Oral tolerization with peptide 336-351 linked to cholera toxin B subunit in preventing relapses of uveitis in Behcet's disease.
Behcet'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 peptide-specific CD4+ T cell proliferation, a decrease in expression of TH1 type cells (CCR5, CXCR3), IFN-gamma and TNF-alpha 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.
Stanford
M
M
Department of Ophthalmology, Guy's, King's and St. Thomas' School of Medicine and Dentistry, Guy's Hospital, London, UK.
Whittall
T
T
Bergmeier
L A
LA
Lindblad
M
M
Lundin
S
S
Shinnick
T
T
Mizushima
Y
Y
Holmgren
J
J
Lehner
T
T
D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000284:Administration, Oral; D000328:Adult; D015703:Antigens, CD / Q000276:immunology; D001528:Behcet Syndrome / Q000150:complications / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes; D002455:Cell Division / Q000276:immunology; D002772:Cholera Toxin / Q000008:administration & dosage*; D006801:Humans; D007108:Immune Tolerance; D007371:Interferon-gamma / Q000276:immunology; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments; D010641:Phenotype; D019707:Receptors, Chemokine / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology; D014605:Uveitis / Q000150:complications / Q000276:immunology / Q000517:prevention & control*
D000276:Adjuvants, Immunologic; D015703:Antigens, CD; D010446:Peptide Fragments; D019707:Receptors, Chemokine; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D002772:Cholera Toxin