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Biomedical subjects

K Mikecz

Publications and source records attributed to K Mikecz.

49 records · Page 3Linked to original sources
PubMed1990

Proteoglycan-induced polyarthritis and spondylitis adoptively transferred to naive (nonimmunized) BALB/c mice.

Mononuclear cells from BALB/c mice with progressive polyarthritis and spondylitis induced by injection of fetal human articular cartilage proteoglycan (PG) were used to transfer arthritis by intravenous injection into irradiated, nonimmunized syngeneic mice. Successful transfer of arthritis to BALB/c mice required the injection of lymphocytes from mice with arthritis, along with 50 micrograms of human fetal PG, or lymphocytes stimulated in vitro with either fetal human PG or with mouse cartilage PG. In addition, interleukin-2 or immune sera from animals with arthritis significantly reduced the time to onset of transferred disease. The onset of adoptively transferred arthritis, using cells and antigen, from the time of the first injection (38.2 +/- 18.2 days, mean +/- SD) was shortened if lymphocytes from mice with transferred arthritis were reinjected (retransferred) into other, irradiated syngeneic mice (6.1 +/- 2.6 days). The appearance of autoreactive antibodies to mouse cartilage PG in the sera of mice with adoptively transferred arthritis (secondary or tertiary) preceded the appearance of the first clinical symptoms by a few days. The transfer of arthritis was blocked by pretreatment of donor (arthritic) lymphocytes with either anti-T cell or anti-B cell antibodies and complement. Exposure of mononuclear cells from mice with arthritis to PG, and its removal prior to transfer, also resulted in transfer of the arthritis. PG-induced arthritis was not transferred to nonirradiated mice, nor to irradiated mice injected with lymphocytes from animals with primary arthritis without chondroitinase ABC-digested fetal human PG. Arthritis never developed after injection of immune sera from mice with arthritis (without cells), nor when cells of nonarthritic animals were used with chondroitinase ABC-digested fetal human PG, with or without interleukin-2.

Animals↗
PubMed1990

Cartilage proteoglycan-induced arthritis in BALB/c mice. Antibodies that recognize human and mouse cartilage proteoglycan and can cause depletion of cartilage proteoglycan with little or no synovitis.

Human fetal cartilage proteoglycan (PG) induces the development of an erosive polyarthritis and spondylitis in BALB/c mice. We have examined the properties of 3 monoclonal antibodies (MAb) to human fetal cartilage PG isolated from immunized mice that cross-react with mouse cartilage PG. Compared with sera from arthritic mice, which contain antibodies reactive with keratan sulfate, MAb 202 (IgG1) reacted only with a protein-related epitope that is distributed on both hyaluronic acid-binding and chondroitin sulfate-attachment regions. MAb 813 (IgG1) reacted with the same fragments and recognized an epitope with the immunologic characteristics of keratan sulfate. MAb 945 (IgM) remains to be further characterized. Introduction of hybridomas secreting MAb 202 and MAb 945 into irradiated mice resulted in the loss of PG from articular cartilage and from growth plate cartilage (with MAb 202 only), as revealed by a loss of staining with toluidine blue. There was no synovial hyperplasia with MAb 202, but some hyperplasia and mononuclear cell infiltration was seen with MAb 945. This was accompanied by the binding of immunoglobulins to articular cartilage, as demonstrated by immunofluorescence. The hybridoma secreting MAb 813 produced no cartilage changes or synovitis, and there was no immunoglobulin binding to cartilage. Polymorphonuclear leukocyte infiltration was never observed with these antibodies. These studies indicate that MAb reactive with mouse cartilage PG can cause the depletion of PG from hyaline cartilage by mechanisms that may be both complement dependent and complement independent. Antibodies may serve to release and expose PG antigen to immune cells, as well as causing a loss of the mechanical properties of cartilage that are PG dependent.

Animals↗
PubMed1988

Isolation of proteoglycan-specific T lymphocytes from patients with ankylosing spondylitis.

Three T-cell lines and clones of the OKT4 phenotype have been isolated from the peripheral blood of three patients with ankylosing spondylitis. Antigen specificities of T cells were determined with purified protein derivative-(PPD) and cartilage-derived antigens, namely proteoglycans from human articular cartilage and intervertebral disc, bovine nasal cartilage, and rat chondrosarcoma and human type II collagen from cartilage. A cell line from one patient reacted with proteoglycans from human articular cartilage and human intervertebral disc, but the other two cell lines (each from a different patient) and four clones from one of the latter two lines proved to be highly specific for the human articular cartilage proteoglycan. From a study of four proteoglycan specific clones isolated from one patient, it is clear that removal of chondroitin sulfate had no effect on immunoreactivity but digestion of proteoglycan with pronase or alkali/sodium borohydride treatment abolished all reactivity. A OKT4-positive T-cell clone isolated from a healthy adult which was reactive to PPD was used to compare the antigen specificity of cells: this clone showed no reactivity to any of the other putative antigens listed above.

