title: Early accumulation of interferon-gamma in grafts tolerized by donor-specific blood transfusion: friend or enemy?
abstract: 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.affiliation: Abdominal Transplant Surgery Department, University Hospitals Leuven, Leuven, Belgium.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Kitade
authors.forename: Masaru
authors.initials: M
authors.lastname: Kawai
authors.forename: Takaaki
authors.initials: T
authors.lastname: Koshiba
authors.forename: Annapaula
authors.initials: A
authors.lastname: Giulietti
authors.forename: Lut
authors.initials: L
authors.lastname: Overbergh
authors.forename: Omer
authors.initials: O
authors.lastname: Rutgeerts
authors.forename: Dirk
authors.initials: D
authors.lastname: Valckx
authors.forename: Mark
authors.initials: M
authors.lastname: Waer
authors.forename: Chantal
authors.initials: C
authors.lastname: Mathieu
authors.forename: Jacques
authors.initials: J
authors.lastname: Pirenne
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001803:Blood Transfusion; D017690:Cell Transplantation; D016207:Cytokines / Q000235:genetics; D006084:Graft Rejection; D006085:Graft Survival; D016027:Heart Transplantation / Q000276:immunology*; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism*; D008198:Lymph Nodes / Q000378:metabolism; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013154:Spleen / Q000166:cytology / Q000378:metabolism; D013934:Thymectomy; D013997:Time Factors; D014019:Tissue Donors; D019172:Transplantation Conditioning / Q000379:methods; D023001:Transplantation Tolerance; D015854:Up-Regulation
chemical_list: D016207:Cytokines; D012333:RNA, Messenger; D007371:Interferon-gamma