Lack of efficacy of oral bovine type II collagen added to existing therapy in rheumatoid arthritis

McKown, Kevin M.; Carbone, Laura D; Kaplan, Stanley B.; Aelion, Jacob; Lohr, Kristine M.; Cremer, Michael A.; Bustillo, Juan; González, Miguel Angel Ferrer; Kaeley, Gurjit S.; Steere, Elaine L.; Somes, Grant W.; Myers, Linda K.; Seyer, Jerome M.; Kang, Andrew H.; Postlethwaite, Arnold E.

doi:10.1002/1529-0131(199906)42:6<1204::aid-anr17>3.0.co;2-u

Cited by 64 publications

(36 citation statements)

References 18 publications

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“…In addition, trials in humans of oral myelin basic protein for multiple sclerosis (35), oral collagen type II for rheumatoid arthritis (36), and oral insulin for T1D (37,38) did not demonstrate clinical benefit. One explanation for these findings could be the simultaneous induction of protective immunity (mucosal tolerance), shown here to be mediated by regulatory CD4 + T cells, and pathogenic immunity mediated by CTL.…”

Section: Figurementioning

confidence: 98%

Disabling an integral CTL epitope allows suppression of autoimmune diabetes by intranasal proinsulin peptide

Martinez¹,

Augstein²,

Moustakas³

et al. 2003

J. Clin. Invest.

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Section: Figurementioning

confidence: 98%

Disabling an integral CTL epitope allows suppression of autoimmune diabetes by intranasal proinsulin peptide

Martinez¹,

Augstein²,

Moustakas³

et al. 2003

J. Clin. Invest.

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“…Enthusiasm to translate therapeutic effects of mucosal tolerance from rodents to humans has been tempered by failure to demonstrate clinical benefit in the following trials of oral antigens: myelin basic protein in multiple sclerosis (15), collagen in rheumatoid arthritis (16,17), and insulin in recently diagnosed (18,19) type 1 diabetes. These trials did not report evidence for an immune effect; therefore, it is not clear that the dose of oral antigen used was in fact immunogenic.…”

mentioning

confidence: 99%

Pancreatic β-Cell Function and Immune Responses to Insulin After Administration of Intranasal Insulin to Humans At Risk for Type 1 Diabetes

et al. 2004

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OBJECTIVE -Mucosal administration of insulin retards development of autoimmune diabetes in the nonobese diabetic mouse model. We conducted a double-blind crossover study in humans at risk for type 1 diabetes to determine if intranasal insulin was safe, in particular did not accelerate ␤-cell destruction, and could induce immune effects consistent with mucosal tolerance. RESEARCH DESIGN AND METHODS-A total of 38 individuals, median age 10.8 years, with antibodies to one or more pancreatic islet antigens (insulin, GAD65, or tyrosine phosphatase-like insulinoma antigen 2) were randomized to treatment with intranasal insulin (1.6 mg) or a carrier solution, daily for 10 days and then 2 days a week for 6 months, before crossover. The primary outcome was ␤-cell function measured as first-phase insulin response (FPIR) to intravenous glucose at 0, 6, and 12 months and then yearly; the secondary outcome was immunity to islet antigens, measured monthly for 12 months.RESULTS -No local or systemic adverse effects were observed. Diabetes developed in 12 participants with negligible ␤-cell function at entry after a median of 1.1 year. Of the remaining 26, the majority had antibodies to two or three islet antigens and FPIR greater than the first percentile at entry, as well as ␤-cell function that generally remained stable over a median follow-up of 3.0 years. Intranasal insulin was associated with an increase in antibody and a decrease in T-cell responses to insulin. CONCLUSIONS -Results from this pilot study suggest that intranasal insulin does not accelerate loss of ␤-cell function in individuals at risk for type 1 diabetes and induces immune changes consistent with mucosal tolerance to insulin. These findings justify a formal trial to determine if intranasal insulin is immunotherapeutic and retards progression to clinical diabetes. Diabetes Care 27:2348 -2355, 2004T ype 1 diabetes is an autoimmune disease in which T-cells mediate destruction of insulin-secreting ␤-cells in the pancreatic islets. Asymptomatic individuals with preclinical type 1 diabetes can be identified by the presence of circulating antibodies (Abs) to insulin, GAD 65-kDa isoform, and tyrosine phosphatase-like insulinoma antigen 2 (IA2) (1-3). Insulin is the only self-antigen specific for ␤-cells, and several lines of evidence indicate that it may play a major role in driving autoimmune ␤-cell destruction (4 -7). In experimental rodent models, administration of self-antigens to mucosa-associated lymphoid tissues can induce immune tolerance and prevent autoimmune disease (8,9). In the nonobese diabetic (NOD) mouse, a spontaneous model of autoimmune type 1 diabetes, oral (10) or naso-respiratory (11) insulin induces regulatory, diabetes-protective Tcells. After naso-respiratory insulin, there was a decrease in T-cell and an increase in Ab responses to insulin (11), conforming to the shift from T-helper (Th)-1 cellular immunity to Th2 humoral immunity that is associated with protection against diabetes in this rodent model (12). In human volunteers, oral (13)...

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“…At present, T cell recognition of only a limited number of self-Ags has been described in RA, e.g., type II collagen (19,20), human cartilage glycoprotein 39 (HC gp-39) (21), hsp60 (22,23), chondrocyte Ag 65 (24), synovial fluid-derived p205 (25), and the endoplasmatic reticulum molecular chaperone BiP (26). In this study, we have identified several new targets for the immune system during the arthritis process.…”

Section: Discussionmentioning

confidence: 99%

Matrix Metalloproteinases as Targets for the Immune System during Experimental Arthritis

Bilsen

Wagenaar-Hilbers

Grosfeld-Stulemeijer

et al. 2004

The Journal of Immunology

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Novel therapies for rheumatoid arthritis aiming at intervention in the inflammatory process by manipulation of autoreactive T and B lymphocytes receive major interest. However, the development of such therapies is largely hampered by the lack of knowledge of self-Ags recognized during the disease process. Recently, we predicted putative T cell self-epitopes based on a computer search profile. In the present study, the predicted self-epitopes were tested for T cell recognition in two experimental arthritis models, and their arthritogenic capacity was analyzed. Fourteen of n = 51 predicted self-epitopes were recognized during experimental arthritis of which six were able to actively induce arthritis. Interestingly, three of these six peptides were derived from matrix metalloproteinases (MMP), and only T cells responsive to MMP-derived epitopes were able to passively transfer arthritis to naive rats. Moreover, we demonstrate the presence of Abs to MMP-3 during the course of adjuvant arthritis. Together these data indicate that MMPs play a pivotal role as target for T and B cells during the development of inflammatory arthritis. This finding sheds new light on the pathophysiological role of MMPs during arthritis and opens novel possibilities for Ag-specific immunotherapy.

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Lack of efficacy of oral bovine type II collagen added to existing therapy in rheumatoid arthritis

Cited by 64 publications

References 18 publications

Disabling an integral CTL epitope allows suppression of autoimmune diabetes by intranasal proinsulin peptide

Disabling an integral CTL epitope allows suppression of autoimmune diabetes by intranasal proinsulin peptide

Pancreatic β-Cell Function and Immune Responses to Insulin After Administration of Intranasal Insulin to Humans At Risk for Type 1 Diabetes

Matrix Metalloproteinases as Targets for the Immune System during Experimental Arthritis

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