Search PubMed⌕ Search

Biomedical subjects

N J Olsen

Publications and source records attributed to N J Olsen.

At least 55 records · Page 3Linked to original sources
PubMed1994

Associations of IgA and IgA-rheumatoid factor with disease features in patients with rheumatoid arthritis.

In previous studies we have shown that levels of IgM-rheumatoid factor (RF) in plasma and peripheral blood mononuclear cell supernatants are correlated with disease activity and response to second-line therapy in patients with rheumatoid arthritis (RA). The present studies were designed to examine whether IgA-RF levels are also correlated with clinical features of this disease. Two groups of RA patients were studied. Group I consisted of 87 patients in whom extensive clinical data had been collected. Group II included nine patients beginning treatment with gold or methotrexate who were studied during the first year of therapy. Measurement of IgM, IgA, IgM-RF and IgA-RF in culture supernatants and plasma was done by an ELISA method. These data were examined for correlations with clinical and laboratory features. Levels of IgA-RF in supernatants and plasma were found not to be correlated with disease features in the cross-sectional analysis of Group I patients, while IgM-RF and total IgA levels did show significant clinical correlation. Treatment of Group II patients with gold or methotrexate was associated with significant decreases in plasma levels of total IgA and IgM-RF as well as a small but statistically significant decrease in plasma IgA-RF. Plasma levels of total IgM were not altered during therapy. These findings suggest that production of IgA but not IgA-RF is correlated with disease status in patients with RA.

Arthritis, Rheumatoid↗
PubMed1993

Effects of administration of an anti-CD5 plus immunoconjugate in rheumatoid arthritis. Results of two phase II studies. The CD5 Plus Rheumatoid Arthritis Investigators Group.

OBJECTIVE: To evaluate the safety and activity of an immunoconjugate of ricin A chain and anti-CD5 monoclonal antibody (anti-CD5 IC), with and without concomitant methotrexate and/or azathioprine, in the treatment of rheumatoid arthritis (RA). METHODS: Seventy-nine patients with active RA were enrolled in 2 prospective open-label protocols. RESULTS: Using composite criteria, response rates were 50-68% at 1 month and 22-25% at 6 months. Transient depletion of CD3/CD5 T cells was observed on days 2 and 5 of treatment, with reconstitution on day 15 or day 29. Treatment-associated adverse effects were common but resolved rapidly without sequelae. CONCLUSION: These findings suggest activity of anti-CD5 IC in active RA and warrant confirmation in a multicenter randomized study (currently underway).

Adult↗
PubMed1993

In vivo T cell depletion in rheumatoid arthritis is associated with increased in vitro IgM-rheumatoid factor synthesis.

T cell depletion has been demonstrated to have therapeutic potential in patients with rheumatoid arthritis and several agents which deplete or inactivate T cells are currently being evaluated in clinical trials. We treated six patients with active rheumatoid arthritis with one such agent, the murine IgG1 anti-CD5 immunoconjugate CD5 Plus, as part of a multicenter trial. Measurement of in vitro synthesis of IgM and IgM-rheumatoid factor by peripheral blood mononuclear cells obtained from patients before, during, and after treatment, was performed using enzyme-linked immunoassays. Subsets of T and B lymphocytes were measured by flow cytometry. Significant T cell depletion was observed on Days 2 and 5 during the treatment period and was associated with increased in vitro rheumatoid factor (RF) production on Days 5 and 8 in 4 of the 5 patients with significant pretreatment levels of RF synthesis. No apparent relationship to serum RF levels or clinical responses was noted. These results implicate a role for T cells in the control of IgM-RF production in patients with rheumatoid arthritis.

Adult↗
PubMed1993

Testosterone induces expression of transforming growth factor-beta 1 in the murine thymus.

Castration of adult male mice results in enlargement of the thymus and diminution of peripheral suppressor T cell function. Replacement therapy with physiologic doses of androgens reverses these phenomena. Although the mediators involved are unknown, these effects of androgens on the thymus and peripheral immune system are reminiscent of those reported for transforming growth factor-beta (TGF-beta 1). We examined expression of TGF-beta 1 mRNA and bioactive protein in thymuses from castrate and androgen-replaced animals. Steady-state levels of thymic TGF-beta 1 mRNA fell slightly after castration, but rose 2.3-fold after testosterone replacement. Bioactive TGF-beta 1 production by cultured thymic explants also fell following castration to approx. 50% of the levels observed in intact animals. Following 1 week of testosterone replacement in castrate animals, TGF-beta 1 bioactivity produced in culture was restored to levels indistinguishable from those observed with explants from intact animals. Reverse transcription/polymerase chain reaction amplification of RNA revealed that thymocytes are a source of the androgen-modulated TGF-beta 1. These results suggest that TGF-beta 1 may mediate effects of androgens on the immune system.

