The role of CD154-CD40 versus CD28-B7 costimulatory pathways in regulatingallogeneic Th1 and Th2 responses in vivo

We used signal transducer and activator of transcription 4 (STAT4) and STAT 6 gene knockout (-/-) mice as recipients of fully mismatched cardiac allogr afts to study the role of T-cell costimulatory pathways in regulating allog eneic T-helper 1 (Th1) versus Th2 responses in vivo. STAT4(-/-) mice have i mpaired Th1 responses, whereas STAT6(-/-) mice do not generate normal Th2 r esponses. Cardiac allografts from C57BL/6 mice were transplanted into norma l wild-type (WT), STAT4(-/-), and STAT6(-/-) BALB/c recipients. STAT4(-/-) and STAT6(-/-) mice rejected their grafts with the same tempo as untreated WT recipients. CD28-B7 blockade by a single injection of CTLA4Ig induced lo ng-term engraftment and donor-specific tolerance in all three groups of rec ipients. CD 154 blockade by a single injection of MR1 was effective in prol onging allograft survival and inducing tolerance in STAT4(-/-) mice but was only marginally effective in STAT6(-/-) recipients and WT controls. In add ition, a similar protocol of MR1 was ineffective in prolonging graft surviv al in CD28(-/-) BALB/c recipients, suggesting that the lack of efficacy see n in WT and STAT6(-/-) mice is not due to the presence of a functional CD28 -B7 pathway. Furthermore, there was a similar differential effect of CD28-B 7 versus CD154-CD40 blockade in inhibiting immune responses in animals immu nized with ovalbumin and complete Freund's adjuvant. These novel data indic ate that Th1 and Th2 cells are differentially regulated by CD28-B7 versus C D154-CD40 costimulation pathways in vivo and may have potential implication s for the development of therapeutic strategies such as T-cell costimulator y blockade in humans.