ENHANCED TYPE-2 AND DIMINISHED TYPE-1 CYTOKINES IN NEONATAL TOLERANCE

We examined the cytokine profiles associated with tolerance and reject ion using the mouse model of neonatal tolerance. BALB/c mice primed wi th CAF(1) splenocytes during the neonatal stage showed increased A/J s kin graft survival of >60 days and failed to develop anti-A/J cytotoxi c responses, but rejected third-party C57BL/6 grafts. Lymph node cells that drained A/J grafts on neonatal-primed mice produced allospecific immune cytokine responses characterized by high IL-4 and low IFN-gamm a levels. In contrast, lymph node cells that drained either rejected t hird-party grafts or rejected A/J grafts placed on adult controls prod uced less IL-4 and more IFN-gamma. Tolerogen-specific immune responses from neonatal-primed mice made up to 100 times higher IL-4 to IFN-gam ma ratios than did controls. Alloantigen priming during the immediate neonatal stage induced constitutive expression of IL-4 mRNA in the spl een without IFN-gamma mRNA, whereas alloantigen stimulation during adu lthood induced the opposite pattern. IL-4 production from neonatal pri med mice was confined to the CD4 population. The altered cytokine prof ile of enhanced IL-4/IFN-gamma in neonatal primed mice persisted for u p to 12 weeks after priming in in vitro secondary MLR assays, which su ggests that the initial timing of antigen stimulation critically influ enced CD4 maturation. The results support a model of immunoredirection as a mechanism of tolerance and provide rationale for examining the t herapeutic use of cytokines in transplantation.