Association of interleukin4 gene polymorphisms of recipients and donors with acute rejection following living donor liver transplantation

Kamei, Hideya; Masuda, Satohiro; Ishigami, Masatoshi; Nakamura, Taro; Fujimoto, Yasuhiro; Takada, Yasutsugu; Hamajima, Nobuyuki

doi:10.1016/j.clinre.2015.06.019

Cited by 8 publications

(9 citation statements)

References 55 publications

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“…In organ transplantation, genetic or environmental factors associated with either the donor or the recipient could influence the rejection of the transplanted organ. For instance, polymorphisms of both the transplant donor [ 37 , 38 ] and recipient [ 39 – 41 ] have been shown to impact graft rejection, and we have previously demonstrated that antibiotic pre-treatment needs to be administered to both the donor and the recipient to result in prolonged skin graft survival [ 20 ]. In the cohousing and fecal transfer experiments described in Figs.…”

Section: Resultsmentioning

confidence: 99%

Gut microbes contribute to variation in solid organ transplant outcomes in mice

McIntosh¹,

Chen²,

Shaiber³

et al. 2018

Microbiome

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BackgroundSolid organ transplant recipients show heterogeneity in the occurrence and timing of acute rejection episodes. Understanding the factors responsible for such variability in patient outcomes may lead to improved diagnostic and therapeutic approaches. Rejection kinetics of transplanted organs mainly depends on the extent of genetic disparities between donor and recipient, but a role for environmental factors is emerging. We have recently shown that major alterations of the microbiota following broad-spectrum antibiotics, or use of germ-free animals, promoted longer skin graft survival in mice. Here, we tested whether spontaneous differences in microbial colonization between genetically similar individuals can contribute to variability in graft rejection kinetics.ResultsWe compared rejection kinetics of minor mismatched skin grafts in C57BL/6 mice from Jackson Laboratory (Jax) and Taconic Farms (Tac), genetically similar animals colonized by different commensal microbes. Female Tac mice rejected skin grafts from vendor-matched males more quickly than Jax mice. We observed prolonged graft survival in Tac mice when they were exposed to Jax mice microbiome through co-housing or fecal microbiota transplantation (FMT) by gastric gavage. In contrast, exposure to Tac mice did not change graft rejection kinetics in Jax mice, suggesting a dominant suppressive effect of Jax microbiota. High-throughput sequencing of 16S rRNA gene amplicons from Jax and Tac mice fecal samples confirmed a convergence of microbiota composition after cohousing or fecal transfer. Our analysis of amplicon data associated members of a single bacterial genus, Alistipes, with prolonged graft survival. Consistent with this finding, members of the genus Alistipes were absent in a separate Tac cohort, in which fecal transfer from Jax mice failed to prolong graft survival.ConclusionsThese results demonstrate that differences in resident microbiome in healthy individuals may translate into distinct kinetics of graft rejection, and contribute to interpersonal variability in graft outcomes. The association between Alistipes and prolonged skin graft survival in mice suggests that members of this genus might affect host physiology, including at sites distal to the gastrointestinal tract. Overall, these findings allude to a potential therapeutic role for specific gut microbes to promote graft survival through the administration of probiotics, or FMT.Electronic supplementary materialThe online version of this article (10.1186/s40168-018-0474-8) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Gut microbes contribute to variation in solid organ transplant outcomes in mice

McIntosh¹,

Chen²,

Shaiber³

et al. 2018

Microbiome

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“…[9][10][11] Despite a longstanding interest in immune monitoring strategies, there are currently no available assays other than IS drug levels, liver function tests (LFTs), or biopsies, which are either suboptimal or impractical for assessing individual IS requirements. [12][13][14] Several genomic biomarkers have been proposed to distinguish causes of graft dysfunction, [15][16][17][18][19][20][21][22][23][24][25][26][27][28][29] but these have not been subjected to robust validation and not analyzed before these events. Having a biomarker that can serially distinguish the onset of rejection versus continued stable graft function, before liver injury occurs, could more specifically enhance current "trial and error" IS practices and outcomes.…”

