Peri- and Postoperative Treatment with the Interleukin-1 Receptor Antagonist Anakinra Is Safe in Patients Undergoing Renal Transplantation: Case Series and Review of the Literature

Mulders-Manders, Catharina M.; Baas, Marije C.; Molenaar, F.; Simon, Anna

doi:10.3389/fphar.2017.00342

Cited by 28 publications

(17 citation statements)

References 42 publications

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“…Previous studies identified associations between levels of IL-1β and IL-1Ra in serum and urine and negative graft outcome; studies in experimental animals and observations in humans also substantiated a possible protective effect of blocking IL-1 after solid organ transplantation (reviewed in Mulders-Manders et al, 2017 ). New evidence suggests that in patients undergoing solid organ transplantation, IL-1 inhibition in addition to standard immunosuppressive regimens may dampen inflammation and protect against negative graft outcome.…”

Section: Multifactorial Inflammatory Conditionsmentioning

confidence: 93%

“…Three patients undergoing renal transplantation were receiving treatment with anakinra in the peri-operative and post-operative period for underlying IL-1-driven autoinflammatory diseases (AOSD, CAPS, and FMF, respectively). Kidney function increased rapidly in all patients; anakinra was well tolerated and safe with the exception of minor infections ( Mulders-Manders et al, 2017 ). The beneficial effects of treatment are likely due to dampening of ischemia-reperfusion injury, which accompanies renal transplantation and leads to release of IL-1 and to impaired graft function.…”

Section: Multifactorial Inflammatory Conditionsmentioning

confidence: 96%

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Anakinra Therapy for Non-cancer Inflammatory Diseases

2018

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Interleukin-1 (IL-1) is the prototypical inflammatory cytokine: two distinct ligands (IL-1α and IL-1β) bind the IL-1 type 1 receptor (IL-1R1) and induce a myriad of secondary inflammatory mediators, including prostaglandins, cytokines, and chemokines. IL-1α is constitutively present in endothelial and epithelial cells, whereas IL-1β is inducible in myeloid cells and released following cleavage by caspase-1. Over the past 30 years, IL-1-mediated inflammation has been established in a broad spectrum of diseases, ranging from rare autoinflammatory diseases to common conditions such as gout and rheumatoid arthritis (RA), type 2 diabetes, atherosclerosis, and acute myocardial infarction. Blocking IL-1 entered the clinical arena with anakinra, the recombinant form of the naturally occurring IL-1 receptor antagonist (IL-1Ra); IL-1Ra prevents the binding of IL-1α as well as IL-1β to IL-1R1. Quenching IL-1-mediated inflammation prevents the detrimental consequences of tissue damage and organ dysfunction. Although anakinra is presently approved for the treatment of RA and cryopyrin-associated periodic syndromes, off-label use of anakinra far exceeds its approved indications. Dosing of 100 mg of anakinra subcutaneously provides clinically evident benefits within days and for some diseases, anakinra has been used daily for over 12 years. Compared to other biologics, anakinra has an unparalleled record of safety: opportunistic infections, particularly Mycobacterium tuberculosis, are rare even in populations at risk for reactivation of latent infections. Because of this excellent safety profile and relative short duration of action, anakinra can also be used as a diagnostic tool for undefined diseases mediated by IL-1. Although anakinra is presently in clinical trials to treat cancer, this review focuses on anakinra treatment of acute as well as chronic inflammatory diseases.

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Section: Multifactorial Inflammatory Conditionsmentioning

confidence: 93%

Section: Multifactorial Inflammatory Conditionsmentioning

confidence: 96%

Anakinra Therapy for Non-cancer Inflammatory Diseases

2018

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“…97 Administration of anakinra to a small number of renal transplant patients appears to be safe and efficacious. 98 Besides limited study in kidney transplant recipients with familial Mediterranean fever, 99 canakinumab has yet to be assessed as a diseasemodifying therapy in transplant patients.…”

