Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0003864 (arthritis)
 69,039 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Intra-articular injection of streptococcal cell wall Ag followed by i.v. challenge ("reactivation") results in a destructive lymphocyte-dependent monoarticular arthritis. To further define the role of immune mechanisms in the model, Abs to Th1 and Th2-related cytokines were evaluated. Treatment of rats with antibodies to IL-4 reduced swelling, while treatment with anti-IL-10 or anti-IFN-gamma either had no effect or slightly enhanced the inflammatory response. These results suggest that Th-2 immune mechanisms may be, at least in part, operative in the model. To more precisely define the role of IL-4, the effects of anti-IL-4 on monocyte chemoattractant protein-1 (MCP-1) expression were evaluated. Initial studies demonstrated that mRNA (as determined by in situ hybridization) and protein (as determined by immunofluorescence) for MCP-1 were detectable in inflamed synovial tissue in a time-dependent manner. Anti-IL-4 treatment significantly reduced the expression of mRNA for MCP-1 24 and 72 h after reactivation. In addition, anti-MCP-1 inhibited swelling and reduced influx of (111)In-labeled T cells. These data suggest that the reactivation model of streptococcal cell wall Ag-induced arthritis is Th-2 dependent, and that an inter-relationship exists between IL-4 and the expression of MCP-1.
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PMID:Streptococcal cell wall-induced arthritis: requirements for IL-4, IL-10, IFN-gamma, and monocyte chemoattractant protein-1. 957 May 68

Previous studies showed that mice with pristane-induced arthritis (PIA) and those protected from the disease by preimmunization with mycobacterial 65-kDa heat shock protein (hsp65) possess raised immune responses to hsp65. Additionally, T cells from hsp65-protected mice, but not from pristane-injected or normal mice, produced the Th2-associated cytokines IL-4, IL-5, and IL-10 in response to stimulation with hsp65. Here we demonstrate that the specificity of the immune response to hsp65 and related heat shock protein (hsps) differs between protected and PIA mice. T cells from hsp65-protected mice respond to the bacterial hsps tested but not to the mammalian homologue, hsp58. Similarly, they exhibit high serum titers of anti-hsp65 Abs, yet they have virtually undetectable levels of anti-hsp58 IgG. By contrast, both cellular and humoral immune responses are detectable to bacterial and mammalian hsps in mice with PIA. An immunodominant T cell epitope has been identified in hsp65-protected mice corresponding to amino acids 261-271 from hsp65. Immunization of mice, either before or after the induction of arthritis, with this bacterial peptide, but not its mammalian homologue, protects mice from the development of PIA, and protection is associated with the production of Th2-type cytokines. Other experiments revealed that T cells primed with bacterial 261-271 or the mammalian homologue do not cross-react at the proliferative or cytokine level. These results demonstrate that an hsp65 peptide-specific Th2 response confers protection from PIA but do not support the idea that protection is mediated by a cross-reaction with self hsp58 in the joints.
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PMID:An immunodominant epitope from mycobacterial 65-kDa heat shock protein protects against pristane-induced arthritis. 957 71

Lack of IL-4 has been shown to be protective in some experimental models of infectious diseases in mice such as cutaneous leishmaniasis. At the same time IL-4, together with other Th2 cytokines, including IL-10 and IL-13, is known as an anti-inflammatory cytokine with the potential to down-regulate proinflammatory cytokine production. To investigate the role of IL-4 in experimental Staphylococcus aureus-induced and T lymphocyte-mediated arthritis, IL-4-deficient C57BL/6 mice (IL-4(-/-)) and their congenic controls (IL-4(+/+)) were inoculated with a toxic shock syndrome toxin-1-producing S. aureus strain. In IL-4(+/+) mice, arthritis peaked 14 days after bacterial inoculation, whereas, at that time, IL-4(-/-) mice displayed significantly less frequent (p < 0.05) joint inflammation. Paralleling lower frequency of arthritis, IL-4-deficient mice showed a decreased bacterial burden in joints (p = 0.014) and kidneys (p = 0.029), as well as lower infection-triggered weight decrease and mortality. In vitro, IL-4 inhibited intracellular killing of S. aureus in infected macrophages, without affecting phagocytosis. This finding may explain the enhanced staphylococcal clearance observed in IL-4(-/-) mice in vivo. Our results suggest that IL-4 and IL-4-dependent Th2 responses promote septic arthritis and sepsis-related mortality by inhibition of bacterial clearance during S. aureus infection.
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PMID:Staphylococcus aureus-induced septic arthritis and septic death is decreased in IL-4-deficient mice: role of IL-4 as promoter for bacterial growth. 959 Feb 59

