Attenuation of Cross-Talk Between the Complement and Coagulation Cascades by C5a Blockade Improves Early Outcomes After Intraportal Islet Transplantation

Tokodai, Kazuaki; Goto, Masafumi; Inagaki, Akiko; Nakanishi, Waka; Ogawa, N.; Satoh, Kazushige; Kawagishi, Naoki; Sekiguchi, Satoshi; Nilsson, Bo; Okada, Noriko; Okada, Hidechika; Satoh, Susumu

doi:10.1097/tp.0b013e3181ffb9f5

Cited by 47 publications

(29 citation statements)

References 34 publications

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“…Neutralizing antibodies against C5a have demonstrated protective effects in experimental sepsis (67), and this promising therapeutic concept appears to apply to the use of mAb IFX-1 (CaCP29, InflaRx; target has not been officially disclosed) that has been evaluated in phase I trials (NCT01319903). In addition, two strategies have been developed that exploit structurally complementary molecules as C5a inhibitors; whereas NOX-D19 (Noxxon) is based on spiegelmer technology ( i.e., biostable RNA aptamers), antisense peptides (C5aIP, AcPepA) have been tested in islet transplantation and sepsis (68, 69). As a GPCR, the C5aR represents a druggable target and several small molecule antagonists have indeed been developed over the years (11, 50).…”

Section: The Therapeutic Arsenal To Tackle Complement-related Diseasesmentioning

confidence: 99%

Complement in Immune and Inflammatory Disorders: Therapeutic Interventions

Ricklin

Lambris

2013

The Journal of Immunology

203

230

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With the awareness that immune-inflammatory crosstalk is at the heart of many disorders, the desire for novel immunomodulatory strategies in the therapy of such diseases has grown dramatically. As a prime initiator and important modulator of immunological and inflammatory processes, the complement system has emerged as an attractive target for early and upstream intervention in inflammatory diseases and has moved into the spotlight of drug discovery. While prevalent conditions such as age-related macular degeneration have attracted the most attention, the diverse array of complement-mediated pathologies, with distinct underlying mechanisms, demands a multifaceted arsenal of therapeutic strategies. Fortunately, efforts in recent years have not only introduced the first complement inhibitors to the clinic but also filled the pipelines with promising candidates. With a focus on immunomodulatory strategies, this review discusses complement-directed therapeutic concepts and highlights promising candidate molecules.

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Section: The Therapeutic Arsenal To Tackle Complement-related Diseasesmentioning

confidence: 99%

Complement in Immune and Inflammatory Disorders: Therapeutic Interventions

Ricklin

Lambris

2013

The Journal of Immunology

203

230

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“…Thrombin-antithrombin levels were also reduced with the combined treatment. TF was downregulated by complement protein C5a inhibitory peptide treatment, but only on the liver granulocytes and not on the islet grafts [61]. The use of a complement inhibitor such as compstatin has been shown to significantly improve graft survival in in vivo models [62].…”

Section: Peritransplant Inflammationmentioning

confidence: 99%

Inflammatory Response in Islet Transplantation

Kanak

Takita²,

Kunnathodi³

et al. 2014

International Journal of Endocrinology

110

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Islet cell transplantation is a promising beta cell replacement therapy for patients with brittle type 1 diabetes as well as refractory chronic pancreatitis. Despite the vast advancements made in this field, challenges still remain in achieving high frequency and long-term successful transplant outcomes. Here we review recent advances in understanding the role of inflammation in islet transplantation and development of strategies to prevent damage to islets from inflammation. The inflammatory response associated with islets has been recognized as the primary cause of early damage to islets and graft loss after transplantation. Details on cell signaling pathways in islets triggered by cytokines and harmful inflammatory events during pancreas procurement, pancreas preservation, islet isolation, and islet infusion are presented. Robust control of pre- and peritransplant islet inflammation could improve posttransplant islet survival and in turn enhance the benefits of islet cell transplantation for patients who are insulin dependent. We discuss several potent anti-inflammatory strategies that show promise for improving islet engraftment. Further understanding of molecular mechanisms involved in the inflammatory response will provide the basis for developing potent therapeutic strategies for enhancing the quality and success of islet transplantation.

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“…Recently, an acetylated form of PepA (AcPepA) was generated to improve the inhibition capacity of PepA (30). AcPepA prevented acute skin inflammation (30) and acute rejection of islet transplantations in models (38).…”

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confidence: 99%