Animals↗
PubMed1993

Variability of immunologic and clinical features in patients with rheumatoid arthritis studied over 24 hours.

Disease activity measures in patients with rheumatoid arthritis (RA) are influenced by many factors. Bedrest has been long recognized to effect decreased disease activity. In addition, most patients note maximal levels of pain and stiffness in the early morning hours with improvement in the afternoon. Cytokines and hormones with circadian rhythms may also contribute to variability in disease status during the day. Our purpose was to investigate variability of clinical and immunologic measures over a 24-h period of hospitalization in patients with RA. Production of rheumatoid factors and immunoglobulins, joint counts and questionnaire evaluations were measured 3 to 6 times over a 24-h period of hospitalization in 10 patients with RA who were not receiving steroids or second line drugs. Total joint counts were significantly decreased as soon as 4 h after admission, and continued to decrease during the 24-h period of observation. Significant decreases in mononuclear cell proliferation and antibody synthesis were also observed. Our findings are consistent with the presence of decreased levels of immunostimulatory mediators in hospitalized patients especially during late afternoon or evening hours.

Activities of Daily Living↗
PubMed1992

Schistosoma mansoni: mortality, pathophysiology, and susceptibility differences in male and female mice.

In parallel studies of Schistosoma mansoni infections in male and female CBA/J mice, major sex-related differences are seen in the development of infection and disease. Upon equal subcutaneous exposures to 45 cercariae female mice present a more severe clinical course with consequent higher mortality than male mice. By 12 weeks of infection, more than 80% of female mice die, while less than 20% of infected males succumb to infection. This greater index of mortality is apparently due to the higher susceptibility of female mice to the development of adult worms. Exposed to 45 cercariae, virtually all females develop patent infections, but 8-34% of male mice do not do so. Also, the recovery rate of adult worms per cercariae from female mice is much higher than that from males, indicating that schistosomula are more successful in developing into adult worms in female mice. Additional studies indicate that this dichotomy of schistosomiasis in the sexes is not restricted to mice of the CBA/J strain, but also occurs in C57BL/6 and outbred CF1 strain mice.

Animals↗
PubMed1992

Lymphocyte-derived adrenocorticotropin is insufficient to stimulate adrenal steroidogenesis in hypophysectomized rats.

Cells of the immune system can produce and respond to peptide hormones associated with the endocrine system. However, the physiological significance of these endocrine-immune interactions is not known. It has been postulated that cells of the immune system, when stimulated with viruses that induce interferon-alpha, produce sufficient levels of ACTH to stimulate adrenal steroidogenesis and, thus, function as an auxiliary source of ACTH that may have a role in the response to stress. However, we have confirmed that levels of ACTH-related peptides produced by immunocompetent cells are far lower than those produced by the pituitary, raising questions about the ability of lymphocyte-derived ACTH to stimulate adrenal function. Furthermore, we have rigorously examined this issue using intact and hypophysectomized rats treated with Newcastle disease virus. Although high levels of interferon-alpha were produced by both intact and hypophysectomized rats, and the plasma corticosterone concentration increased dramatically in intact animals, corticosterone remained undetectable in hypophysectomized rats. The lack of a corticosterone response in these animals was not due to adrenal insensitivity to ACTH, as shown by a normal rise in corticosterone following Cosyntropin injection 8 h after hypophysectomy. The findings demonstrate that levels of ACTH produced by nonpituitary sources in response to viral infection are not sufficient to stimulate adrenal steroidogenesis.

Adrenal Cortex Hormones↗
PubMed1991

Transforming growth factor beta 1 (TGF-beta 1) induced neutrophil recruitment to synovial tissues: implications for TGF-beta-driven synovial inflammation and hyperplasia.

We have studied the consequences of introducing human recombinant transforming growth factor beta 1 (hrTGF-beta 1) into synovial tissue of the rat, to begin to better understand the significance of the fact that biologically active TGF-beta is found in human arthritic synovial effusions. Within 4-6 h after the intra-articular injection of 1 microgram of hrTGF-beta 1 into rat knee joints, extensive recruitment of polymorphonuclear leukocytes (PMNs) was observed. Cytochemistry and high resolution histological techniques were used to quantitate the influx of PMNs, which peaked 6 h post-injection. In a Boyden chamber assay, hrTGF-beta 1 at 1-10 fg/ml elicited a chemotactic response from PMNs greater in magnitude than that evoked by FMLP, establishing that TGF-beta 1 is an effective chemotactic agent for PMNs in vitro as well as in vivo. That PMNs may represent an important source of TGF-beta in inflammatory infiltrates was strongly suggested by a demonstration that stored TGF-beta 1 was secreted during phorbol myristate acetate-stimulated degranulation in vitro. Acid/ethanol extracts of human PMNs assayed by ELISA contained an average of 355 ng of TGF/beta 1 per 10(9) cells potentially available for secretion during degranulation of PMNs. [3H]Thymidine incorporation in vivo and autoradiography of tissue sections revealed that widespread cell proliferation was triggered by TGF-beta 1 injection. Synovial lining cells and cells located deep within the subsynovial connective tissue were identified as sources of at least some of the new cells that contribute to TGF-beta 1-induced hyperplasia. Our results demonstrate that TGF-beta is capable of exerting pathogenic effects on synovial tissue and that PMNs may represent a significant source of the TGF-beta present in synovial effusions.

