PREVENTION OF THE RESPONSES IS CRITICAL FOR TOLERANCE

We investigated the role of Th1 and Th2 cytokines in rejection and tol erance using the neonatal tolerance model. We reported previously that lymph nodes that drained immunogen-bearing tolerant grafts produced a 10- to 100-fold higher ratio of interleukin (IL)-4 to interferon (IFN )-gamma compared with lymph node cells from rejected grafts. Moreover, because neonatal antigen exposure triggers allospecific Th2 CD4 memor y cells, whereas antigen exposure during adulthood triggers Th1 CD4 me mory cells, we speculated that immunoredirection toward Th2 and away f rom Th1 functions as another mechanism of tolerance. To test the immun oredirection hypothesis, we examined whether recovery of Th1 cytokine responses abrogates tolerance. We now show that treatment with exogeno us IFN-gamma at the time of neonatal priming recovered mixed lymphocyt e reaction hypoproliferation and restored the ability of mice to rejec t skin grafts. Mice that received IFN-gamma at the time of neonatal pr iming produced more IFN-gamma and contained more A/J-reactive IFN-gamm a-producing CD4 cells compared with untreated neonatal primed mice, bu t failed to recover A/J-specific IFN-mu-producing CDS cells or CTL res ponses, which suggests that graft rejection occurred via Th1 CD4 cells . Interestingly, draining lymph node cells from rejected grafts on IFN -gamma-treated neonatal primed mice also produced more IL-4, compared with cells from healthy grafts on untreated neonatal primed mice. None theless, lower IL-4 to IFN-gamma ratios predicted graft rejection and higher ratios predicted acceptance. We conclude that neonatal toleranc e depends on the ability to block generation of allospecific Th1 respo nses that lead to rejection. Thus, immunoredirection involves both the inhibition of Th1 and expansion of Th2 immune responses.