HMGB1-Mediated Early Loss of Transplanted Islets Is Prevented by Anti–IL-6R Antibody in Mice

Itoh, Takeshi; Nitta, Tomoyuki; Nishinakamura, Hitomi; Kojima, Daisuke; Mera, Toshiyuki; Ono, Junko; Kodama, Shohta; Yasunami, Yohichi

doi:10.1097/mpa.0000000000000188

Cited by 26 publications

(23 citation statements)

References 26 publications

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“…38 Moreover, it has been previously reported that cytokines secreted from transplanted islets cause local inflammation that triggers the innate response and graft failure. 39 Although we confirmed that the islets maintained their viability just after papain treatment in vitro (Fig. 5), it is possible that islets pretreated with a higher papain concentration cause stronger inflammation by releasing high levels of cytokines, leading to early graft loss.…”

Section: Discussionsupporting

confidence: 53%

Pretreatment of donor islets with papain improves allograft survival without systemic immunosuppression in mice

Kumano

Nishinakamura

Mera

et al. 2016

Islets

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Although current immunosuppression protocols improve the efficacy of clinical allogenic islet transplantation, T cell-mediated allorejection remains unresolved, and major histocompatibility complexes (MHCs) play a crucial role in this process. Papain, a cysteine protease, has the unique ability to cleave the extracellular domain of the MHC class I structure. We hypothesized that pretreatment of donor islets with papain would diminish the expression of MHC class I on islets, reducing allograft immunogenicity and contributing to prolongation of islet allograft survival. BALB/ c islets pretreated with papain were transplanted into C57BL/6J mice as an acute allorejection model. Treatment with 1 mg/mL papain significantly prolonged islet allograft survival. In vitro, to determine the inhibitory effect on T cell-mediated alloreactions, we performed lymphocyte proliferation assays and mixed lymphocyte reactions. Host T cell activation against allogenic islet cells was remarkably suppressed by pretreatment of donor islet cells with 10 mg/mL papain. Flow cytometric analysis was also performed to investigate the effect of papain treatment on the expression of MHC class I on islets. One or 10 mg/mL papain treatment reduced MHC class I expression on the islet cell surface. Pretreatment of donor islets with papain suppresses MHC class Imediated allograft rejection in mice and contributes to prolongation of islet allograft survival without administration of systemic immunosuppressants. These results suggest that pretreatment of human donor islets with papain may reduce the immunogenicity of the donor islets and minimize the dosage of systemic immunosuppressants required in a clinical setting.

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Section: Discussionsupporting

confidence: 53%

Pretreatment of donor islets with papain improves allograft survival without systemic immunosuppression in mice

Kumano

Nishinakamura

Mera

et al. 2016

Islets

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“…MNCs in the peritoneal cavity were collected and examined by flow cytometry (FACSVerse; Becton Dickinson, San Jose, CA, USA) . The following mAbs were used as follows: anti‐mouse Fcγ III/II R (2.4G2), fluorescein‐isothiocyanate‐conjugated anti‐CD11b (M1/70), PerCP/Cy5.5‐conjugated anti‐F4/80 (BM8), Gr‐1 (Rb6‐8c5), major histocompatibility complex (MHC)‐class II (M5/114.15.2), PE‐conjugated CD11c (N418), allophycocyanin‐conjugated anti‐interferon (IFN)‐γ (XMG1.2), tumor necrosis factor (TNF)‐α (MP6‐XT22), interleukin (IL)‐6 (MP‐5‐20F3), IL‐12 (C15.6), and isotype control (R3‐34, Rat IgG1κ) (BD Biosciences, San Jose, CA, USA) . For intracellular staining, cells were incubated with anti‐Fcγ III/II R (BD Biosciences), surface stained, fixed, permeabilized, stained with mAbs, and analyzed on a flow cytometer .…”

Section: Methodsmentioning

confidence: 99%

“…One of the major reasons for the limited efficacy was early non‐function of transplanted microencapsulated NPIs due to inflammatory reactions at the site of transplantation . Previously, we have demonstrated that high‐mobility group box 1 (HMGB1), a damage‐associated molecular pattern (DAMP) molecule , was released from transplanted islets and triggered inflammatory reactions, leading to early loss of intrahepatic syngeneic islet grafts in a mouse model .…”

Section: Introductionmentioning

confidence: 99%

Islet‐derived damage‐associated molecular pattern molecule contributes to immune responses following microencapsulated neonatal porcine islet xenotransplantation in mice

Itoh

Hata

Nishinakamura

et al. 2016

Xenotransplantation

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“…Instead, there were studies focusing on the role of HMGB1 in islet transplantation [128–133]. HMGB1 inhibition by anti-IL-6R antibody, HMGB1 A-box, NF- κ B inhibitor, or the Na(+)/Ca(2+) exchanger inhibitor was able to ameliorate inflammatory responses and islet survival after islet transplantation by reducing the amount of innate immune cells and cytokines like TNF- α and interferon- (IFN-) γ [129–132]. And blockade of HMGB1 with anti-HMGB1 monoclonal antibody (mAb, 2g7) inhibited inflammatory response by reducing TNF- α and IL-1 β production and thereby improved islet viability after islet cells transplantation [134].…”

Section: Role Of Hmgb1 In Type 2 Diabetesmentioning

confidence: 99%

The Role of HMGB1 in the Pathogenesis of Type 2 Diabetes

Wang

Zhong

Zhang

et al. 2016

Journal of Diabetes Research

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Significance. With an alarming increase in recent years, diabetes mellitus has become a global challenge. Despite advances in treatment of diabetes mellitus, currently, medications available are unable to control the progression of diabetes and its complications. Growing evidence suggests that inflammation is an important pathogenic mediator in the development of diabetes mellitus. The perspectives including suggestions for new therapies involving the shift from metabolic stress to inflammation should be taken into account. Critical Issues. High-mobility group box 1 (HMGB1), a nonhistone nuclear protein regulating gene expression, was rediscovered as an endogenous danger signal molecule to trigger inflammatory responses when released into extracellular milieu in the late 1990s. Given the similarities of inflammatory response in the development of T2D, we will discuss the potential implication of HMGB1 in the pathogenesis of T2D. Importantly, we will summarize and renovate the role of HMGB1 and HMGB1-mediated inflammatory pathways in adipose tissue inflammation, insulin resistance, and islet dysfunction. Future Directions. HMGB1 and its downstream receptors RAGE and TLRs may serve as potential antidiabetic targets. Current and forthcoming projects in this territory will pave the way for prospective approaches targeting the center of HMGB1-mediated inflammation to improve T2D and its complications.

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HMGB1-Mediated Early Loss of Transplanted Islets Is Prevented by Anti–IL-6R Antibody in Mice

Abstract: These findings demonstrate that anti-IL-6R antibody prevented the early loss of intrahepatic islet grafts with inhibiting HMGB1-induced immune activation after islet transplantation.

Cited by 26 publications

References 26 publications

Pretreatment of donor islets with papain improves allograft survival without systemic immunosuppression in mice

Pretreatment of donor islets with papain improves allograft survival without systemic immunosuppression in mice

Islet‐derived damage‐associated molecular pattern molecule contributes to immune responses following microencapsulated neonatal porcine islet xenotransplantation in mice

The Role of HMGB1 in the Pathogenesis of Type 2 Diabetes

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