Antigen-Specific Tolerogenic and Immunomodulatory Strategies for the Treatment of Autoimmune Arthritis

Abstract

Objectives-To review various antigen-specific tolerogenic and immunomodulatory approaches for arthritis in animal models and patients in regard to their efficacy, mechanisms of action and limitations.Methods-We reviewed the published literature in Medline (PubMed) on the induction of antigenspecific tolerance and its effect on autoimmune arthritis, as well as the recent work on B cell-mediated tolerance from our laboratory. The prominent key words used in different combinations included arthritis, autoimmunity, immunotherapy, innate immunity, tolerance, treatment, and rheumatoid arthritis (RA). Although this search spanned the years 1975 to 2007, the majority of the short-listed articles belonged to the period 1990 to 2007. The relevant primary as well as cross-referenced articles were then collected from links within PubMed and reviewed.Results-Antigen-specific tolerance has been successful in the prevention and/or treatment of arthritis in animal models. The administration of soluble native antigen or an altered peptide ligand intravenously, orally, or nasally, and the delivery of the DNA encoding a particular antigen by gene therapy have been the mainstay of immunomodulation. Recently, the methods for in vitro-expansion of CD4+CD25+ regulatory T cells have been optimized. Furthermore, interleukin-17 has emerged as a promising new therapeutic target in arthritis. However, in RA patients, non-antigen-specific therapeutic approaches have been much more successful than antigen-specific tolerogenic regimens.Conclusion-An antigen-specific treatment against autoimmune arthritis is still elusive. However, insights into newly emerging mechanisms of disease pathogenesis provide hope for the development of effective and safe immunotherapeutic strategies in the near future.

Huo-Luo-Xiao-Ling Dan modulates antigen-directed immune response in adjuvant-induced inflammation

“…The cytokines tested in our study belong to two main categories - pro-inflammatory cytokines (IFN-γ and IL-17) and anti-inflammatory cytokine (IL-10) (Romagnani, 2006; Chen and O’Shea, 2008). The type of cytokine response induced is dependent on the nature of the antigen besides other critical factors (Tao et al, 1997; Rogers and Croft, 1999; Satpute et al, 2008). We observed that the control rats raised a predominantly pro-inflammatory cytokine response following Mtb injection, whereas HLXL-treated rats showed significantly reduced IL-17 response.…”

“…In addition, the enhanced IL-10 response in HLXL-fed rats resulted in shifting of the overall cytokine milieu of the antigen-draining lymphoid tissues toward an anti-inflammatory type. Such a shift or deviation of the cytokine response (immune deviation) is a well-documented phenomenon that provides the rationale for the beneficial effects of immunotherapeutic approaches against RA, diabetes mellitus, multiple sclerosis and some other autoimmune disorders (Tao et al, 1997; Harber et al, 2000; Romagnani, 2006; Satpute et al, 2008). One of the most studied therapeutic approaches in this regard is the induction of immune tolerance by the administration (i.v., i.p., or mucosally) of soluble antigen without an adjuvant (Tao et al, 1997; Harber et al, 2000; Romagnani, 2006; Satpute et al, 2008), which leads to the deviation of Th1 type (IFN-γ) to Th2 type (IL-4, IL-10) of response (Tao et al, 1997; Rogers and Croft, 1999; Harber et al, 2000; Romagnani, 2006; Satpute et al, 2008).…”

“…However, evidence from genetic and immunological studies suggest the involvement of antigen-induced immune response in disorders involving autoimmune inflammation, for example, rheumatoid arthritis (RA) and type 1 diabetes. Accordingly, both general anti-inflammatory agents (Simon and Yocum, 2000) as well as experimental antigen-based approaches (Satpute et al, 2008) are being employed for the management of some of the inflammatory autoimmune diseases. However, despite significant advances in the development and use of conventional anti-inflammatory drugs, the significant adverse effects associated with such drugs remain a major obstacle in designing an optimal and safe therapeutic strategy for such diseases (Stiel, 2000; Weir, 2002; Fitzgerald, 2004).…”

Prevention of autoimmune rheumatic disease: state of the art and future perspectives

“…The fact that these control mechanisms sometimes fail means that the immune system in most individuals retains the capacity for re-regulation. Accordingly, experimental studies, mainly in rodent models of autoimmune disease, have revealed several different ways whereby autoimmunity can be manipulated to prevent or cure autoimmune disease 1–3…”

Immune Tolerance Induction with Multiepitope Peptide Derived from Citrullinated Autoantigens Attenuates Arthritis Manifestations in Adjuvant Arthritis Rats

“…Induction of peripheral tolerance using synthetic peptides delineated from self-autoantigen sequences were previously shown to suppress disease manifestations in arthritis models (22,23). The tolerance mechanisms include clonal deletion of autoreactive T and B cells (24), clonal anergy (25), and induction of T cells with a regulatory phenotype (26).…”