Early passenger leukocyte migration and acute immune reactions in the rat recipient spleen during liver engraftment: with particular emphasis on donor major histocompatibility complex class II+ cells.
After a short course of tacrolimus, Lewis rat liver allografts induce donor-specific nonreactivity in Brown Norway recipients that is immunosuppression-independent after 28 days. To clarify the role of donor major histocompatibility complex (MHC) class II+ cells, we investigated the migration to the recipient splenic T- and B-cell compartments of different subsets of Lewis MHC class II+ passenger leukocytes. The rise and decline of immune activation were monitored in the hepatic allograft and in the host spleen by analyses of BrdU+ (proliferating) leukocytes, TUNEL+ (apoptotic) cells, apoptosis-associated molecules, TH1/TH2 cytokine profiles, and histoimmunocytochemical examination of graft and splenic tissues. Serial flow cytometry studies during the 28-day period of drug-assisted "hepatic tolerogenesis" showed that migratory MHC class II+ cells accounted for less than half of the donor cells in the host spleen. The class II+ cells consisted mostly of B cells that homed to splenic B-cell follicles with only a sparse representation of dendritic cells that were exclusively found in the splenic periarteriolar lymphoid sheath. In parallel studies, transplantation of the less tolerogenic heart produced a diminutive version of the same events, but with far fewer donor cells in the host spleen, evidence of sustained immune activation, and the development of chronic rejection by 100 days. The data are consistent with the paradigm that migration of donor leukocytes is the prime determinant of variable tolerance induction induced by transplantation of the liver and other organs, but without regard for donor MHC class II+ expression.
Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh Medical Center, Pennsylvania 15213, USA.
Toyokazu
T
Okuda
Takashi
T
Ishikawa
Olga
O
Azhipa
Naoya
N
Ichikawa
Anthony J
AJ
Demetris
Thomas E
TE
Starzl
Noriko
N
Murase
D000208:Acute Disease; D000818:Animals; D017209:Apoptosis / Q000276:immunology; D002455:Cell Division / Q000276:immunology; D002465:Cell Movement / Q000276:immunology; D005434:Flow Cytometry; D015870:Gene Expression / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000032:analysis / Q000276:immunology*; D007371:Interferon-gamma / Q000235:genetics; D007376:Interleukin-2 / Q000235:genetics; D007962:Leukocytes / Q000737:chemistry / Q000166:cytology* / Q000276:immunology; D016031:Liver Transplantation / Q000276:immunology*; D008297:Male; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D013154:Spleen / Q000276:immunology* / Q000473:pathology; D014019:Tissue Donors; D014184:Transplantation, Homologous
D000949:Histocompatibility Antigens Class II; D007376:Interleukin-2; D012333:RNA, Messenger; D007371:Interferon-gamma