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)

By the introduction of single-amino acid substitutions in well-defined T cell epitopes of autoimmunogenic proteins, e.g., mycobacterial heat shock protein (hsp60) in adjuvant arthritis (AA) and myelin basic protein (MBP) in experimental allergic encephalomyelitis (EAE), efficiently blocking MHC binding peptides were selected. Despite the finding that a substituted variant of epitope 180-188 of hsp60 was 'blocking' not only responses of the 180-188 specific arthritogenic T cell A2b, but also responses of the MBP specific encephalitogenic T cell Z1a, in vivo testing of this competitor peptide revealed a very prominent disease inhibitory activity in AA but not in MBP-induced EAE. The selectivity of this peptide in suppressing the disease in which native 180-188 appears to be of critical relevance, offers the possibility of achieving disease specific immunological intervention. Based on the results collected so far, it seems that, in vivo in addition to blocking activity, a variant peptide itself could trigger responses that confer protective activity in AA. Such combined activities may well be required for achieving full in vivo inhibition of a disease in which multiple distinct epitopes may play a role, possibly through presentation by more than one MHC product.
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PMID:Towards peptide immunotherapy in rheumatoid arthritis: competitor-modulator concept. 138 Feb 44

Nonobese diabetic (NOD) mice spontaneously develop an autoimmune form of diabetes associated with insulitis. A number of immunomodulatory therapies have been investigated as a treatment for the disease process. Oral administration of the autoantigens myelin basic protein and collagen type II suppresses experimental models of encephalomyelitis and arthritis. We have now found that oral administration of insulin delays the onset and reduces the incidence of diabetes in NOD mice over a 1-year period in animals administered 1 mg of porcine insulin orally twice a week for 5 weeks and then weekly until 1 year of age. As expected, orally administered insulin had no metabolic effect on blood glucose levels. The severity of lymphocytic infiltration of pancreatic islets was also reduced by oral administration of insulin. Furthermore, splenic T cells from animals orally treated with insulin adoptively transfer protection against diabetes, demonstrating that oral insulin administration generates active cellular mechanisms that suppress disease. These results show that oral insulin affects diabetes and the pancreatic cellular inflammatory process in the NOD mouse and raise the possibility that oral administration of insulin or other pancreatic autoantigens may provide a new approach for the treatment of autoimmune diabetes.
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PMID:Suppression of diabetes in nonobese diabetic mice by oral administration of porcine insulin. 194 45

Adjuvant arthritis is induced by intradermal injection of Mycobacterium tuberculosis (MT) in oil. The role of immunity to type II collagen (CII) in adjuvant arthritis (AA) has not been well defined. We found that oral administration of chicken CII given 3 micrograms per feeding on days -7, -5, and -2 before disease induction consistently suppressed the development of AA. A decrease in delayed-type hypersensitivity responses to CII was also observed that correlated with suppression of AA. AA was optimally suppressed by 3 and 30 micrograms of collagen type II variably by 300 micrograms, and not by 0.3 microgram or 1 mg. Oral administration of collagen type I also suppressed AA; only minimal effects were seen with collagen type III. Suppression was Ag specific: feeding CII did not suppress experimental autoimmune encephalomyelitis; feeding myelin basic protein suppressed experimental autoimmune encephalomyelitis, but not AA. Suppression of AA could not be consistently obtained by feeding MT. Suppression of AA could be adoptively transferred by T cells from CII fed animals and could be obtained when CII was fed after disease onset. Our results suggest that autoimmunity to CII has a pathogenic role in AA and raise the possibility that cross-reactive epitopes exist between CII and MT. Alternatively, the pathogenesis of AA may be dependent on developing immunity to CII. These results further demonstrate the effectiveness of oral tolerance as a means to suppress experimental autoimmune diseases.
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PMID:Suppression of adjuvant arthritis in Lewis rats by oral administration of type II collagen. 212 Mar 32