Section: Introductionmentioning

confidence: 99%

Discovery and validation of a novel blood-based molecular biomarker of rejection following liver transplantation

Levitsky

Asrani

Schiano

et al. 2020

American Journal of Transplantation

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“…More specifically, F-actin-dependent DNGR-1 signaling facilitates the process whereby antigens associated with dead cell cargo taken up by cDC1 are shuttled into the MHC class I (MHC I) cross-presentation pathway. The latter includes the transporter associated with antigen processing 1 (Tap1) complex, which is essential for antigenic peptide translocation into the ER and, in synergy with other ER chaperones, for loading of the MHC I heavy chain/β-2-microglobulin (β2M) light chain complex [30][31][32][33][34][35][36][37].…”

Section: Introductionmentioning

confidence: 99%

Cross‐presentation of dead‐cell‐associated antigens by DNGR‐1⁺ dendritic cells contributes to chronic allograft rejection in mice

Balam¹,

Kesselring²,

Eggenhofer³

et al. 2020

Eur J Immunol

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The purpose of this study was to elucidate whether DC NK lectin group receptor-1 (DNGR-1)-dependent cross-presentation of dead-cell-associated antigens occurs after transplantation and contributes to CD8 + T cell responses, chronic allograft rejection (CAR), and fibrosis. BALB/c or C57BL/6 hearts were heterotopically transplanted into WT, Clec9a −/− , or Batf3 −/− recipient C57BL/6 mice. Allografts were analyzed for cell infiltration, CD8 + T cell activation, fibrogenesis, and CAR using immunohistochemistry, Western blot, qRT 2-PCR, and flow cytometry. Allografts displayed infiltration by recipient DNGR-1 + DCs, signs of CAR, and fibrosis. Allografts in Clec9a −/− recipients showed reduced CAR (p < 0.0001), fibrosis (P = 0.0137), CD8 + cell infiltration (P < 0.0001), and effector cytokine levels compared to WT recipients. Batf3-deficiency greatly reduced DNGR-1 + DC-infiltration, CAR (P < 0.0001), and fibrosis (P = 0.0382). CD8 cells infiltrating allografts of cytochrome C treated recipients, showed reduced production of CD8 effector cytokines (P < 0.05). Further, alloreactive CD8 + T cell response in indirect pathway IFN-γ ELISPOT was reduced in Clec9a −/− recipient mice (P = 0.0283). Blockade of DNGR-1 by antibody, similar to genetic elimination of the receptor, reduced CAR (P = 0.0003), fibrosis (P = 0.0273), infiltration of CD8 + cells (p = 0.0006), and effector cytokine levels. DNGR-1-dependent alloantigen cross-presentation by DNGR-1 + DCs induces alloreactive CD8 + cells that induce CAR and fibrosis. Antibody against DNGR-1 can block this process and prevent CAR and fibrosis. Keywords: CD8 + T cells r cDC1 r cross-presentation r DNGR-1 r transplantation Additional supporting information may be found online in the Supporting Information section at the end of the article.

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Association of interleukin4 gene polymorphisms of recipients and donors with acute rejection following living donor liver transplantation

Cited by 8 publications

References 55 publications

Gut microbes contribute to variation in solid organ transplant outcomes in mice

Gut microbes contribute to variation in solid organ transplant outcomes in mice

Discovery and validation of a novel blood-based molecular biomarker of rejection following liver transplantation

Cross‐presentation of dead‐cell‐associated antigens by DNGR‐1⁺ dendritic cells contributes to chronic allograft rejection in mice

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Association of interleukin4 gene polymorphisms of recipients and donors with acute rejection following living donor liver transplantation

Cited by 8 publications

References 55 publications

Gut microbes contribute to variation in solid organ transplant outcomes in mice

Gut microbes contribute to variation in solid organ transplant outcomes in mice

Discovery and validation of a novel blood-based molecular biomarker of rejection following liver transplantation

Cross‐presentation of dead‐cell‐associated antigens by DNGR‐1+ dendritic cells contributes to chronic allograft rejection in mice

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Product

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Cross‐presentation of dead‐cell‐associated antigens by DNGR‐1⁺ dendritic cells contributes to chronic allograft rejection in mice