IL-10 is a potent anti-inflammatory cytokine that has received growing attention for its therapeutic potential. We examined the efficiency of adenoviral-mediated gene transfer of IL-10 on the incidence and severity of murine collagen-induced arthritis (CIA). Male DBA1 mice immunized with collagen II were treated by systemic administration of 10(9) plaque-forming units of replication-defective adenoviral vector expressing viral IL-10 (vIL-10) on day 30, when clinical symptoms of arthritis start. The transgene was shown to inhibit the onset of CIA, to decrease severity, and profoundly suppress the overall joint histopathology of the experimental arthritis. Significant IL-10 concentrations were obtained in the serum of injected animals for 7 days. Inhibition of arthritis was enhanced by administration of increasing doses of adenovirus-vIL-10. In addition, the local immunosuppressive effect of gene-delivered vIL-10 could be neutralized by a monoclonal anti-vIL-10 Ab. The CIA symptoms in the group treated with the same construct expressing inactive vIL-10 (vIL-10 mut) were similar to those in untreated animals. Our data indicate that a single systemic administration of an adenoviral vector encoding vIL-10 may be a good candidate to suppress arthritis.
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PMID:Adenovirus-mediated transfer of viral IL-10 gene inhibits murine collagen-induced arthritis. 960 16

In the present study, we investigated the kinetics and the activation thresholds for the production of a number of pro-inflammatory cytokines and cytokine antagonists in Escherichia coli lipopolysaccharide (LPS) or phytohaemagglutinin (PHA) stimulated whole blood cultures of 13 patients with systemic juvenile chronic arthritis (SJCA) and 10 healthy children. In unstimulated cultures, the levels of interleukin (IL)-1beta, IL-6 and tumour necrosis factor alpha (TNF-alpha) were undetectable in both groups, suggesting that there was no spontaneous production of these cytokines by circulating leucocytes. The activation thresholds for the production of these cytokines, as well as the capacity for production, did not differ significantly between patients and controls. The level of interleukin-1 receptor antagonist (IL-1ra) in plasma of the patients was significantly elevated, while the in vitro production of IL-1ra was essentially normal and it did not correlate with plasma levels of IL-1ra. Supernatant levels of soluble TNF-alpha receptor (sTNF-R) I and II were both significantly elevated and correlated with the global activity score. In contrast, the supernatant levels of IL-10 were reduced in both PHA- and LPS-driven cultures. Although IL-10 levels did not correlate with laboratory or clinical indices of disease activity, the results suggest that reduced IL-10 production may play a pathogenetic role in SJCA.
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PMID:Inflammatory cytokines and cytokine antagonists in whole blood cultures of patients with systemic juvenile chronic arthritis. 965 Oct 86

Autoimmune arthritides are characterized by an imbalance between pro- and anti-inflammatory cytokines. Viral IL-10 (vIL-10) shares many of the anti-inflammatory properties of mouse and human IL-10, but lacks their immunostimulatory properties and may therefore offer superior immunosuppression. Viral IL-10 has a short half-life; however, genetic modification of cells in vivo offers a potential means of achieving prolonged therapeutic titers. To determine the effects on collagen-induced arthritis of vIL-10 gene transfer, DBA/1 mice were administered i.v. or intra-articular injections of Av(vIL-10), a replication-deficient adenovirus encoding vIL-10. The i.v. injection of Av(vIL-10) before disease onset delayed the onset and reduced the severity of collagen-induced arthritis, but treatment of established disease was ineffective. The preventative effects were not due to decreased anti-type II collagen Ab production. Rather, T cells from mice treated with Av(vIL-10) demonstrated a decreased in vitro proliferative response to type II collagen, and a delay was observed in up-regulation of synovial mRNA for the proinflammatory cytokines IL-2 and IL-1beta. Intra-articular injection of Av(vIL-10) into knee joints did not reduce arthritis in the knees, but inhibited the development of arthritis in the paws. Humoral and cellular immune responses against Av(vIL-10) were observed. These results demonstrate that vIL-10 can significantly alter the course of autoimmune arthritis and emphasize the complexities of using gene transfer as a method of drug delivery for arthritis.
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PMID:Inhibition of collagen-induced arthritis in mice by viral IL-10 gene transfer. 968 19

IL-10 has anti-inflammatory and immunoregulatory properties that suggest a potential therapeutic role in RA. IL-10 inhibits proinflammatory cytokine and chemokine production in addition to blocking T-cell responses to specific antigens. It acts primarily through inhibition of costimulatory properties of macrophages. IL-10 stimulates proliferation and differentiation of antibody-forming B-cells. Preclinical studies in a variety of animal models, including collagen-induced arthritis, have shown that IL-10 is effective in preventing or inhibiting inflammation and autoreactivity. Although in RA, circulating and synovial levels of IL-10 are increased, accumulated evidence suggests that there may be a relative deficit of available IL-10. Moreover, exogenous addition of IL-10 in vitro has been shown to affect the immunopathological processes involved in RA. Preliminary studies of human recombinant IL-10 in patients with RA have demonstrated a trend towards efficacy with a good safety profile. Taken together, the data support a therapeutic role for IL-10 in the treatment of RA.
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PMID:IL-10 as a therapeutic strategy in the treatment of rheumatoid arthritis. 971 Aug 91

