Graft Produced Interleukin-6 Functions as a Danger Signal and Promotes Rejection After Transplantation

Liang, Yurong; Christopher, Kenneth B.; Finn, Patricia W.; Colson, Yolonda L.; Perkins, David L.

doi:10.1097/01.tp.0000281384.24333.0b

Cited by 67 publications

(88 citation statements)

References 33 publications

(28 reference statements)

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“…This possibility is supported by the finding of a negative correlation between intragraft IL-6 expression and Treg numbers and by higher numbers of IL-17-producing cells in Tir8 Ϫ/Ϫ than in Tir8 ϩ/ϩ grafts. On this line, in a published study in rodents, IL-6 deletion in the heart allograft was found to significantly delay rejection by a Treg-dependent mechanism (62).…”

Section: Discussionsupporting

confidence: 52%

The Toll-IL-1R Member Tir8/SIGIRR Negatively Regulates Adaptive Immunity against Kidney Grafts

Noris

Cassis

Azzollini³

et al. 2009

The Journal of Immunology

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Members of the TLR/IL-1R superfamily mediate ischemia/reperfusion injury and initiate immune response in transplanted organs. In this study, we tested the hypothesis that Toll-IL-1R8 (TIR8), a negative regulator of TLR/IL-1R highly expressed in the kidney, modulates immune cell activation underlying kidney rejection. In a mouse model of fully mismatched kidney allotransplantation in which the graft is spontaneously accepted, intragraft Tir8 expression was enhanced compared with naive kidneys. Targeted deletion of Tir8 in the graft exerted a powerful antitolerogenic action leading to acute rejection. Similarly, in a mouse model of kidney graft acceptance induced by costimulation blockade, most Tir8−/− grafts were acutely rejected. Despite similar levels of TLR4, IL-1R, and their ligands, the posttransplant ischemia/reperfusion-induced inflammatory response was more severe in Tir8−/− than in Tir8+/+ grafts and was followed by expansion and maturation of resident dendritic cell precursors. In vitro, Tir8−/− dendritic cell precursors acquired higher allostimulatory activity and released more IL-6 upon stimulation with a TLR4 ligand and TNF-α than Tir8+/+ cells, which may explain the increased frequency of antidonor-reactive T cells and the block of regulatory T cell formation in recipients of a Tir8−/− kidney. Thus, TIR8 acts locally as a key regulator of allogeneic immune response in the kidney. Tir8 expression and/or signaling in donor tissue are envisaged as a novel target for control of innate immunity and amelioration of graft survival.

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Section: Discussionsupporting

confidence: 52%

The Toll-IL-1R Member Tir8/SIGIRR Negatively Regulates Adaptive Immunity against Kidney Grafts

Noris

Cassis

Azzollini³

et al. 2009

The Journal of Immunology

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“…8 However, our results show that anti-donor Ab formation is reduced by blocking IL-6 receptor signaling. Thus, multiple factors (including adaptive immunity) may be responsible for inducing allograftproduced and recipient-produced IL-6 after clinical transplant.…”

Section: Discussioncontrasting

confidence: 46%

“…Elevated IL-6 levels in a donor's heart, kidney, and liver have been shown to worsen ischemia-reperfusion injury in recipients, resulting in deteriorating organ function. 7,8 Although advances in immunosuppressive drugs have greatly decreased the incidence of acute graft rejection and chronic rejection 9 remain a barrier to long-term graft survival. 10 Chronic rejection of cardiac allografts manifests as interstitial fibrosis, vascular occlusion, and progressive deterioration of graft function.…”

Section: Introductionmentioning

confidence: 99%

Interleukin-6 Receptor Signaling Disruption Prevents Cardiac Allograft Deterioration in Mice

