Role of Kupffer cells in tolerance induction after portal venous administration of alloantigen.
OBJECTIVE
A number of studies have shown that portal venous (PV) administration of donor antigen induces allospecific immunosuppression. The purpose of this study was to clarify the role of Kupffer cells (KCs) in PV tolerance.


METHODS
KCs were isolated from LEW liver 7 days after PV injection of DA splenocytes (PV-KCs) or saline (n-KCs). Mixed lymphocyte culture (MLC) responses of LEW splenocytes to y-irradiated DA splenocytes in the presence of PV-KCs or n-KC were investigated. Proliferative responses of MLC in the conditioned medium prepared from co-culture of PV-KCs or n-KCs with DA splenocytes, were also assessed. Meanwhile, Th1 and Th2 cytokines and reactive nitrogen intermediates (RNI), which were degradation products of nitric oxide (NO) in MLC supernatants, were measured.


RESULTS
Significant reduction of MLC proliferative response was observed, when PV-KCs were added to the MLC. MLC responses in the conditioned medium prepared from co-culture of PV-KCs with DA splenocytes were also decreased, as compared to the control. Furthermore, significantly increased PGE2 and RNI levels in supernatants of MLC with PV-KCs were found. IL-4 production in MLC with PV-KCs also significantly increased, as compared to that in MLC without KCs.


CONCLUSIONS
PV administration of alloantigen may promote PGE2 and NO production by KCs. In such an altered hepatic environment, migrating naive lymphocytes may easily differentiate into Th2 cells, resulting in hyporesponsiveness state to the alloantigen.
Shimizu
Hiroaki
H
Department of General Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan. h-shimizu@umin.ac.jp
Kataoka
Masaaki
M
Kimura
Fumio
F
Yoshidome
Hiroyuki
H
Ohtsuka
Masayuki
M
Kato
Atsushi
A
Miyazaki
Masaru
M
D000818:Animals; D018929:Cell Culture Techniques; D016207:Cytokines / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D007165:Immunosuppression Therapy / Q000379:methods*; D007275:Injections, Intravenous; D007519:Isoantigens / Q000008:administration & dosage*; D007728:Kupffer Cells / Q000502:physiology*; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D011169:Portal Vein; D051381:Rats; D011917:Rats, Inbred Lew; D026361:Reactive Nitrogen Species / Q000378:metabolism; D013154:Spleen / Q000473:pathology
D016207:Cytokines; D007519:Isoantigens; D026361:Reactive Nitrogen Species; D015232:Dinoprostone