Adult↗
PubMed1987

Proteoglycan-induced arthritis in BALB/c mice. Clinical features and histopathology.

Immunization with chondroitinase ABC-digested fetal human cartilage proteoglycan and Freund's complete adjuvant induced polyarthritis and ankylosing spondylitis in female BALB/c mice. The initial external symptoms of the joint inflammation were swelling and redness. This was associated with edema of the synovium and periarticular tissues and gross proliferation of cells, which reached a peak during weeks 7-9 of the experiment. Mononuclear cell infiltration, with perivascular concentration and occlusion of small vessels, was common. Synovitis increased in severity, villous pannus developed, and erosions of bone, articular cartilage, and occasionally, growth plate were observed. The lumbar spine and the proximal intervertebral discs of the tail also exhibited inflammatory and degenerative changes. As the arthritis progressed, sometimes with acute inflammatory exacerbations, more joints became involved and, by the sixteenth to the twentieth weeks of the experiment, a progressive polyarthritis, with gross joint deformities and restricted function, developed in the majority of the limb joints. Clinical and morphologic features of the disease correlated well with radiologic analysis and with an increased deposition of 99mTc-methylene diphosphonate (determined by radionuclide imaging). The development of this arthritis was accompanied by the expression of cell-mediated and humoral immunity to the immunizing antigen. However, this immunity was also observed, although it was generally less well developed, in mice that received the intact or digested proteoglycan without adjuvant. These mice did not usually develop arthritis. Control mice that received only adjuvant did not develop arthritis.

Animals↗
PubMed1987

Immunity to cartilage proteoglycans in BALB/c mice with progressive polyarthritis and ankylosing spondylitis induced by injection of human cartilage proteoglycan.

Intraperitoneal injection of human fetal cartilage proteoglycan (depleted of chondroitin sulfate) in Freund's complete or incomplete adjuvant induces a chronic erosive polyarthritis and spondylitis in all female BALB/c mice. This occurrence is strain-specific but not haplotype-specific, and it is sex-related. The development of the arthritis is associated with the natural presence of cellular immunity to the immunizing antigen and to chondroitinase ABC-treated mouse cartilage proteoglycan. In addition, relatively more antibody to the immunizing proteoglycan is elicited in arthritic mice, and antibodies are produced that cross-react with native mouse proteoglycan. This combination of immune responses is not observed in mice that do not develop arthritis. Associated with the arthritis is the development of cytotoxicity to mouse chondrocytes and, in some animals, of rheumatoid factor, immune deposits in joint tissues and kidneys, and the production of autoantibodies to mouse type II collagen. These observations might be related to our earlier demonstration that immunity to human cartilage proteoglycan is observed in some patients with ankylosing spondylitis.

Adult↗
PubMed1986

Age-related changes in protein-related epitopes of human articular-cartilage proteoglycans.

Monoclonal antibodies were prepared that recognize different age-related epitopes on proteoglycan subunits of high buoyant density isolated from human epiphysial and articular cartilages. Antibody EFG-4 (IgG1) recognizes a proteinase-sensitive segment associated with the core protein. Antibody BCD-4 (IgG1) reacts with keratan sulphate bound to core protein. Both epitopes are minimally expressed in foetal cartilage and increase with age after birth to become maximally expressed in adult cartilage by about 30 years of age. In contrast, monoclonal antibody alpha HFPG-846 (IgM) recognizes a core-protein-related epitope that is maximally expressed in young foetal cartilage, declines up to birth and thereafter and is almost absent after about 30 years of age. Antibody alpha HFPG-846 was used to isolate by immuno-affinity chromatography two subpopulations of proteoglycan subunits from a 16-year-old-human cartilage proteoglycan subunit preparation. Only the antibody-unbound population showed a significant reaction with antibodies EGF-4 and BCD-4. The amino acid and carbohydrate compositions of these proteoglycan fractions were different, and one (antibody-bound) resembled those of foetal and the other (antibody-unbound) resembled those of adult proteoglycans isolated from 24-27-week-old-foetal and 52-56-year-old-adult cartilage respectively. These observations demonstrate that human cartilages contain at least two chemically and immunochemically distinct populations of proteoglycans, the proportions and content of which are age-dependent. It is likely that these populations represent the products of different genes, though their heterogeneity may be compounded by the result of different post-translation modifications.

Adolescent↗
PubMed1986

Monoclonal antibodies to different protein-related epitopes of human articular cartilage proteoglycans.