DA rats develop transient arthritis after subcutaneous immunization with adjuvant-oil, while chronic arthritis and collagen autoreactivity ensues when collagen is added to the oil. We show here that DA rats can be protected from oil-induced arthritis (OIA) and rat collagen-induced arthritis (rCIA) by addition of antigen to these arthritogenic inocula. We have investigated this remarkable phenomenon and demonstrate that both foreign and self antigens can be protective, apparently provided they are immunogenic; hence HSP-65kDa, ovalbumin, rat myelin basic protein, rat IgG and bovine albumin are effective while rat albumin is not. This protection is long-lasting and disease-specific because rats protected from rCIA resist a later attempt to induce arthritis, but not experimental autoimmune encephalomyelitis (EAE). Protection from rCIA depends neither on the blocking of humoral autoreactivity to collagen nor on a change in the isotype profile of anti-collagen antibodies. We demonstrate that immunogens can also be protective when injected intraperitoneally only a few days before onset of arthritis. Our results indicate that protection is mediated through bystander immune reactions towards the co-immunized antigen and that the arthritogenicity of a given provocation, be it adjuvants, microbes or autoantigens, may be a complex net result of arthritogenic and contra-arthritogenic immune reactions.
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PMID:Specific and long-lasting protection from collagen-induced arthritis and oil-induced arthritis in DA rats by administration of immunogens. 754 14

Oral desensitization or oral tolerance is induced by giving antigenic peptides by the mucosal route. In man only the oral route has been used up to now. Experiments in animal models of human autoimmune diseases, have shown that it is not necessary to use the primary antigen responsible for disease induction. Antigens implicated in secondary immune phenomenon can act similarly by means of the so-called "bystander suppression". Thus for diseases such as multiple sclerosis (MS) and rheumatoid arthritis (RA) candidate antigens for desensitization are available. Many patients with MS have immunity to myelin basic protein (MBP). A recent controlled trial giving MBP to patients with MS is discussed (Weiner et al., Science 259, p. 1321, 1993). No clear-cut effect was obtained. Collagen II is used to induce experimental arthritis in rats; signs of immunity against it can be found in patients with RA. Collagen-induced arthritis has been successfully modified in animals by feeding of collagen II. In man one open uncontrolled trial and one other placebo controlled blind trial have been reported, and these are discussed (Trentham et al., Science 261, 1727, 1993). These trials suggest that oral desensitization might be useful and devoid of side effects. Subreum is a peptic E. coli extract containing heat shock protein 60. Its efficacy as a disease-controlling agent in RA has been documented (Clin. Exp. Rheum. 11, p. 121, 1993). It is given orally. Data suggesting that Subreum acts by oral desensitization are discussed. Considering the low incidence of side effects observed with oral desensitization, this therapeutic approach should also be tested in other forms of arthritis and other inflammatory diseases.
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PMID:Oral desensitization in the treatment of human immune diseases. 754 38

T cells play a critical role in the development of collagen-induced arthritis (CIA). Immunization with heterologous (chick) type II collagen (cII) results in chronic inflammation with progressive damage to the joints. The expression of specific MHC Class II alpha beta dimers, including IAq, is critical to induction of disease. The alpha chains of IAq and IAp are identical in sequence. The IAq and IAp beta chains differ by only four amino acid residues: 85, 86, 88, and 89. However, mice of the H-2p haplotype are not susceptible to CIA. To examine the impact of these structural differences in IA molecules on T cell Ag recognition, we studied presentation of cII peptides and denatured cII by APCs obtained from H-2q and H-2p mice. We also assessed presentation of ovalbumin, myelin basic protein (MBP), and MBP peptides by these APC populations. H-2q APCs presented both peptides and proteins to our T cell hybrids. In contrast, APCs obtained from H-2p mice presented peptides, but were defective in the processing and/or presentation of protein Ags. We then altered pairs of the residues in IAq to those found in IAp using site-directed mutagenesis and transfected these constructs into M 12.C3 B cells. All transfectants were able to present peptides, but those expressing IAp were unable to present protein Ags. The use of transfectants expressing hybrid molecules (residues 85 and 86 from IAp, 88 and 89 from IAq, or vice versa) allowed us to localize the region responsible for this defect to residues 85 and 86 of the beta chain. The presence of IAp residues (glu and thr versus gly and val in IAq) at these sites severely compromised the capacity for protein presentation. Resistance to CIA in H-2p haplotype mice may be a reflection of the limited repertoire of epitopes to which these mice can respond relative to susceptible H-2q mice.
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PMID:Polymorphism in the beta chain of IAq versus IAp influences presentation of protein but not peptide antigens. 755 84

