Modulation of T Cell Function by Combination of Epitope Specific and Low Dose Anticytokine Therapy Controls Autoimmune Arthritis

Abstract

Innate and adaptive immunity contribute to the pathogenesis of autoimmune arthritis by generating and maintaining inflammation, which leads to tissue damage. Current biological therapies target innate immunity, eminently by interfering with single pro-inflammatory cytokine pathways. This approach has shown excellent efficacy in a good proportion of patients with Rheumatoid Arthritis (RA), but is limited by cost and side effects. Adaptive immunity, particularly T cells with a regulatory function, plays a fundamental role in controlling inflammation in physiologic conditions. A growing body of evidence suggests that modulation of T cell function is impaired in autoimmunity. Restoration of such function could be of significant therapeutic value. We have recently demonstrated that epitope-specific therapy can restore modulation of T cell function in RA patients. Here, we tested the hypothesis that a combination of anti-cytokine and epitope-specific immunotherapy may facilitate the control of autoimmune inflammation by generating active T cell regulation. This novel combination of mucosal tolerization to a pathogenic T cell epitope and single low dose anti-TNFα was as therapeutically effective as full dose anti-TNFα treatment. Analysis of the underlying immunological mechanisms showed induction of T cell immune deviation.

Oral or Nasal Antigen Induces Regulatory T Cells That Suppress Arthritis and Proliferation of Arthritogenic T Cells in Joint Draining Lymph Nodes

“…Such combination of therapies will then broadly target autoaggressive T effector cells while inducing or expanding Ag-specific Tr cells, diverting the autoimmune response into a more regulatory type (42). Recently, the effectiveness of such a combined approach was demonstrated in RA patients (43,44). The skewing of Ag-specific inflammatory responses toward more tolerogenic responses can become a major addition to available therapeutic options for autoimmune diseases.…”

Regulatory T cells that recognize a ubiquitous stress-inducible self-antigen are long-lived suppressors of autoimmune arthritis

“…For therapeutic application, we propose applying the B29 peptide under subimmunogenic (36) conditionsfor instance during anti-TNF treatment-to yield a maximum induction or conversion of T cells into antigen-specific Tregs. Alternatively, B29 may be used for maintaining tolerance subsequent to, or after discontinuation of, anti-TNF treatment (38,39).…”

Restoring the balance: Harnessing regulatory T cells for therapy in rheumatoid arthritis

“…This exciting approach has been developed further using an experimental arthritis model in which low-dose anti-TNF therapy was given in conjunction with nasal administration of heat shock protein 60 [30]. The combination of low-dose anti-cytokine and epitope-specific therapy was highly effective and raises the prospect that in a favourable immunological environment, such as engendered by anti-cytokine therapy, induction of tolerance is achievable.…”