Monoclonal antibodies produced against chondroitinase-treated human adult cartilage proteoglycans were selected for their ability to recognize epitopes on native proteoglycans. Binding analyses revealed that four of these monoclonal antibodies (BCD-4, BCD-7, EFG-4 and KPC-190) each recognized a different epitope on the same proteoglycan molecule which represents a subpopulation of a high buoyant density (D1) fraction of human articular cartilage proteoglycans (10, 30, 50 and 60% in fetal-newborn, 1.5 years old, 15 years old and 52-56 years old cartilages, respectively). Analysis of epitope specificities revealed that BCD-7 and EFG-4 monoclonal antibodies recognized epitopes on proteoglycan monomer which are associated with the protein structure in that they are sensitive to cleavage by Pronase, papain and alkali treatment and do not include keratan sulphate, chondroitin sulphate or oligosaccharides. The BCD-4 and KPC-190 epitopes also proved to be sensitive to Pronase or papain digestion or to alkali treatment, but keratanase or endo-beta-galactosidase also reduced the immunoreactivity of these epitopes. These observations indicate that the BCD-4 and KPC-190 epitopes represent peptides substituted with keratan sulphate or keratan sulphate-like structures. The BCD-4 epitope is, however, absent from a keratan sulphate-rich fragment of human adult proteoglycan, while the other three epitopes were detected in this fragment. None of these four epitopes were detected in the link proteins of human cartilage, in the hyaluronic acid-binding region of human newborn cartilage proteoglycan, in Swarm rat chondrosarcoma proteoglycan, in chicken limb bud proteoglycan monomer and in the small dermatan sulphate-proteoglycan of bovine costal cartilage. EFG-4 and KPC-190 epitopes were not detected in human fetal cartilage proteoglycans, although fetal molecules contained trace amounts of epitopes reactive with BCD-4 and BCD-7 antibodies.

Age Factors↗
PubMed1986

Antigenic profiles of human, bovine and canine articular chondrocytes.

Human, bovine and canine articular chondrocytes have been shown to bear cartilage matrix, chondrocyte-specific and histocompatibility antigens. These cell-surface antigens of chondrocytes were demonstrated both simultaneously and separately either by complement-mediated cytotoxicity or by immunohistochemical reactions. The chondrocyte-specific antigens involve subsets of species-common and species-specific determinants, which are also present on the surfaces of rib and laryngeal chondrocytes. In addition to these antigens, human and calf articular chondrocytes also express unique cell-surface components that are capable of producing a blastogenic stimulation of autologous T-lymphocytes in vitro. These putative autoantigens segregated from lymphocytes in vivo could be released in trauma and in inflammatory joint diseases triggering the immune system of the host.

Animals↗
PubMed1985

Appearance and persistence of fibronectin in cartilage. Specific interaction of fibronectin with collagen type II.

Binding of fibronectins (FN) to collagen types I-IV were studied using polyclonal antibodies against human and chicken FNs, proteoglycan monomers, collagen type II and monoclonal antibodies reacting with both soluble and insoluble forms of human FN. Plasma fibronectin and type II collagen were shown to interact specifically in a homologous system. Type II collagen, however, proved to be less effective in inhibition assays compared to other types of collagen. In high density cultures of chicken limb bud cells, fibronectin was first localized within the fibroblast-like cells of 4 hr cultures and an extensive extracellular filamentous network developed by the end of day 1. Fibronectin was present in the newly formed cartilage nodules although it seemed to disappear by day 6, when the proteoglycan accumulation became more intensive. Enzyme treatments (testicular hyaluronidase, chondroitinase ABC) helped to localize FN at this stage of development of chicken cartilage, in microdroplet high density cultures of human fetal chondrocytes and in articular cartilage. Fibronectin was localized only in the pericellular ring of intact human articular cartilage using monoclonal antibodies with the biotin-avidin system.

Animals↗
PubMed1985

Serum IgE level in systemic lupus erythematosus.

The serum total-IgE level has been studied in systemic lupus erythematosus (SLE), in order to obtain data concerning the significance of IgE antibodies in the appearance of SLE symptoms. In most patients the serum IgE content was significantly higher in the active stage of the disease than during remission. The findings indicated a specific statistical distribution due to the multiple factors influencing IgE production and so an augmented IgE level cannot be regarded as a reliable feature of SLE activation.

Humans↗
PubMedDate not supplied

Immunomodulation of proteoglycan-induced progressive polyarthritis by leflunomide.

Proteoglycan-induced arthritis is a mouse model displaying many similarities to human rheumatoid arthritis and ankylosing spondylitis which has been documented by clinical and histopathological studies. The development of the disease in genetically susceptible BALB/c mice is dependent upon the expression of both cell-mediated and humoral immunity to host mouse cartilage proteoglycan. Since both development and regression of acute inflammatory processes in joints correlate directly with the serum antibody level to mouse cartilage proteoglycan, it is believed that these autoreactive antibodies may play a key role in the pathological mechanism of proteoglycan-induced arthritis. The treatment of arthritic animals with an immunomodulating agent (leflunomide) suppressed acute inflammatory events, protected animals from new inflammatory episodes or acute exacerbations in chronically inflamed joints and blocked pathological processes in arthritic joints, which otherwise led to progressive deformities, ankylosis and the loss of articular cartilage. We conclude that the suppressive effect of leflunomide (HWA 486) in proteoglycan-induced arthritis primarily is due to the suppression of autoantibody formation and that the drug may be a potential agent in human therapy as well. Further, we feel that this novel model of murine polyarthritis will extend further the pharmacological repertoire necessary to discover innovative antirheumatic drugs.

Animals↗