We have earlier described a chronic relapsing experimental autoimmune encephalomyelitis (EAE) in B10.RIII mice induced with a peptide of myelin basic protein (MBP), mimicking the course of multiple sclerosis in man. We now show that estrogens ameliorate chronic EAE. Castration of female mice led to an earlier disease onset (day 9 +/- 2 postimmunization (p.i.) in castrated mice vs. day 16 +/- 4 p.i. in normal mice). Long-term treatment with high levels of 17 beta-estradiol (E2) given as Silastic implants led to a dramatically delayed onset of disease in both castrated and normal female mice (mean onset day was day 39 +/- 14 and day 50 +/- 3, respectively). Treatment of castrated females by injections of E2, at a concentration which induces the serum levels seen at late stage pregnancy, delayed the onset approximately 1 week (mean onset 21 +/- 8). In contrast, treatment with estriol (E3), which was also given at doses corresponding to those levels seen during pregnancy, delayed the disease onset for a longer time (mean onset day 31 +/- 5). Five times higher doses of E2, compared with those seen during pregnancy, were required to obtain similar effects as the low E3 dose. The same mouse strain (B10.RIII) is also susceptible to induction of collagen-induced arthritis (CIA). We show here that also CIA is suppressed by the same treatments with E2 and E3, suggesting that similar estrogen-mediated mechanisms may operate to suppress these T-cell-dependent autoimmune disease models.
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PMID:Estrogen induces a potent suppression of experimental autoimmune encephalomyelitis and collagen-induced arthritis in mice. 807 34

Lewis rats undergo a relapsing paralytic disease upon challenge with spinal cord emulsified in complete Freund's adjuvant (CFA). Treatment with two intracardiac injections of liposomes composed of whole myelin significantly reduced the severity of disease. Protection was disease-specific since treatment with myelin liposomes did not protect Lewis rats against adjuvant arthritis (AA), a CNS-unrelated T-cell-mediated autoimmune disease. Myelin-liposome-treated, spinal cord/CFA-immunized rats displayed borderline reduction of delayed-type hypersensitivity (DTH) (ear swelling) reactions to myelin and myelin basic protein (MBP), but significantly reduced in vitro lymphnode cell proliferation in response to these antigens. Responses to purified protein derivative of Mycobacterium tuberculosis (PPD) were not reduced, emphasizing the antigen-specific nature of the myelin-liposome-mediated suppression. Spleen cell proliferative responses were inconsistent and often poor. However, when cultured in the presence of NG-monomethyl-L-arginine (MMA), antigen-specific proliferation of spleen cells from both treated and control rats was greatly enhanced, indicating that reactive nitrogen intermediates contributed to the decrease in spleen cell proliferation. Purified splenic T cells from treated rats displayed a pattern of proliferation similar to that of unseparated lymphnode cells. Treatment of rats with a single injection of myelin liposomes after recovery from the first clinical episode significantly reduced the severity of the relapses.
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PMID:Myelin-liposome protection against experimental autoimmune encephalomyelitis is associated with reduced neuroantigen-specific T-cell-mediated responses. 842 33