Section: Inhibition Of Mac Signaling and Pro-inflammatory Effectsmentioning

confidence: 99%

Complement Membrane Attack Complex

Xie

Jane‐wit

Pober

2020

The American Journal of Pathology

129

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The complement membrane attack complex (MAC) is classically known as a cytolytic effector of innate and adaptive immunity that forms pores in the plasma membrane of pathogens or targeted cells, leading to osmolysis. Nucleated cells resist MAC-mediated cytolysis by expression of inhibitors that block MAC assembly or by rapid removal of MAC through endocytosis or shedding. In the absence of lysis, MAC may induce intracellular signaling and cell activation, responses implicated in a variety of autoimmune, inflammatory, and transplant disease settings. New discoveries into the structure and biophysical properties of MAC revealed heterogeneous MAC precursors and conformations that provide insights into MAC function. In addition, new mechanisms of MAC-mediated signaling and its contribution to disease pathogenesis have recently come to light. MAC-activated cells have been found to express proinflammatory proteinsdoften through NF-kBedependent transcription, assemble inflammasomes, enabling processing, and facilitate secretion of IL-1b and IL-18, as well as other signaling pathways. These recent insights into the mechanisms of action of MAC provide an updated framework to therapeutic approaches that can target MAC assembly, signaling, and proinflammatory effects in various complement-mediated diseases.

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“…antagonists and membrane decoys have been exploited for therapeutics that target IL-1 cytokine function during rheumatoid arthritis, autoinflammatory disease, cardiovascular disease, restenosis following angioplasty, systemic sclerosis, IRI, and diabetes. 41,44,45 In our IRI model, the natural rat IL-1RA was upregulated at POD3, but this is likely too late to prevent immune-mediated damage. However, Anakinra presents a prime candidate for clinical intervention by targeting IRI early inflammatory processes.…”

Section: Discussionmentioning

confidence: 92%

“…Natural mechanisms limit IL‐1‐induced immunopathogenesis and promote adaptive immunity and wound healing. Soluble IL‐1R antagonists and membrane decoys have been exploited for therapeutics that target IL‐1 cytokine function during rheumatoid arthritis, autoinflammatory disease, cardiovascular disease, restenosis following angioplasty, systemic sclerosis, IRI, and diabetes 41,44,45 . In our IRI model, the natural rat IL‐1RA was upregulated at POD3, but this is likely too late to prevent immune‐mediated damage.…”

Section: Discussionmentioning

confidence: 99%

Blocking the IL-1 receptor reduces cardiac transplant ischemia and reperfusion injury and mitigates CMV-accelerated chronic rejection

Orloff

Burg

Haese

et al. 2021

American Journal of Transplantation

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Ischemia-reperfusion injury (IRI) is an important risk factor for accelerated cardiac allograft rejection and graft dysfunction. Utilizing a rat heart isogeneic transplant model, we identified inflammatory pathways involved in IRI in order to identify therapeutic targets involved in disease. Pathway analyses identified several relevant targets, including cytokine signaling by the IL-1 receptor (IL-1R) pathway and inflammasome activation. To investigate the role of IL-1R signaling pathways during IRI, we treated syngeneic cardiac transplant recipients at 1-hour posttransplant with Anakinra, a US Food and Drug Administration (FDA)-approved IL-1R antagonist; or parthenolide, a caspase-1 and nuclear factor kappa-light-chain-enhancer of activated B cells inhibitor that blocks IL-1β maturation. Both Anakinra and parthenolide significantly reduced graft inflammation and cellular recruitment in the treated recipients relative to nontreated controls. Anakinra treatment administered at 1-hour posttransplant to recipients of cardiac allografts from CMV-infected donors significantly increased the time to rejection and reduced viral loads at rejection. Our results indicate that reducing IRI by blocking IL-1Rsignaling pathways with Anakinra or inflammasome activity with parthenolide provides a promising approach for extending survival of cardiac allografts from CMV-infected donors.

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Peri- and Postoperative Treatment with the Interleukin-1 Receptor Antagonist Anakinra Is Safe in Patients Undergoing Renal Transplantation: Case Series and Review of the Literature

Cited by 28 publications

References 42 publications

Anakinra Therapy for Non-cancer Inflammatory Diseases

Anakinra Therapy for Non-cancer Inflammatory Diseases

Complement Membrane Attack Complex

Blocking the IL-1 receptor reduces cardiac transplant ischemia and reperfusion injury and mitigates CMV-accelerated chronic rejection

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