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Summary -The presence of peptides with opioid (exorphins) or immunomodulatingactivity has been demonstrated in the sequence of milk proteins. These activities were detected using in vitro technics. Active sequences are particularly present in the sequence of caseins. Their physiological significance remains unclear. The in vivo expression of these activities is first dependent on the existence of mechanisms that modulate the degradation and absorption of the active compounds, and that permit their transport to specifie receptors. Opio id receptors are present at different levels in the gut or in the central nervous system. The action of exorphins is similar to that of other endogenous and exogenous opiates. Other peptides have been shown to act on macrophage and lymphocyte functions. The protective effect of these natural compounds constitutes an interesting potential application. témique. Des récepteurs réagissant avec les exorphines ont été trouvés aussi bien au niveau digestif, qu'au niveau du système nerveux central. Les effets observés sont analogues à ceux des autres opiacés endogènes ou exogènes. D'autres peptides agissent sur la fonction des macrophages, sur les lymphocytes B, sur les lymphocytes T. Le rôle "protecteur» de ces molécules d'origine naturelle est une voie d'étude prometteuse.protéine alimentaire 1peptide 1 opiacé 1 immunomodulation * Correspondence and reprints 242 in the intact animal after intracerebroventricular injection (Zioudriou et al, 1979; Brantl et al, 1981 Brantl et al, , 1982 Liebman et al, 1986).Several types of opiate agonistic peptides have been characterized and exert naloxone inhibitable opioid activities. The first opioid peptides described were in the 60-70 fragment of bovine~-casein (Brantl et al, 1979). This fragment and the Cterminally shortened derived peptides are called~-casomorphins, and characterized by the N-terminal sequence Tyr-Pro-PhePro. Similar peptides, called hurnan-Bcasomorphins, have been found in the 41-44, 51-58, and 59-63 fragments of humañ -casein (Brantl, 1985; Koch et al, 1985). An oe-casein exorphin was identified as the 90-96 fragment of bovine oe-casein (Loukas et al, 1983). Moreover, B-casomorphin analogs have been prepared by C-terminal amidation and amine acid substitution, in order to increase opioid potency and to modify opiate receptor specificity (Brant! et al, 1981(Brant! et al, , 1982 Liebman et al, 1986).

Despite pathophysiologic effects including diarrhea, cholera toxin (CT) is a potent mucosal immunogen and adjuvant. We investigated the influence of CT on T helper (Th)-type 1 (Th1) and Th2 cell-regulated Ag-specific B cell isotype and IgG subclass Ab responses elicited when the toxin was co-administered orally with different protein Ags. When mice were orally immunized with tetanus toxoid (TT) and CT as adjuvant, this regimen induced TT-specific secretory IgA responses in the gastrointestinal tract as well as serum IgG, including IgG1 and IgG2b subclasses, and IgA responses. This oral regimen also induced TT- and CT-B-specific IgE responses. In addition, CT also elicited adjuvant effects for Ag-specific IgG1, IgE, and IgA responses when two other protein Ags, OVA and hen egg white lysozyme, were given by the oral route. Quantitative reverse transcriptase-PCR was performed to assess levels of mRNA for Th1 (IFN-gamma) and Th2 (IL-4) cytokine expression in TT-stimulated CD4+ T cell cultures. Both Peyer's patches and splenic CD4+ T cells expressed markedly increased levels of IL-4-specific message, but did not result in changes in IFN-gamma mRNA expression. To determine whether the route of immunization influenced IgE responses, mice were immunized s.c. with TT and CT as adjuvant. Significant increases in total and TT-specific IgE Abs were induced when CT was co-administered. Taken together, these results show that CT acts as a mucosal adjuvant to enhance Th2-type responses and in particular, the IL-4 produced results in a characteristic Ab isotype pattern associated with this cytokine.

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Iota-carrageenans are high molecular weight polygalactans commonly used in the food industry. Their immunomodulating effects were examined on the reaginic and IgG ovalbumin-specific responses after systemic or oral administration to Brown Norway rats. Intraperitoneal injection of ovalbumin with either iota-carrageenan or alum induced both a reaginic and IgG response. Reaginic antibodies were detected in the primary response with alum, but only in the secondary response with iota-carrageenan. Oral tolerance to ovalbumin was similarly induced whether the protein was given alone or admixed in solution with iota-carrageenan. These results confirmed the systemic adjuvant action of iota-carrageenan described earlier, and showed that this effect did not take place when orally administered.