Oral tolerization with peptide 336–351 linked to cholera toxin B subunit in preventing relapses of uveitis in Behcet's disease

Abstract

SUMMARYBehcet's disease (BD) specific peptide (p336-351) was identified within the human 60 kD heat shock protein (HSP60). Oral p336-351 induced uveitis in rats which was prevented by oral tolerization with the peptide linked to recombinant cholera toxin B subunit (CTB). This strategy was adopted in a phase I/II clinical trial by oral administration of p336-351-CTB, 3 times weekly, followed by gradual withdrawal of all immunosuppressive drugs used to control the disease in 8 patients with BD. The patients were monitored by clinical and ophthalmological examination, as well as extensive immunological investigations. Oral administration of p336-351-CTB had no adverse effect and withdrawal of the immunosuppressive drugs showed no relapse of uveitis in 5 of 8 patients or 5 of 6 selected patients who were free of disease activity prior to initiating the tolerization regimen. After tolerization was discontinued, 3 of 5 patients remained free of relapsing uveitis for 10-18 months after cessation of all treatment. Control of uveitis and extra-ocular manifestations of BD was associated with a lack of peptidespecific CD4 + T cell proliferation, a decrease in expression of TH1 type cells (CCR5, CXCR3), IFN-g and TNF-a production, CCR7 + T cells and costimulatory molecules (CD40 and CD28), as compared with an increase in these parameters in patients in whom uveitis had relapsed. The efficacy of oral peptide-CTB tolerization will need to be confirmed in a phase III trial, but this novel strategy in humans might be applicable generally to autoimmune diseases in which specific antigens have been identified.

Behcet’s disease: from heat shock proteins to infections

“…Recent clinical observations suggest that exposure to Streptococcal antigens (such as HSPs) may be a major factor for provoking disease activity [2]. By contrast, the therapeutic approaches involving HSP immunomodulation may be available as "oral toleration" [18,89]. According to a recent study, a significant role of HSPs in BD immunopathogenesis through high sequence homology and molecular mimicry between microbial and self-8HSPs is suggested.…”

The Cholera Toxin as a Biotechnological Tool

“…Furthermore, a I/II phase clinical trial of the same peptide conjugated to CTB administered orally to 8 patients allowed the withdrawal of all immunosuppressive drugs in 5 of the 8 patients without a relapse of uveitis [Stanford et al, 2004].…”

Immunité muqueuse et vaccination

“…En effet, la co-administration par voie orale ou nasale d'auto-antigènes liés à la sous-unité B de la toxine cholérique (CTB), vecteur de ciblage cellulaire d'antigènes aux propriétés tolérogènes, favorise la tolérance muqueuse dans différents modèles animaux de maladies expérimentales pré-établies [32]. De manière intéressante, le traitement par voie orale de patients atteints de maladie de Behcet par la CTB couplée à un peptide immuno-dominant de la HSP (heat shock protein) 65 (essai clinique de phase I/II incluant 8 patients) s'est avéré efficace comme le suggère l'absence d'uvéite [35]. L'efficacité clinique de cette approche doit être confirmée par un essai de phase III réalisé sur un plus grand nombre de patients.…”