Interleukin-2 and interleukin-12 mediate distinct effector mechanisms of liver allograft rejection.
Interleukin-2 (IL-2), interleukin-12 (IL-12) or interleukin-4 (IL-4) were administered postoperatively to otherwise spontaneously accepting mouse liver allograft recipients (C57BL/10-->C3H) to test whether TH1 cytokines are critical mediators of rejection in this model. The induction of rejection at days 5 to 7 by exogenously administered IL-2 and IL-12, but not IL-4, suggests that mouse liver allograft rejection can be induced by TH1 cytokines; however, there appeared to be differences in the mechanism by which these cytokines induce liver rejection. IL-2 administration was accompanied by an increased intragraft infiltration of CD4+ and CD8+ cells and an up-regulation of natural killer (NK), lymphokine-activated killer (LAK), allospecific cytotoxic killer (CTL) activity and perforin mRNA when compared with media-treated controls. In contrast, exogenous IL-12 treatment was associated with a suppression of CTL, NK, and LAK activity compared with controls but an enhanced infiltration of F4/80+ macrophages as determined by immunohistochemistry. Determination of cytokine mRNA profiles by semi-quantitative reverse transcription polymerase chain reaction showed the up-regulation of interferon (IFN)-gamma, IL-4, IL-6, and IL-10 mRNA with IL-2 treatment when compared with media-treated controls. Interestingly, IL-2 mRNA was down-regulated in these animals, suggesting a negative feedback mechanism in IL-2 regulation. IL-12 treatment resulted in the up-regulation of IFN-gamma, IL-6, and IL-10 mRNA, but not IL-2 or IL-4 mRNA. Higher complement-directed cytotoxic antibody titers were seen in IL-12-treated recipients compared with controls, whereas IL-2 treatment showed no apparent differences in antibody titers compared with media treatment. These in vivo observations were mimicked in a mixed leukocyte reaction by supplementing the reaction with IL-2, IL-12, or media. These results suggest that rejection of mouse liver allografts may involve more than one distinct cellular immunological effector mechanism. One is mediated by IL-2 and appears to favor alloreactive CTL, whereas the other pathway is mediated by IL-12/IFN-gamma and involves macrophages and cytotoxic antibodies largely resembling a delayed-type hypersensitivity reaction.
Thai
N L
NL
Pittsburgh Transplantation Institute, PA, USA.
Li
Y
Y
Fu
F
F
Qian
S
S
Demetris
A J
AJ
Duquesnoy
R J
RJ
Fung
J J
JJ
D000818:Animals; D003167:Complement Activation / Q000187:drug effects; D003601:Cytotoxicity Tests, Immunologic; D006084:Graft Rejection / Q000139:chemically induced / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D007150:Immunohistochemistry; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism / Q000494:pharmacology*; D007376:Interleukin-2 / Q000378:metabolism / Q000494:pharmacology*; D015847:Interleukin-4 / Q000378:metabolism / Q000494:pharmacology; D015850:Interleukin-6 / Q000378:metabolism; D016031:Liver Transplantation / Q000276:immunology* / Q000473:pathology; D007959:Lymphocyte Culture Test, Mixed; D008264:Macrophages / Q000187:drug effects; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000032:analysis; D016176:T-Lymphocyte Subsets / Q000187:drug effects; D013997:Time Factors
D007376:Interleukin-2; D015850:Interleukin-6; D012333:RNA, Messenger; D016753:Interleukin-10; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma