Constraints on the efficacy of mucosal tolerance in treatment of human and animal arthritic diseases.

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.

Autoreactivity in collagen-induced arthritis of rats: a potential role for T cell responses to self MHC peptides.

Collagen-induced arthritis (CIA) is a chronic inflammatory arthropathy of rats which follows immunization with bovine type II collagen (bCII). T cell lines generated from arthritic rats have been shown to be self-reactive and proliferate in an autologous MLR, which is MHC-dependent. However, the peptides which drive this autoreactive response remain to be elucidated. T cell lines, generated initially to bCII, were cultured with synthetic peptides representing potential autoreactive self epitopes. C1q-c(50-64) peptide, which demonstrates sequence homology to the bCII(184-198) peptide, failed to stimulate T cell proliferation suggesting that the autologous MLR was not due to antigen cross-reactivity with this self peptide. In contrast, several peptides from the amino-terminal region of the RT1D(u) MHC class II molecule stimulated proliferative responses. These results suggest that immunization with bCII leads to activation of a population of autoreactive T cells which respond in an autologous MLR, and that this response could be due, in part, to T cell reactivity to self MHC peptides.

Histone peptide-induced nasal tolerance: suppression of murine lupus.

Induced mucosal tolerance has been shown to be beneficial in preventing or treating a number of murine and human autoimmune disorders. However, this particular form of therapy has not been thoroughly tested in systemic lupus erythematosus. In this study, we investigated the conditions for induction of nasal tolerance using a histone peptide named H471 expressing a dominant T cell epitope in the histone protein H4 of mononucleosome in lupus-prone SNF(1) female mice. We also tested the effect of chronic peptide nasal treatment on the development of autoimmune reactivities in these mice. Results demonstrated that a dose-dependent nasal tolerance to peptide H471 can be achieved before or after peptide sensitization in SNF(1) mice. In addition, tolerance to mononucleosomes was induced by nasal instillation of SNF(1) mice with H471. This was accompanied by an increase in IL-10 and suppression of IFN-gamma production by lymph node cells. Suppression of Th1-type cytokines was also observed in SNF(1) mice that were nasally administered with H471 before intradermal injection with the peptide. Finally, chronic nasal instillation of mice with the H471 peptide not only suppressed the development of autoantibodies, but also altered the severity of glomerulonephritis in lupus-prone SNF(1) mice.

Autologous mixed lymphocyte responses in experimentally-induced arthritis of the Lewis rat.

Lewis rats develop immune-mediated arthritis following injection with a variety of agents including bovine type II collagen (bCII), mycobacteria, muramyl dipeptide and CP20961. Since susceptibility to experimentally-induced arthritis has been linked to the genes encoding the major histocompatibility complex, it is hypothesized that antigen presentation to autoreactive T-cells is a critical event in the pathogenesis of disease. T-cells, isolated from Lewis rats immunized with bCII or mycobacteria, were co-cultured with splenic or thymic antigen presenting cells (APC) and proliferative responses to antigen were assessed by 3H-thymidine incorporation. T-cell proliferation was observed upon culture with APC without requiring the addition of antigen. T-cells from rats injected with non-immunogenic adjuvants also demonstrated an increased autologous MLR compared to T-cells from non-injected animals. In contrast, T-cells from animals immunized with non-arthritogenic antigens, including ovalbumin or tetanus toxoid, proliferated only when co-cultured with specific antigen-pulsed APC. These results suggest that immunization with arthritogens activates a population of self-reactive T-cells, which respond in an autologous MLR. We propose that these autoreactive T-cells recognize endogenously-derived self peptides rather than peptides derived from a joint autoantigen.