Antigen-driven tolerance is an effective method of suppressing cell-mediated immune responses. We have previously demonstrated that exposure of gut-associated lymphoid tissue to myelin basic protein (MBP) via oral administration suppresses experimental autoimmune encephalomyelitis (EAE). To further study presentation of antigen to the immune system by mucosal surfaces as a method of antigen-driven tolerance, the effect of inhalation of MBP was investigated. MBP was given as an aerosol to Lewis rats on Days -10, -7, -5, and -3 prior to immunization with MBP in Freund's adjuvant and on Days 0, 2, and 4 following immunization. Aerosolization of MBP completely abrogated clinical EAE in 100% of treated rats. Central nervous system inflammation and delayed-type hypersensitivity and antibody responses to MBP were also significantly reduced in aerosol-treated animals. Aerosolization of histone, a basic protein of similar weight and charge as MBP, had no effect. Disease was also suppressed with one aerosol treatment on Day -3 or by administering MBP nasally. Aerosolization was more effective than oral administration of MBP over a wide dose range (0.005-5 mg). Splenic T cells isolated from animals postaerosolization adoptively transferred protection to naive animals immunized with MBP. Aerosolization of MBP to animals with relapsing EAE after recovery from the first attack decreased the severity of a subsequent attack. Aerosol and oral MBP were equally effective at suppressing the in vitro immune response as measured by proliferation and interferon-gamma production. We then tested aerosolization of a different autoantigen in a different disease model and found that aerosolization of type II collagen was effective in suppressing collagen-induced arthritis. Thus, aerosolization of an autoantigen is a potent method to downregulate an experimental T cell-mediated autoimmune disease and suggests that exposure of antigen to lung mucosal surfaces preferentially generates immunologic tolerance.
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PMID:Antigen-driven peripheral immune tolerance: suppression of experimental autoimmmune encephalomyelitis and collagen-induced arthritis by aerosol administration of myelin basic protein or type II collagen. 866 Aug 45

Multiple sclerosis (MS) is a chronic demyelinating disease of the human central nervous system (CNS) which can be characterized clinically by a remitting-relapsing or a chronic progressive course. There is a striking similarity between the clinical and histopathological features of MS and the experimentally induced disease, experimental autoimmune encephalomyelitis (EAE). Induced by the injection of myelin basic protein (MBP) and adjuvants, EAE is characterized by clinical neurologic signs of paralysis and histopathologic changes consisting of perivascular mononuclear infiltration and demyelination. We have reported that the oral administration of MBP exerts a profoundly suppressive effect on EAE induced in the Lewis rat. This MBP-induced oral tolerance is characterized by an inhibition of EAE clinical neurologic signs, reduced CNS histopathologic changes, a profound decrease in the T-lymphocyte proliferative response specific for the fed antigen, and a decrease in serum antibody specific for MBP. In a chronic relapsing model of EAE in the B10.PL mouse, we have shown that the oral administration of MBP either prior to MBP challenge or on the first day of clinical signs results in a decreased number and severity of EAE relapses. The oral tolerance approach has also proven effective in the suppression of other organ-specific autoimmune diseases including collagen-induced arthritis, adjuvant arthritis, uveoretinitis, experimental myasthenia gravis, diabetes, and thyroiditis as well as graft rejection. Two primary mechanisms have been proposed to explain oral tolerance in EAE-active suppression following feeding of lower doses of antigen and clonal anergy or deletion following administration of higher doses. In vivo approaches in rats and transgenic mice have been used to further explore the mechanisms underlying oral tolerance. Administration of recombinant interleukin (IL)-2 was shown to reverse the tolerance induced by feeding low doses of MBP, but not the tolerance induced by feeding high doses of MBP, indicating that deletion had occurred in the high-dose group. Moreover, the oral administration of MBP to MBP-specific T-cell receptor (TCR) transgenic mice resulted in a profound decrease of the transgenic T cells in the blood, lymph node cells (LNC), mesenteric LNC, and spleen compartments. The proliferative response to MBP was also profoundly reduced in these organs, indicating that the cells had been deleted from these sites. The results achieved in animal models have led to clinical trials of oral tolerization in three human autoimmune diseases--MS, uveoretinitis, and rheumatoid arthritis--with promising results.
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PMID:Treatment of autoimmune disease by oral tolerance to autoantigens. 881 Oct 61


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