Antigen contact via the alimentary tract prior to sensitization may re
sult in systemic immunologic unresponsiveness (''oral tolerance''). Th
e induction of oral tolerance seems an attractive strategy to combat u
ndesired immune responses, such as allograft rejection and autoimmune
and allergic diseases. We describe clear and reproducible sensitizatio
n to nickel in mice reared under nickel-free conditions. Hypersensitiv
ity was induced by injecting nickel sulfate intradermally into the fla
nk skin and elicited by injecting the metal salt into the pinnae of th
e ears. The effectiveness of orally induced hyporesponsiveness could b
e inferred from a low degree of hypersensitivity obtained with mice ra
ised and maintained in cages with nickel-releasing covers and water ni
pples. This mouse model for the assay of nickel hypersensitivity was u
sed for oral tolerance studies by administrating non-toxic doses of ni
ckel sulfate in drinking water or intragastrically prior to sensitizat
ion. In these animals, the development of delayed-type hypersensitivit
y was suppressed in a dose-dependent way, and the hyporesponsiveness c
ould be transferred by CD8+ cells. The antigen specificity of this ora
l tolerance could be demonstrated by the concomitant use of sensitizat
ion and challenge procedures for nickel and chromium. The hypersensiti
vity assay described provides a versatile, highly reproducible experim
ental model to study immunoregulation of oral tolerance to clinically
relevant metal allergens.