BACKGROUND: We previously documented an early (day-2) interferon (IFN)-gamma accumulation in cardiac allografts of rats made tolerant by donor-specific blood transfusion (DSBT) but not in rejecting controls. This contrasted with the IFN-gamma peak seen later (day 5) in rejecting but not in tolerant rats. METHODS: To further examine the role of early intragraft IFN-gamma in DSBT-induced tolerance, we studied whether IFN-gamma up-regulation correlates with the magnitude of the DSBT effect and how IFN-gamma 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-gamma 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-gamma, and led to rejection, although graft survival was still prolonged. CONCLUSIONS: Day 2 intragraft IFN-gamma correlates with the DSBT protective effect. Thymectomy abrogates DSBT-induced tolerance, prevents regulatory cell development, and paradoxically causes further accumulation of intragraft IFN-gamma. These data indicate that DSBT has a stimulatory and a (thymus-dependent) inhibitory effect on early intragraft IFN-gamma. Intragraft IFN-gamma is beneficial, providing it occurs early and remains moderate. The role of intragraft IFN-gamma in tolerance and rejection depends upon the timing and the degree of production and perhaps the type of IFN-gamma producing cells (regulatory or effector).
BACKGROUND: We previously documented an early (day-2) interferon (IFN)-gamma accumulation in cardiac allografts of rats made tolerant by donor-specific blood transfusion (DSBT) but not in rejecting controls. This contrasted with the IFN-gamma peak seen later (day 5) in rejecting but not in tolerant rats. METHODS: To further examine the role of early intragraft IFN-gamma in DSBT-induced tolerance, we studied whether IFN-gamma up-regulation correlates with the magnitude of the DSBT effect and how IFN-gamma 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-gamma 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-gamma, and led to rejection, although graft survival was still prolonged. CONCLUSIONS: Day 2 intragraft IFN-gamma correlates with the DSBT protective effect. Thymectomy abrogates DSBT-induced tolerance, prevents regulatory cell development, and paradoxically causes further accumulation of intragraft IFN-gamma. These data indicate that DSBT has a stimulatory and a (thymus-dependent) inhibitory effect on early intragraft IFN-gamma. Intragraft IFN-gamma is beneficial, providing it occurs early and remains moderate. The role of intragraft IFN-gamma in tolerance and rejection depends upon the timing and the degree of production and perhaps the type of IFN-gamma producing cells (regulatory or effector).
Authors: Shoba Amarnath; Hao Chen; Jason E Foley; Carliann M Costanzo; Joel D Sennesh; Michael A Solomon; Daniel H Fowler Journal: PLoS One Date: 2011-04-29 Impact factor: 3.240
Authors: Stephane Esnault; Ruedi K Braun; Zhong-Jian Shen; Zhuzai Xiang; Erika Heninger; Robert B Love; Matyas Sandor; James S Malter Journal: PLoS One Date: 2007-02-21 Impact factor: 3.240