Coupling of oral human or porcine insulin to the B subunit of cholera toxin (CTB) overcomes critical antigenic differences for prevention of type I diabetes.
Our earlier investigations have demonstrated a critical difference in the efficacy of orally administered porcine compared to human or mouse insulin (no effect) in preventing type I diabetes in two distinct experimental models. Based on these findings one has to assume that certain insulins might not be suitable for the induction of oral 'tolerance'/bystander suppression, which might be one cause for recent failures in human oral antigen trials. Here we demonstrate that coupling to the non-toxic subunit of cholera toxin (CTB) can abolish these differences in efficacy between human and porcine insulin. As expected, an added benefit was the much smaller oral antigen dose required to induce CD4+ insulin-B specific regulatory cells that bystander-suppress autoaggressive responses. Mechanistically we found that uptake or transport of insulin-CTB conjugates in the gut occurs at least partially via binding to GM-1, which would explain the enhanced clinical efficacy. Both B chains bound well to major histocompatibility complex (MHC) class II, indicating comparable immunological potential once uptake and processing has occurred. Thus, our findings delineate a pathway to overcome issues in oral antigen choice for prevention of type I diabetes.
Petersen
J S
JS
La Jolla Institute for Allergy and Immunology, San Diego, CA 92121, USA.
Bregenholt
S
S
Apostolopolous
V
V
Homann
D
D
Wolfe
T
T
Hughes
A
A
De Jongh
K
K
Wang
M
M
Dyrberg
T
T
Von Herrath
M G
MG
D000284:Administration, Oral; D000818:Animals; D001324:Autoantigens / Q000008:administration & dosage* / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002772:Cholera Toxin / Q000008:administration & dosage* / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000517:prevention & control*; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007114:Immunization / Q000379:methods*; D007328:Insulin / Q000008:administration & dosage* / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D023421:Models, Animal; D013552:Swine; D018074:Vaccines, Conjugate / Q000008:administration & dosage* / Q000378:metabolism
D001324:Autoantigens; D007328:Insulin; D018074:Vaccines, Conjugate; C400103:cholera toxin B-insulin conjugate; D002772:Cholera Toxin