Prevention of mucosally induced uveitis with a HSP60-derived peptide linked to cholera toxin B subunit.
Oral administration of the uveitogenic peptide (aa 336-351) derived from human HSP60 induced clinical and histological manifestations of uveitis in 65.8% (48/73) of Lewis rats. Uveitis was significantly decreased to 16.7% (11/66) in parallel experiments with the peptide linked to recombinant cholera toxin B subunit (rCTB), also given by mouth (chi(2)=34.2, p<0.0001). The protective efficacy between tolerized and immunized animals was 74.7%. Adoptive transfer of mesenteric lymph node cells from tolerized rats prevented the development of uveitis. A significantly higher proportion of regulatory CD4(+)CD45RC(low)RT6(+) subset of Th2 memory cells were found in the mesenteric lymph nodes (p<0.005) and spleens (p</=0.05) of tolerized rats without uveitis, as compared with immunized rats and uveitis. In situ hybridization studies of mesenteric lymph nodes and/or the uveal tract showed significant increases in IL-10 and TGF-beta mRNA but decreases in IFN-gamma and IL-12 mRNA in tolerized, as compared with immunized animals. Thus, the mechanism of tolerance, preventing the development of uveitis may involve a regulatory subset of memory cells and a shift from Th1 to Th2 and Th3 cytokines. We suggest that mucosally induced uveitis can be prevented by oral administration of the peptide-rCTB conjugate.
Phipps
Paula A
PA
Peter Gorer Department of Immunobiology, Guy's, King's and St. Thomas' School of Medicine and Dentistry, Guy's Hospital, London,GB.
Stanford
Miles R
MR
Sun
Jia-Bin
JB
Xiao
Bao-Guo
BG
Holmgren
Jan
J
Shinnick
Thomas
T
Hasan
Adam
A
Mizushima
Yutaka
Y
Lehner
Thomas
T
D019264:Adoptive Transfer; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D018834:Chaperonin 60 / Q000008:administration & dosage / Q000494:pharmacology*; D002772:Cholera Toxin / Q000008:administration & dosage / Q000494:pharmacology*; D005434:Flow Cytometry; D007108:Immune Tolerance / Q000187:drug effects; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism; D010446:Peptide Fragments / Q000008:administration & dosage / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D014605:Uveitis / Q000139:chemically induced / Q000276:immunology* / Q000517:prevention & control*
D018834:Chaperonin 60; D010446:Peptide Fragments; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D018664:Interleukin-12; D007371:Interferon-gamma; D002772:Cholera Toxin