THE ROLE OF INTERLEUKIN-4 IN THE INDUCTION-PHASE OF ALLOGENEIC NEONATAL TOLERANCE

We previously reported that prolonged graft survival in neonatally tol erant mice was associated with enhanced Th2/Th1 cytokines. To determin e whether Th2 CD4 cells function in tolerance, we examined whether we could prevent tolerance by blocking Th2 CD4 maturation, using anti-int erleukin (IL)-4 monoclonal antibody treatment during neonatal antigen exposure. Anti-IL-4 treatment restored the ability BALB/c of mice to r eject A/J skin grafts and blocked the induction of tolerance through m ultiple mechanisms. Anti-IL-4 treatment blocked the development of don or microchimerism and recovered the ability of mice to proliferate and to generate appropriate delayed-type hypersensitivity (DTH) and cytot oxic T lymphocyte (CTL) responses against A/J in a dose-dependent mann er. Low-dose anti-IL-4 recovered DTH responses and interferon (IFN)-ga mma production, but failed to completely prevent IL-4 production or to recover the CTL activity. No A/J-reactive IFN-gamma-producing CD8 cel ls were detected in these mice. In contrast, mice treated with higher doses of anti-IL-4 generated normal CTL responses against A/J, and con tained A/J-reactive IFN-gamma-producing CD8 cells. The recovery of CTL responses and IFN-gamma-producing CD8 cells was associated with a mor e complete blocking of Th2 cytokine production. Therefore, the presenc e of IL-4 may play an important role in the induction of neonatal tole rance by shifting maturation of CD4 cells toward Th2 cells and away fr om Th1 cells, and also by preventing maturation of alloreactive CD8 CT L cells.