Iida¹,

Omoto²,

Kanemitsu³

et al. 2012

Exp Clin Transplant

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Objectives: Interleukin-6, a pleiotropic cytokine that functions in both innate and adaptive immune responses, has been implicated in allograft rejection. We analyzed the efficacy of anti interleukin-6 receptor monoclonal antibody in delaying allograft rejection in a murine model of a heart. Materials and Methods: To investigate the role of interleukin-6 receptor signal transduction in acute and chronic allograft rejection, we blocked interleukin-6 receptor signaling to suppress the alloimmune response in C57BL/6 recipients of BALB/c cardiac allografts. Results: Administration of a high-dose α-interleukin-6 receptor monoclonal antibody prevented the intragraft infiltration of inflammatory cells and lymphocytes and prolonged allograft survival during the peritransplant period. However, all allografts were rejected by 23.5 days after transplant. In contrast, cardiac allograft recipients treated with a cytotoxic T-lymphocyte antigen 4-immunoglobulin plus continued administration of low-dose α-interleukin-6 receptor monoclonal antibody showed long-term graft survival compared with cytotoxic T-lymphocyte antigen 4-immunoglobulin monotherapy. A histologic analysis revealed that graft fibrosis was prevented in cytotoxic T-lymphocyte antigen 4-immunoglobulin plus highdose α-interleukin-6 receptor monoclonal antibody group, but not in the cytotoxic T-lymphocyte antigen 4-immunoglobulin alone group. This suggests that deterioration of graft function associated with chronic rejection could be prevented by blocking interleukin-6 receptor signaling. Conclusions: Disruption of interleukin-6 receptor signaling is an effective strategy for modulating proinflammatory immune responses and preventing chronic rejection.

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“…Indeed, the Th1-polarizing cytokine IL-12 is highly associated with acute allograft rejection (42,43). Additionally, IL-6 has been shown to play a key role in acute inflammatory response (44) and in early injuries following allograft in transplantation models (45,46). Interestingly, whereas in 1-h H/R DCs, eATP decreased IL-12 and IL-6 production by these cells, in 5-h H/R DCs this effect was completely lost.…”

Section: Discussionmentioning

confidence: 88%

Hypoxia/Reoxygenation Inhibits P2Y11 Receptor Expression and Its Immunosuppressive Activity in Human Dendritic Cells

Chadet

Ivanès

Benoist

et al. 2015

The Journal of Immunology

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High concentrations of extracellular ATP (eATP) resulting from cell damage may be found during an ischemia/reperfusion (I/R) episode at the site of injury. eATP activates purinergic receptors in dendritic cells (DCs) and may inhibit inflammation. This immunosuppressive activity could be of interest in the field of I/R, which is an inflammatory condition involved in myocardial infarction, stroke, and solid organ transplantation. However, the specific purinergic receptor responsible for this effect remains to be identified. In this study, we report that eATP induced maturation of human monocyte-derived DCs. Additionally, eATP inhibited IL-12 production whereas IL-10 levels remained unchanged in activated DCs. These effects were prevented by the P2Y11R antagonist NF340. Interestingly, a 5-h hypoxia prevented the effects of eATP on cytokine production whereas a 1-h hypoxia did not affect the eATP-mediated decrease of IL-12 and IL-6. We showed a time-dependent downregulation of P2Y11R at both mRNA and protein levels that was prevented by knocking down hypoxia-inducible factor-1α. In this study, we showed an immunosuppressive role of P2Y11R in human DCs. Additionally, we demonstrated that the time-dependent downregulation of P2Y11R by hypoxia orientates DCs toward a proinflammatory phenotype that may be involved in post-I/R injuries as observed after organ transplantation.

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Graft Produced Interleukin-6 Functions as a Danger Signal and Promotes Rejection After Transplantation

Cited by 67 publications

References 33 publications

The Toll-IL-1R Member Tir8/SIGIRR Negatively Regulates Adaptive Immunity against Kidney Grafts

The Toll-IL-1R Member Tir8/SIGIRR Negatively Regulates Adaptive Immunity against Kidney Grafts

Interleukin-6 Receptor Signaling Disruption Prevents Cardiac Allograft Deterioration in Mice

Hypoxia/Reoxygenation Inhibits P2Y11 Receptor Expression and Its Immunosuppressive Activity in Human Dendritic Cells

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