models provide only clues or potential insights, not final answers, for human disease.

Animals↗
PubMed1987

Progress in the understanding of inducible models of chronic arthritis.

Definitive information regarding the etiology of most rheumatic syndromes is not available, but studies of several inducible models of chronic arthritis have helped to identify pathogenetic mechanisms in human inflammatory arthritis. Animal models offer an opportunity to analyze morphologic and biochemical changes occurring during the course of an arthritis, probe the role of genetics, and predict the effects of therapeutic interventions in the human disease. This article describes some contributions obtained from animal studies.

Animals↗
PubMed1986

Potential of indium-111 to measure inflammatory arthritis.

Since an objective noninvasive method for measuring inflammation in arthritis is lacking, radioimaging experiments were conducted with 111indium-chloride (111InCl3) in the collagen model. A computer imaging index, reflecting uptake in the feet and ankles, was significantly greater in 16 rats immunized with collagen than in 6 nonimmunized rats (mean +/- SEM 1.18 +/- 0.04 vs 0.39 +/- 0.02, for the 2 groups, respectively, p less than 0.001). Additional analyses provided evidence that the 111InCl3 technique can be used to measure objectively progression of the arthritic response of rats of immunization with collagen, and pilot comparisons with conventional bone scintigraphy in 2 patients with rheumatoid arthritis suggested that the method is applicable to human arthritic disease.

Animals↗
PubMed1985

An arthritogenic lymphokine in the rat.

A type II collagen-specific arthritogenic lymphokine has been identified in the rat. Arthritogenic factor (AF) is a 65 kD protein generated in vitro by T cells from rats with collagen arthritis, and it induces an erosive, proliferative synovitis when injected into the knee joint of syngeneic naive recipients. Complement does not appear to be required. These data identify a potential T cell-mediated effector mechanism in this model, and suggest that AF may function in other inflammatory synovial diseases.

Animals↗
PubMed1985

Cellular immunity to sperm in infertile women.

To investigate further whether immunity to sperm contributes to some cases of infertility in women, the production of leukocyte inhibitory factor by blood mononuclear cells challenged with human sperm in vitro was measured in women with infertility associated with poor results of postcoital tests or long-term unexplained infertility. Five (36%) of 14 infertile patients but none of nine fertile volunteers responded significantly to sperm in this assay. No study subject had serum IgG or IgM antibodies to sperm detected. These data provide additional evidence consistent with the possibility that cellular immunity to sperm-specific antigen(s) functions in the primary pathogenesis of infertility in some women.

Adult↗
PubMed1985

Efficacy of low-dose methotrexate in rheumatoid arthritis.

Twenty-eight patients with refractory rheumatoid arthritis completed a randomized 24-week double-blind crossover trial comparing oral methotrexate (2.5 to 5 mg every 12 hours for three doses weekly) with placebo. The methotrexate group had significant reductions (P less than 0.01 as compared with the placebo group) in the number of tender or painful joints, the duration of morning stiffness, and disease activity according to physician and patient assessments at the 12-week crossover visit; reductions in the number of swollen joints (P less than 0.05) and 15-m walking time (P less than 0.03) also occurred. These variables, as well as the grip strength and erythrocyte sedimentation rate, showed significant (P less than 0.01) improvement at 24 weeks in the population crossed over to methotrexate. A significantly increased frequency (P less than 0.03) of the HLA-DR2 haplotype occurred in the eight patients with the most substantial response to methotrexate. Adverse reactions during methotrexate therapy included transaminase elevation (21 per cent), nausea (18 per cent), and diarrhea (12 per cent); one patient was withdrawn from the trial because of diarrhea. One patient died while receiving the placebo. Methotrexate did not affect measures of humoral or cellular immunity. We conclude that this trial provides evidence of the short-term efficacy of methotrexate in rheumatoid arthritis, but the mechanism of action is unknown. Longer trials will be required to determine the ultimate safety and effectiveness of this drug.

Administration, Oral↗
PubMed1985

The immunopathogenesis of rheumatoid arthritis.

Rheumatoid arthritis (RA) may represent a T cell dependent immune response to a restricted antigen(s) within the joint, with inflammatory pathways reflecting secondary recruitment. The nature of the inciting antigen is unknown--the stimulus could be an infectious agent or a host constituent. In patients with RA, the centrality of antiself reactivities and immunogenetic influences is apparent. Further clarification of these mechanisms would result in a potential for antigen-specific immunosuppressive therapy.

Antigens↗