Graft-Derived IL-6 Amplifies Proliferation and Survival of Effector T Cells That Drive Alloimmune-Mediated Vascular Rejection

Rossum, Anna von; Rey, Kevin; Enns, Winnie; Manku, Sukhbir; Cheema, Rajan; MacEwan, Grace E.; Choy, Jonathan C.

doi:10.1097/tp.0000000000001227

Cited by 15 publications

(13 citation statements)

References 53 publications

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“…Von Rossom et al (29) used a murine aortic interposition model of vascular rejection to examine the mechanism via which IL-6 contributes to the pathogenesis of vascular rejection and transplant arteriosclerosis. Von Rossom et al (29) used a murine aortic interposition model of vascular rejection to examine the mechanism via which IL-6 contributes to the pathogenesis of vascular rejection and transplant arteriosclerosis.…”

Section: Discussionmentioning

confidence: 99%

“…Data from relevant animal models are also supportive of an important role for IL-6 in the mediation of allograft vasculopathy. Von Rossom et al (29) used a murine aortic interposition model of vascular rejection to examine the mechanism via which IL-6 contributes to the pathogenesis of vascular rejection and transplant arteriosclerosis. The authors conclude that donor-derived IL-6 amplifies and expands allogeneic T cell response that cause vascular rejection.…”

Section: Discussionmentioning

confidence: 99%

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Assessment of Tocilizumab (Anti–Interleukin-6 Receptor Monoclonal) as a Potential Treatment for Chronic Antibody-Mediated Rejection and Transplant Glomerulopathy in HLA-Sensitized Renal Allograft Recipients

Choi

Aubert

et al. 2017

American Journal of Transplantation

293

256

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Extending the functional integrity of renal allografts is the primary goal of transplant medicine. The development of donor-specific antibodies (DSAs) posttransplantation leads to chronic active antibody-mediated rejection (cAMR) and transplant glomerulopathy (TG), resulting in the majority of graft losses that occur in the United States. This reduces the quality and length of life for patients and increases cost. There are no approved treatments for cAMR. Evidence suggests the proinflammatory cytokine interleukin 6 (IL-6) may play an important role in DSA generation and cAMR. We identified 36 renal transplant patients with cAMR plus DSAs and TG who failed standard of care treatment with IVIg plus rituximab with or without plasma exchange. Patients were offered rescue therapy with the anti-IL-6 receptor monoclonal tocilizumab with monthly infusions and monitored for DSAs and long-term outcomes. Tocilizumab-treated patients demonstrated graft survival and patient survival rates of 80% and 91% at 6 years, respectively. Significant reductions in DSAs and stabilization of renal function were seen at 2 years. No significant adverse events or severe adverse events were seen. Tocilizumab provides good long-term outcomes for patients with cAMR and TG, especially compared with historical published treatments. Inhibition of the IL-6-IL-6 receptor pathway may represent a novel approach to stabilize allograft function and extend patient lives.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Assessment of Tocilizumab (Anti–Interleukin-6 Receptor Monoclonal) as a Potential Treatment for Chronic Antibody-Mediated Rejection and Transplant Glomerulopathy in HLA-Sensitized Renal Allograft Recipients

Choi

Aubert

et al. 2017

American Journal of Transplantation

293

256

View full text Add to dashboard Cite

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“…TNF-α is one of the earliest and most important mediators of inflammation. IL-6 induces a humoral response, more specifically B cell differentiation and antibody production, as well as a cell-mediated response, more specifically T cell activation, proliferation and differentiation, and it participates in the immune response [48,49]. A previous study demonstrated that thymol inhibits TNF-α and IL-6 production via the nuclear factor-kappa B (NF-κB) signaling pathway in mice with an LPS-induced acute lung injury [46,50].…”

