Constraints on the Efficacy of Mucosal Tolerance in Treatment of Human and Animal Arthritic Diseases

Abstract

Mucosal administration of an autoantigen has been shown to be a powerful way of inducing tolerance in both animal and human arthritis clinical trials. Bovine or chicken type II collagen has been administered orally to rheumatoid arthritis patients, resulting in some, although in many cases rather limited, clinical improvement. Animal studies have revealed that the mechanisms that underlie induction of mucosal tolerance include clonal deletion, suppression of the proinflammatory Th1 cells, and the induction of regulatory T cells. These cells, defined as a persistently CD25-expressing subset of CD4(+) cells, are frequently anergic, may produce anti-inflammatory cytokines such as IL-10 and TGF-beta, and are likely to be agents of bystander suppression. A key feature that may affect the induction of these cells and other suppressive mechanisms is the dose of antigen administered. The results from human clinical trials suggest a daily dose of significantly less than 1 mg is optimal. Similarly data from collagen-induced arthritis studies reveal an optimal dose above and below which there is little or no immune suppression. Indeed, the incorrect dose can prime the immune response and aggravate disease. The timing and frequency of administration is also vital to the level of immune tolerance induced and the control of the pathological process. This and other findings derived from animal studies are discussed here in relation to the results from human clinical trials.

Mucosal Tolerance Induced by an Immunodominant Peptide from Rat α3(IV)NC1 in Established Experimental Autoimmune Glomerulonephritis

“…Successful treatment of established EAG would clearly be more relevant to the management of patients with anti-GBM disease. To investigate further the potential of mucosal tolerance induced by immunodominant peptides in the treatment of established disease, we examined the effect of nasal administration of pCol (24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38) 24 after the onset of disease in EAG induced by recombinant ␣3(IV)NC1 in FCA.…”

“…All positive control rats produced high levels of circulating anti-␣3(IV)NC1 IgG1, IgG2a, IgG2b, and IgG2c anti- (24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38) at 3000 g nasally after the onset of disease (H&E) (B); large numbers of macrophages in a cellular crescent in a positive control animal by immunoperoxidase (IP) (C); marked reduction in the number of glomerular macrophages in an animal given pCol (24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38) at 3000 g nasally after the onset of disease (IP) (D); strong linear deposits of IgG on the GBM in a positive control animal by direct immunofluorescence (DIF) (E); and no reduction in the deposition of IgG on the GBM in an animal given pCol (24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38) atbody by day 28 after immunization. Animals treated with im...…”

“…Groups of WKY rats with EAG were given pCol (24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38) nasally at total cumulative doses of 300 g (n ϭ 6), 1000 g (n ϭ 6), or 3000 g (n ϭ 6), over 3 consecutive days after the onset of proteinuria (day 18 after immunization). In addition, positive control groups (POS) (n ϭ 5) (immunized with ␣3(IV)NC1 in FCA) and negative control groups (NEG) (n ϭ 5) (injected with FCA alone) were both given control peptide pCol (38-52) nasally at a total cumulative dose of 3000 g, or saline alone.…”

“…24 -27 Recent studies from our group have identified a 15-mer immunodominant peptide, pCol, (24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38) from the N-terminus of rat ␣3(IV)NC1, which contains the major B-and T-cell epitopes in EAG, and which can induce crescentic nephritis. 24 Previous studies by Luo and colleagues 25 showed that a 24-mer synthetic peptide, pCol, from the N-terminus of ␣3(IV)NC1 was capable of inducing glomerulonephritis, although this was mild and inconsistent, whereas Wu and colleagues 26 showed that a 13-mer peptide, pCol, (28-40) containing a T-cell epitope from ␣3(IV)NC1, induced severe crescentic glomerulonephritis.…”

“…28 -30 Mucosal tolerance is a phenomenon whereby peripheral immunological tolerance may be induced by the mucosal administration of autoantigens. [31][32][33][34][35] The inhibitory effect of orally or nasally administered autoantigens, or immunodominant peptides, has been widely reported in experimental models of autoimmune disease in rodents, including encephalomyelitis, 36 -38 arthritis, 39 -41 myasthenia gravis, 42,43 interstitial nephritis, 44 and glomerulonephritis. 9,45,46 In several of these studies, it has been shown that nasal administration of lower doses of antigen than those given orally has been effective in inducing mucosal tolerance, 36,40,42 and in treating established disease.…”