Inhibition of Tumor Necrosis Factor-α Attenuates Myocardial Remodeling in Rat Cardiac Allografts

Sihvola, Roope; Koskinen, Petri; Pulkkinen, Ville; Tikkanen, Jussi; Lemström, Karl

doi:10.1016/j.healun.2006.01.002

Cited by 6 publications

(3 citation statements)

References 37 publications

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“…The latter difference could depend on the type of injury; we studied rejection whereas Torre-Amione et al (32) studied congestive failure. Our results are consistent with previous findings in rat cardiac allografts (33, 34), demonstrating increased levels of intragraft TNF and TNFR2 mRNA but not TNFR1 mRNA expression in CM of rejecting hearts. Although the role of myocardial TNFR2 is unclear, neutralizing anti-TNFR2 antibodies exacerbate TNF-induced cell death, consistent with a protective role (27, 35).…”

Section: Discussionsupporting

confidence: 93%

TNF Receptors Differentially Signal and Are Differentially Expressed and Regulated in the Human Heart

Al-Lamki

Brookes

Wang

et al. 2009

American Journal of Transplantation

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Tumor necrosis factor (TNF) utilizes two receptors, TNFR1 and 2, to initiate target cell responses. We assessed expression of TNF, TNFRs and downstream kinases in cardiac allografts, and compared TNF responses in heart organ cultures from wild-type (WTC57BL/6), TNFR1-knockout (KO), TNFR2KO, TNFR1/2KO mice. In non-rejecting human heart TNFR1 was strongly expressed coincidentally with inactive apoptosis signal-regulating kinase-1 (ASK1) in cardiomyocytes (CM) and vascular endothelial cells (VEC). TNFR2 was expressed only in VEC. Low levels of TNF localized to microvessels. Rejecting cardiac allografts showed increased TNF in microvessels, diminished TNFR1, activation of ASK1, upregulated TNFR2 co-expressed with activated endothelial/epithelial tyrosine kinase (Etk), increased apoptosis and cell cycle entry in CM. Neither TNFR was expressed significantly by cardiac fibroblasts. In WTC57BL/6 myocardium, TNF activated both ASK1 and Etk, and increased both apoptosis and cell cycle entry. TNF-treated TNFR1KO myocardium showed little ASK1 activation and apoptosis but increased Etk activation and cell cycle entry, while TNFR2KO myocardium showed little Etk activation and cell cycle entry but increased ASK1 activation and apoptosis. These observations demonstrate independent regulation and differential functions of TNFRs in myocardium, consistent with TNFR1-mediated cell death and TNFR2-mediated repair.

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Section: Discussionsupporting

confidence: 93%

TNF Receptors Differentially Signal and Are Differentially Expressed and Regulated in the Human Heart

Al-Lamki

Brookes

Wang

et al. 2009

American Journal of Transplantation

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“…In this study, the blockade of TNF‐α using chimeric antibody infliximab reduced the formation of transplant arteriosclerosis in a murine aortic allograft model. This finding is in contrast to a previous study that could not demonstrate a beneficial effect of TNF‐α blockade on arteriosclerotic lesion formation despite attenuation of myocardial remodelling in a rat cardiac allograft model [19]. Besides differences in the transplant models, another possible explanation are variations in the biological activity of the construct or antibody used for TNF‐α blockade.…”

Section: Discussioncontrasting

confidence: 97%

Inhibition of TNF-α reduces transplant arteriosclerosis in a murine aortic transplant model

Wollin

Abele

Bruns³

et al. 2009

Transplant International

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Summary Experimental and clinical data provide evidence that TNF‐α contributes to acute and chronic allograft rejection. In this study, we explored the effect of TNF‐α blockade using the chimeric monoclonal antibody infliximab on the development of transplant arterisoclerosis in a fully mismatched aortic allograft model. Post‐transplant treatment of CBA (H2k) recipients with 250 μg infliximab (cumulative dose 1.25 mg) reduced luminal occlusion of C57Bl/6 (H2b) aortic grafts on day 30 from 77 ± 5% in untreated controls to 52 ± 6%. Increasing the dose of anti‐TNF‐α antibody had no further beneficial effect. Treatment with human control immunoglobulin had no effect on intima proliferation. Under TNF‐α blockade, ICAM‐1 and PDGF mRNA expression within the grafts was strongly reduced, whereas iNOS expression was enhanced. The data show that TNF‐α blockade using infliximab can reduce the development of transplant arteriosclerosis in fully mismatched murine aortic grafts.

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“…On the other hand, both TNFR1 and TNFR2 have been associated with graft arterial disease in cardiac allografts ( 119 ). Also, in rat cardiac allograft models, treatment with TNFR2 recombinant protein decreased TNFα expression as well as decreased cardiac remodeling ( 120 ).…”

Section: Tnfr2 In Solid Organ Transplantation and Acute Rejectionmentioning

confidence: 99%

TFNR2 in Ischemia-Reperfusion Injury, Rejection, and Tolerance in Transplantation

Kouyoumdjian

Paraskevas

2022

Front. Immunol.

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Tumor necrosis factor receptor 2 (TNFR2) has been shown to play a crucial role in CD4+ T regulatory cells (CD4+Tregs) expansion and suppressive function. Increasing evidence has also demonstrated its role in a variety of immune regulatory cell subtypes such as CD8+ T regulatory cells (CD8+ Tregs), B regulatory cells (Bregs), and myeloid-derived suppressor cells (MDSCs). In solid organ transplantation, regulatory immune cells have been associated with decreased ischemia-reperfusion injury (IRI), improved graft survival, and improved overall outcomes. However, despite TNFR2 being studied in the context of autoimmune diseases, cancer, and hematopoietic stem cell transplantation, there remains paucity of data in the context of solid organ transplantation and islet cell transplantation. Interestingly, TNFR2 signaling has found a clinical application in islet transplantation which could guide its wider use. This article reviews the current literature on TNFR2 expression in immune modulatory cells as well as IRI, cell, and solid organ transplantation. Our results highlighted the positive impact of TNFR2 signaling especially in kidney and islet transplantation. However, further investigation of TNFR2 in all types of solid organ transplantation are required as well as dedicated studies on its therapeutic use during induction therapy or treatment of rejection.

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Inhibition of Tumor Necrosis Factor-α Attenuates Myocardial Remodeling in Rat Cardiac Allografts

Cited by 6 publications

References 37 publications

TNF Receptors Differentially Signal and Are Differentially Expressed and Regulated in the Human Heart

TNF Receptors Differentially Signal and Are Differentially Expressed and Regulated in the Human Heart

Inhibition of TNF-α reduces transplant arteriosclerosis in a murine aortic transplant model

TFNR2 in Ischemia-Reperfusion Injury, Rejection, and Tolerance in Transplantation

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