Animals↗
PubMed1991

Clinical correlations with serum C1q levels in patients with rheumatoid arthritis.

Previous studies have suggested that serum C1q levels measured during the first 5 years of rheumatoid arthritis (RA) may be predictive of the extent of subsequent joint damage. To further evaluate the clinical significance of this marker in RA, levels of C1q were measured by radial immunodiffusion in serum samples from 107 well-characterized patients with RA. Mean levels of C1q were higher in patients with a disease duration less than or equal to 5 years (173 micrograms/ml) than in patients with a disease duration greater than 5 years (148 micrograms/ml) (P = 0.032). Serum C1q levels were correlated with total joint counts and activities of daily living scores, but no correlation was observed with erythrocyte sedimentation rates or with radiographic scores. The results suggest that C1q may be a useful early marker of disease activity in patients with RA.

Arthritis, Rheumatoid↗
PubMed1991

HLA-DPB1*0301 is a major risk factor for rheumatoid factor-negative adult rheumatoid arthritis.

HLA-DPB1 alleles were determined using the polymerase chain reaction and allele-specific oligonucleotide probes in Caucasoid patients with rheumatoid arthritis (RA) and in healthy controls. DPB1*0301 was found to be increased in seronegative patients (50.0% versus 10.8% in controls; relative risk = 8.3, P less than 0.0001). With our previous finding that DPB1*0301 is increased in seronegative children with polyarticular-onset arthritis, the results suggest a relationship between this disease and seronegative RA in adults.

Adult↗
PubMed1991

IgM-rheumatoid factor and responses to second-line drugs in rheumatoid arthritis.

We have examined the relationship between IgM-rheumatoid factor (RF) and responses to second-line drugs in patients with rheumatoid arthritis (RA). Patients with active RA who were beginning treatment with gold, methotrexate or both were studied. Clinical responses were assessed with ESR, joint count, grip strength and activities of daily living questionnaire scores. Production of IgM-RF by peripheral blood mononuclear cells in vitro and plasma levels of IgM-RF were measured by ELISA. Overall, 31 of 44 patients completing more than 6 months treatment improved including 10 treated with gold, 12 with MTX and 9 with both. Production of IgM-RF by peripheral blood mononuclear cells was decreased by 59% in patients who improved on treatment, but increased 2-fold in the unimproved group. Plasma levels of IgM-RF were decreased from 121 to 66 micrograms/ml in the improved group after 6 months of treatment, with similar decreases seen for each of the three treatments. In contrast, plasma IgM-RF levels in the unimproved group did not decrease until 1 year of treatment was completed. Nine patients converted to seronegativity, and all but one of these were in the improved group. The results suggest that IgM-RF is correlated with responses to second-line drug in RA patients.

Adult↗
PubMed1991

Immunogenetics of autoantibodies and autoimmune diseases.

The genetic contribution to the development of autoimmune disease is most likely complex. Along with loci controlling histocompatibility antigens and T-cell receptor proteins, genes that encode autoreactive immunoglobulins may have an important role in the pathogenesis of rheumatoid arthritis and related autoimmune diseases. Although much previous work in this area has concentrated on human monoclonal paraproteins and autoimmune mouse strains, the studies reviewed here examine immunoglobulin genes in the normal human population and normal mouse strains as well as in patients with autoimmune disease. Taken together, these studies suggest that genetic control of the expression of autoimmunity in rheumatoid arthritis and related autoimmune disorders is complex and most likely involves multiple gene loci.

Arthritis, Rheumatoid↗
PubMed1991

Molecular basis of an autoantibody-associated restriction fragment length polymorphism that confers susceptibility to autoimmune diseases.

Recently, combined serological and molecular studies of autoantibodies have revealed that these antibodies play an important role in the normal function of the immune system and in the development of the B cell repertoire. Accordingly, we hypothesized that a homozygous deletion of a critical autoantibody-associated Ig variable (V) gene may alter the immune system and thus predispose the host to autoimmune disorders. Initial experiments revealed several restriction fragment length polymorphisms (RFLP) of the Humhv3005 gene, that is likely to encode heavy chains of rheumatoid factors, and the closely related 1.9III gene. By probing EcoR1-digested DNA with the Humhv3005/P1 probe, we found that one of the four major hybridizing bands was missing in approximately 20% of patients with either rheumatoid arthritis or systemic lupus erythematosus, but only 2% of normal subjects. To delineate the genetic basis of this polymorphism, we have now employed the PCR to amplify and analyze hv3005, 1.9III, and homologous genes in individuals with characteristic RFLP genotypes. Our results indicate that the human Vh gene repertoire contains several hv3005- and 1.9III-like genes, and that a complete deletion of the hv3005-like genes is relatively restricted to a subset of autoimmune patients. These findings provide initial evidence for deletion of developmentally regulated autoreactive V genes in autoimmune diseases.

