TH1 and TH2 cytokines in mouse liver transplantation

The spontaneous acceptance of mouse liver allografts despite a vigorous anti-graft immune response in virtually all strain combinations renders it an ideal model to study transplantation immunity. Beyond the obvious potential of this model to study the immune interactions that lead to tolerance, the need to actively induce rejection can also provide important insights into the process of rejection, insights that would complement studies in spontaneously rejecting allograft models.; The TH1/TH2 paradigm has provided an important framework to study T helper cells and their cytokines in liver transplantation immunity. TH1 cytokines (IL-2, IFN-{dollar}gamma{dollar}) were hypothesized to be responsible for allograft rejection because of their role in mediating cellular mediated immune responses, including DTH and cytotoxic T cells. Since TH2 cells can inhibit TH1 cells, the spontaneous acceptance of mouse liver allografts may be due to a TH2 suppression of TH1.; Radioactive reverse transcription-polymerase chain reaction (RT-PCR) detecting cytokine mRNA showed both TH1 and TH2 cytokine expression in spontaneous accepting allogeneic graft compared to syngeneic grafts, thus refuting our hypothesis of TH2 suppression. On the other hand, skin sensitized rejection was associated with a markedly increased IFN-{dollar}gamma{dollar} mRNA and intragraft IgG2a deposition compared to allogeneic controls, suggesting that a TH1 response is associated with mouse rejection.; The induction of rejection by TH1-type cytokines (IL-2, IL-12), but not TH2-type cytokines (IL-4) further supports the contention that TH1 cytokines do mediate rejection. Furthermore, IL-2 and IL-12 mediate rejection by distinctly different pathways. While IL-2 induced rejection in association with increased CD4, CD8 infiltration and allospecific cellular cytotoxicity, IL-12 induced rejection correlated with inhibited cellular cytotoxicity, and increased macrophage and complement mediated antibody killing. The differential effects mediated by IL-2 and IL-12 were further supported by results in mixed leukocyte cultures. These findings may lend some insight in the debate of whether DTH or cytotoxic T cells are crucial in rejection. This dissertation asserts that both pathways are independently capable of mediating rejection, and suggests that allograft rejection may represent a more diverse and heterogeneous immune response than previously thought. Further investigation is underway to more precisely characterize these different pathways and their role in spontaneous rejection.