Interleukin-2 and interleukin-12 mediate distinct effector mechanisms of liver allograft rejection

Abstract

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 mediatreated 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 semiquantitative reverse transcription polymerase chain reaction showed the up-regulation of interferon (IFN)-␥, 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-␥, 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-␥ and involves macrophages and cytotoxic antibodies largely resembling a delayed-type hypersensitivity reaction.

DONOR PRETREATMENT WITH Flt-3 LIGAND AUGMENTS ANTIDONOR CYTOTOXIC T LYMPHOCYTE, NATURAL KILLER, AND LYMPHOKINE-ACTIVATED KILLER CELL ACTIVITIES WITHIN LIVER ALLOGRAFTS AND ALTERS THE PATTERN OF INTRAGRAFT APOPTOTIC ACTIVITY1,2

“…This in turn, may be associated with increased levels of secreted IL-12 and/or other cytokines/growth factors that promote graft immunogenicity, and possibly, DC proliferation. DC-derived IL-12 could augment CD4 + Th1 cell responses that have been linked previously to murine liver allograft rejection (4,41). Although not examined in the present study, it is conceivable that a component of the multilineage NPC accumulation within the liver is derived from local lineage-committed progenitor cell proliferation and maturation (30).…”

“…With recipient presensitization, the liver is rejected acutely (within 4-5 days). Mouse liver allograft rejection also results from recipient treatment with recombinant mouse interleukin (1L)-2 (14) or IL-12 (41).…”

Immune activation is required for the induction of liver allograft tolerance: Implications for immunosuppressive therapy

“…Administration of IL-2 to liver transplant recipients at the time of transplantation leads to rapid rejection of the graft. 42,74,76 In 2 of these studies, the liver was rejected in accelerated tempo, with a median survival time of 5 days, and showed evidence of massive T-cell-mediated rejection. 74,76 These results are consistent with the rapid maturation and development of effector function of large numbers of activated T cells.…”

“…42,74,76 In 2 of these studies, the liver was rejected in accelerated tempo, with a median survival time of 5 days, and showed evidence of massive T-cell-mediated rejection. 74,76 These results are consistent with the rapid maturation and development of effector function of large numbers of activated T cells. The possibility thus arises that exogenous IL-2 promotes survival of the large population of IL-2 receptor-expressing cells observed early after transplantation in tolerant livers.…”

IL-12 p80 Is an Innate Epithelial Cell Effector That Mediates Chronic Allograft Dysfunction

“…The IL-12-related cytokines have distinct biologic properties and p80, but not the other p40-containing IL-12 family members, is a macrophage chemoattractant that signals through IL-12 receptor ␤ 1 (IL-12R␤ 1 ) (14,15). Interestingly, exaggerated macrophage accumulation has been observed in animal and human models of lung allograft dysfunction (16)(17)(18)(19), and the IL-12 family members have been implicated in kidney (20), liver (21), bone marrow (22)(23)(24), and cardiac allograft dysfunction (25,26). Accordingly, we set out to examine whether innate epithelial injury response proteins belonging to the IL-12 family were critical mediators that linked epithelial cell injury with macrophage accumulation and chronic lung allograft dysfunction.…”