Early accumulation of interferon-gamma in grafts tolerized by donor-specific blood transfusion: friend or enemy?

Background. We previously documented an early (day-2) interferon (IFN)-γ accumulation in cardiac allografts of rats made tolerant by donor-specific blood transfusion (DSBT) but not in rejecting controls. This contrasted with the IFN-γ peak seen later (day 5) in rejecting but not in tolerant rats. Methods. To further examine the role of early intragraft IFN-y in DSBT-induced tolerance, we studied whether IFN-γ up-regulation correlates with the magnitude of the DSBT effect and how IFN-y is influenced by interventions abrogating tolerance. Results. The protective effect of DSBT depended upon the timing of administration: day-12 DSBT induced indefinite graft survival; day-6 DSBT gave a moderate, and day-0 DSBT, no graft prolongation. IFN-γ up-regulation correlated with the DSBT effect: it was maximal after day-12 DSBT, intermediate after day-6 DSBT, and absent after day-0 DSBT. Tolerant splenocytes transferred tolerance into naive rats in a donor-specific manner, indicating that alloantigen-specific regulatory cells operate. Thymectomy prevented regulatory cells development, caused further amplification of intragraft IFN-y, and led to rejection, although graft survival was still prolonged. Conclusions. Day 2 intragraft IFN-y correlates with the DSBT protective effect. Thymectomy abrogates DSBT-induced tolerance, prevents regulatory cell development, and paradoxically causes further accumulation of intragraft IFN-y. These data indicate that DSBT has a stimulatory and a (thymus-dependent) inhibitory effect on early intragraft IFN-γ. Intragraft IFN-γ is beneficial, providing it occurs early and remains moderate. The role of intragraft IFN-γ in tolerance and rejection depends upon the timing and the degree of production and perhaps the type of IFN-y producing cells (regulatory or effector).