Th1 and Th2 alloreactive responses in neonatal tolerance

The thesis examines the theory that cytokine production imbalance during the alloreactive immune response may determine the outcome of allograft transplantation. Using the classic model of neonatally acquired immunological tolerance, we determined that neonatal alloantigen priming induces a state of transplantation tolerance that is associated with an enhanced alloreactive Th2 response and a diminished alloreactive Th1 response. In contrast, allograft rejection is associated with an opposite cytokine profile. Phenotypic analysis demonstrates that neonatal alloantigen priming induces an expansion of CD4 cells bearing the Mel-14{dollar}sp{lcub}1circ{rcub}{dollar}CD45RB{dollar}sp{lcub}1circ{rcub}{dollar} phenotype, similar to that found in the adult primed mice. However, unlike adult primed mice, CD4{dollar}sp+{dollar}Mel-14{dollar}sp{lcub}1circ{rcub}{dollar} cells from neonatally primed mice produce predominant Th2 cytokines IL-4 and IL-10, instead of IFN-{dollar}gamma{dollar}. Adding neutralizing antibodies to type-2 cytokines IL-4 and IL-10 into MLR cultures with CD4{dollar}sp+{dollar}Mel-14{dollar}sp{lcub}1circ{rcub}{dollar} cells from neonatally primed mice restored the ability of these cells to produce IFN-{dollar}gamma{dollar} upon second allostimulation, implying that the expanded Th2 cells in neonatally primed mice may actively expanded Th2 cells in neonatally primed mice may actively prevent the activation of Th1 cells. To determine the causality of enhanced Th2 and diminished Th1 response to tolerance, we administered either IFN-{dollar}gamma{dollar} or anti-IL-4 to neonatal mice in vivo at the time of alloantigen priming. Both treatments restore the ability of neonatally primed mice to produce IL-2, IFN-{dollar}gamma{dollar} and mediate skin graft rejection. However, neither treatment reduces the IL-4 production by neonatally primed mice, indicating that the diminished IFN-{dollar}gamma{dollar} is important for maintaining the tolerance, whereas enhanced IL-4 production is important for downregulating Th1 response at the time of tolerance induction.