The role of cytokines in leukemic arthritis is unknown. The presentation of a patient with B cell chronic lymphocytic leukemia and destructive arthritis of the wrist joints prompted us to study the synovial cytokine pattern by immunohistologic analysis. In addition, rearranged V(H) and V(L) immunoglobulin genes were sequenced to assess B cell clonality. Heavy infiltrations of CD20+ cells with lambda light chain restriction were found in the synovial tissue. Sequencing demonstrated overexpansion of a single B cell clone (DP58/D/J(H)4b and IGLV3S2/Jlambda2-Jlambda3 for V(H) and V(L), respectively) in the peripheral blood. Identical V(H) and V(L) rearrangements were found in the synovial infiltrates. Somatic mutations were found in both the peripheral blood and the synovial clone. Immunohistologic study revealed the presence of abundant interleukin-1beta (IL-1beta) and, to a lesser degree, tumor necrosis factor beta (TNFbeta) (lymphotoxin). In contrast, TNFalpha, interferon-gamma, IL-4, IL-6, and IL-10 were rarely found in the synovial infiltrates. Therefore, IL-1beta secreted in great amounts by leukemic B cells appears to be the major cytokine that mediates joint destruction in leukemic arthritis.
Arthritis Rheum 1998 Sep
PMID:Overexpanded B cell clone mediating leukemic arthritis by abundant secretion of interleukin-1beta: a case report. 1021 9

Immunization of susceptible strains of mice with type II collagen (CII) elicits an autoimmune arthritis known as collagen-induced arthritis (CIA). One analogue peptide of the immunodominant T cell determinant, A9 (CII245-270 (I260-->A, A261-->B, F263-->N)), was previously shown to induce a profound suppression of CIA when coadministered at the time of immunization with CII. In the present study, A9 peptide was administered i.p., orally, intranasally, or i.v. 2 to 4 wk following CII immunization. We found that arthritis was significantly suppressed even when A9 was administered after disease was induced. To determine the mechanism of action of A9, cytokine responses to A9 and wild-type peptide A2 by CII-sensitized spleen cells were compared. An increase in IL-4 and IL-10, but not in IFN-gamma, was found in A9 culture supernatants. Additionally, cells obtained from A9-immunized mice produced higher amounts of IL-4 and IL-10 when cultured with CII compared with cells obtained from mice immunized with A2, which produced predominantly IFN-gamma. Suppression of arthritis could be transferred to naive mice using A9-immune splenocytes. Lastly, phosphorylation of TCRzeta was not altered in the immunoprecipitates from the lysates of cells exposed to analogue peptides (A9 and A10) together with wild-type A2 in a T cell line and two I-Aq-restricted, CII-specific T hybridomas. We conclude that analogue peptide A9 is effective in suppressing established CIA by inducing T cells to produce a Th2 cytokine pattern in response to CII.
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PMID:Characterization of a peptide analog of a determinant of type II collagen that suppresses collagen-induced arthritis. 975 81

Oral administration of autoantigens can influence the outcome of experimental autoimmune diseases, yet little is known about nonself Ag-induced tolerance. In this study, we administered group A streptococcal cell wall (SCW) peptidoglycan-polysaccharide complexes orally and monitored the impact on SCW-induced erosive polyarthritis. Oral administration of low dose SCW (3 microg/day), initiated 7 days before an arthritogenic dose of systemic SCW, virtually eliminated the joint swelling and destruction typically observed during both the acute and chronic phases of the arthritis. High (300 microg), but not intermediate (30 microg), dose regimens also profoundly inhibited the disease. Most previous studies have demonstrated that prior feeding is required for efficacy, yet oral feeding of low dose SCW suppressed the evolution of arthritis even when administration was begun 10-15 days after induction of the arthritis. While the synovial inflammatory cell infiltration and expression of proinflammatory cytokines were markedly suppressed, no local enhancement of the regulatory cytokines IL-4, IL-10, and TGF-beta was detected. Oral administration of low dose SCW, however, up-regulated circulating levels of TGF-beta, concomitant with decreased circulating TNF-alpha and suppression of chronic arthritis. Moreover, IL-10 was increased in tolerized spleen lymphocytes, and unexpectedly, this SCW-specific IL-10 production was TGF-beta dependent. These data support a pivotal role for TGF-beta, although not necessarily in the joint, in the regulation of specific immune tolerance responsible for suppressed synovial inflammation and matrix destruction. The distant induction and up-regulation of regulatory cytokines and/or cells may contribute to the inhibition of the immune response through blunted infiltration of inflammatory cells to the joint.
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PMID:Oral delivery of group A streptococcal cell walls augments circulating TGF-beta and suppresses streptococcal cell wall arthritis. 983 19


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