SUPPRESSION OF MURINE ALLERGIC CONTACT-DERMATITIS BY CTLA4IG - TOLERANCE INDUCTION OF TH2 RESPONSES REQUIRES ADDITIONAL BLOCKADE OF CD40-LIGAND

Blockade of costimulation through the B7-CD28 pathway by CTLA4Ig can l ead to Ag-specific T cell tolerance. Most models studied to date invol ve a Th1-dependent response. To investigate whether the tolerizing eff ects of CTLA4Ig might vary depending upon the cytokine nature of the i mmune response, we studied its effects on contact hypersensitivity (CH S) in response to two allergens. In BALB/c mice, both 2,4-dinitrofluor obenzene (DNFB) and FITC induce CHS. However, the DNFB response is Th1 -predominant, while the FITC response is Th2 predominant. CTLA4Ig trea tment during primary sensitization induced longlasting unresponsivenes s to DNFB, with 88% and 76% inhibition of primary (first challenge) an d secondary (re-sensitization and re-challenge) CHS, respectively. In contrast, CTLA4Ig inhibited primary CHS to FITC by over 82% but had li ttle effect on secondary CHS. Consistent with its effects on CHS, the suppressive effect of CTLA4Ig on Th2 cells was short-lived in FITC-sen sitized mice, while Th1-like cytokine-secreting cells remained reduced in DNFB-sensitized mice, even when the animals were rechallenged with DNFB. The addition of anti-CD40L Ab to CTLA4Ig was able to induce lon g-lasting unresponsiveness to FITC, indicating the ability of cells mo unting this Th2 response to receive costimulatory signals through eith er pathway. In conclusion, CHS can be mediated by both Th1 and Th2 cel ls, and the ability of CTLA4Ig to lead to long-standing nonresponsiven ess in this model depends on the nature (i.e., cytokine profile) of th e immune response.