Section: Discussionmentioning

confidence: 99%

Thymol Inhibits Biofilm Formation, Eliminates Pre-Existing Biofilms, and Enhances Clearance of Methicillin-Resistant Staphylococcus aureus (MRSA) in a Mouse Peritoneal Implant Infection Model

et al. 2020

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Methicillin-resistant Staphylococcus aureus (MRSA) is a common human pathogen that causes several difficult-to-treat infections, including biofilm-associated infections. The biofilm-forming ability of S. aureus plays a pivotal role in its resistance to most currently available antibiotics, including vancomycin, which is the first-choice drug for treating MRSA infections. In this study, the ability of thymol (a monoterpenoid phenol isolated from plants) to inhibit biofilm formation and to eliminate mature biofilms, was assessed. We found that thymol could inhibit biofilm formation and remove mature biofilms by inhibiting the production of polysaccharide intracellular adhesin (PIA) and the release of extracellular DNA (eDNA). However, cotreatment with thymol and vancomycin was more effective at eliminating MRSA biofilms, in a mouse infection model, than monotherapy with vancomycin. Comparative histopathological analyses revealed that thymol reduced the pathological changes and inflammatory responses in the wounds. Assessments of white blood cell counts and serum TNF-α and IL-6 levels showed reduced inflammation and an increased immune response following treatment with thymol and vancomycin. These results indicate that combinatorial treatment with thymol and vancomycin has the potential to serve as a more effective therapy for MRSA biofilm-associated infections than vancomycin monotherapy.

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“…This is of particular significance given the accumulating evidence suggesting that Foxp3 + Tregs are critical for maintaining immune homeostasis and immune tolerance in transplantation [ 50 , 51 ]. Lastly, amplification and expansion of the allogeneic T-cell response by graft-derived IL-6 have been shown to contribute to vascular rejection and allograft arteriosclerosis [ 52 ].…”

Section: Integral Role Of Il-6 In Inflammation/immunitymentioning

confidence: 99%

IL-6 Directed Therapy in Transplantation

Miller

Madsen

2021

Curr Transpl Rep

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Purpose of Review IL-6 is a pleiotropic, pro-inflammatory cytokine that plays an integral role in the development of acute and chronic rejection after solid organ transplantation. This article reviews the experimental evidence and current clinical application of IL-6/IL-6 receptor (IL-6R) signaling inhibition for the prevention and treatment of allograft injury. Recent Findings There exists a robust body of evidence linking IL-6 to allograft injury mediated by acute inflammation, adaptive cellular/humoral responses, innate immunity, and fibrosis. IL-6 promotes the acute phase reaction, induces B cell maturation/antibody formation, directs cytotoxic T-cell differentiation, and inhibits regulatory T-cell development. Importantly, blockade of the IL-6/IL-6R signaling pathway has been shown to mitigate its harmful effects in experimental studies, particularly in models of kidney and heart transplant rejection. Currently, available agents for IL-6 signaling inhibition include monoclonal antibodies against IL-6 or IL-6R and janus kinase inhibitors. Recent clinical trials have investigated the use of tocilizumab, an anti-IL-6R mAb, for desensitization and treatment of antibody-mediated rejection (AMR) in kidney transplant recipients, with promising initial results. Further studies are underway investigating the use of alternative agents including clazakizumab, an anti-IL-6 mAb, and application of IL-6 signaling blockade to clinical cardiac transplantation. Summary IL-6/IL-6R signaling inhibition provides a novel therapeutic option for the prevention and treatment of allograft injury. To date, evidence from clinical trials supports the use of IL-6 blockade for desensitization and treatment of AMR in kidney transplant recipients. Ongoing and future clinical trials will further elucidate the role of IL-6 signaling inhibition in other types of solid organ transplantation.

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Graft-Derived IL-6 Amplifies Proliferation and Survival of Effector T Cells That Drive Alloimmune-Mediated Vascular Rejection

Abstract: Donor-derived IL-6 amplifies the expansion of allogeneic T cell responses that cause vascular rejection and TA by increasing T cell proliferation and preventing Fas-mediated T cell death.

Cited by 15 publications

References 53 publications

Assessment of Tocilizumab (Anti–Interleukin-6 Receptor Monoclonal) as a Potential Treatment for Chronic Antibody-Mediated Rejection and Transplant Glomerulopathy in HLA-Sensitized Renal Allograft Recipients

Assessment of Tocilizumab (Anti–Interleukin-6 Receptor Monoclonal) as a Potential Treatment for Chronic Antibody-Mediated Rejection and Transplant Glomerulopathy in HLA-Sensitized Renal Allograft Recipients

Thymol Inhibits Biofilm Formation, Eliminates Pre-Existing Biofilms, and Enhances Clearance of Methicillin-Resistant Staphylococcus aureus (MRSA) in a Mouse Peritoneal Implant Infection Model

IL-6 Directed Therapy in Transplantation

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