Amino Acid Sequence↗
PubMed1991

Androgen deprivation induces phenotypic and functional changes in the thymus of adult male mice.

The functional immunological consequences of thymic regeneration after castration were studied in adult male C57Bl/6 mice. Phenotypic profiles of thymocytes present in the enlarged thymuses of castrate animals demonstrated a significant decrease in the proportion of thymocytes positive for the suppressor/cytotoxic phenotype (CD4-CD8+; P = 0.005). Thymic enlargement in castrate animals was accompanied by increased capacity of thymocytes to incorporate thymidine in response to Concanavalin A in vitro. Spleens from castrate mice also were enlarged, and in vitro generation of functional suppressor cells by splenocytes from castrate animals was decreased. Testosterone replacement resulted in thymic regression, with a shift toward expression of mature thymocyte phenotypes, a decrease in the double-positive phenotype (CD4+CD8+), and a relative predominance of the CD4-CD8+ suppressor/cytotoxic phenotype over the CD4+CD8- helper phenotype. Unstimulated thymidine incorporation by thymocytes from androgen-treated animals was decreased compared to controls (P = 0.050). Spleen size was not altered by androgen administration. These findings suggest that in the adult animal, changes in androgen status effect alterations in thymocyte phenotypic profiles and thymocyte function, with removal of androgens shifting the T cell balance toward the CD4 helper subset and administration of androgens changing the balance toward CD8 suppressor/cytotoxic T cell predominance.

Androgens↗
PubMed1991

Studies of immunological function in mice with defective androgen action. Distinction between alterations in immune function due to hormonal insensitivity and alterations due to other genetic factors.

The presence of androgen receptors in thymocytes and the well-described effects of exogenous androgens on thymus size suggest a role for androgenic hormones in thymocyte growth and maturation. Testicular feminization (Tfm/Y) mice which bear a heritable defect in the androgen receptor protein were studied to investigate how androgens might influence immune phenotype and function. These mice were compared to two types of controls; their Tabby/Y normal male littermates and male mice of the C57 Bl/6 strain from which the Tabby and Tfm mice were derived. Thymuses and spleens from Tfm/Y mice were larger than both types of controls. Phenotypic differences in thymocyte and splenocyte subpopulations identified by the T-cell markers CD3, CD4 and CD8 suggested that T-cell maturation was altered in the androgen-resistant animal. However, both Ta/Y and Tfm/Y were found to be high producers of interleukin-4 (IL-4) by both spleen and thymus cells, while cells from the C57 mice produced predominantly IL-2. These findings suggest that some immunological features of the Tfm/Y mouse may be related to its defect in androgen action, but that high levels of IL-4 production are probably related to other genetic changes in the C57 background.

Androgens↗
PubMed1990

HLA-DR alleles with naturally occurring amino acid substitutions and risk for development of rheumatoid arthritis.

To determine the HLA-DR4 subtypes associated with rheumatoid arthritis (RA), we performed amplification of DR4 DRB1 genes by the polymerase chain reaction and dot-blots with oligonucleotide probes. In 52 HLA-DR4+ RA patients, Dw4 was the predominant subtype. This subtype was found in 45 of 52 patients (86.5%) compared with 33 of 59 DR4+ controls (55.9%; P less than 0.001). In the whole population, Dw4 also gave the highest relative risk for RA (RR = 5.31). Relative risk was also associated with DR1.1, the common white DR1 (Dw1) type, which has a third hypervariable region amino acid sequence similar to some forms of DR4 and has glycine at position 86. Variants of DR1 (DR1.2) or DR4 (Dw13.1, Dw14.1) with valine at position 86 appeared less able to confer risk for RA. Substitution of residues in the third hypervariable region of the first domain of DRB1 appeared to correlate with relative risk for RA. Among subjects having 0-1 amino acid substitutions, RA developed in 53%, whereas in subjects with 2-4 amino acid changes, RA was present in only 17.4% (P less than 0.00001). DQw7 (formerly DQw3.1) was slightly increased in DR4+ RA patients compared with controls, but a striking excess of Dw4,DQw7 homozygous patients was observed. The results suggest that DQw7 may have an additional effect, possibly with a recessive mechanism, since it was observed only in DR4 homozygous patients.

Alleles↗