DIFFERENTIAL-EFFECTS OF OVAL VERSUS INTRATHYMIC ADMINISTRATION OF POLYMORPHIC MAJOR HISTOCOMPATIBILITY COMPLEX CLASS-II PEPTIDES ON MONONUCLEAR AND ENDOTHELIAL-CELL ACTIVATION AND CYTOKINE EXPRESSION DURING A DELAYED-TYPE HYPERSENSITIVITY RESPONSE

Oral and intrathymic exposure to antigen can each induce systemic anti gen-specific immune tolerance, but the mechanisms have not been well d efined We studied the effects that the route of exposure to antigen ha s on the mechanisms of tolerance in vivo using synthetic polymorphic c lass II major histocompatibility, complex (MHC) peptides in a skin del ayed-type hypersensitivity (DTH) response model. Lewis rats were immun ized by injection in the footpad with synthetic peptides (RT1.B-u and/ or RT1.D-u) derived from the hypervariable domain of MHC class II beta chain of the Wistar-Furth rat in complete Freund's adjuvant and chall enged 2 weeks later by injection in the ear with the MHC peptides. An ''oral'' group received the peptide mixture by gavage (100 mu g/ day f or 5 days) 3 days before immunization, and an ''intrathymic'' group re ceived a single intrathymic injection of 100 mu g of peptides 48 hours before immunization. Oral therapy reduced the DTH response to 23 +/- 7%, and intrathymic exposure reduced the DTH response to 26 +/- 6% (P < 0.001) as compared with control DTH responses of unmodified Lewis an imals. Immunohistological evaluation of DTH skin lesions showed that o ral and intrathymic therapy each decreased mononuclear cell infiltrati on, fibrin deposition, and endothelial activation when compared with t hat seen in control rats. In contrast, while both protocols markedly r edztced interleukin (IL-2) and interferon-gamma expression, they had d iffering effects on local expression of IL-4, transforming growth fact or-beta, IL-2R, and CD45RC (a possible discriminant between Th1 and Th 2 cells in rats). Oral therapy was associated with increased expressio n of IL-4 and preservation of transforming growth factor-beta expressi on by residual IL-2R(+), CD45RC(-) mononuclear and endothelial cells, whereas thymic exposure suppressed essentially all features of immune activation including IL-2R induction and cytokine expression Our data a) document the detailed pattern of cytokine expression and mononuclea r and endothelial cell activation markers during DTH responses and b) confirm that oral tolerance is associated with immune deviation to a p redominanc of Th2 cell function, whereas intrathymic tolerance may be mediated by T-cell anergy or clonal deletion. -