Innate immune mechanisms in transplant allograft vasculopathy

Jane‐wit, Dan; Fang, Caodi; Goldstein, Daniel R.

doi:10.1097/mot.0000000000000314

Cited by 11 publications

(4 citation statements)

References 63 publications

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“…Because of perioperative renal dysfunction, patients with DGF require dialysis before hospital discharge. Early graft dysfunction (EGD), where uni- or biventricular dysfunction occurs perioperatively, is believed to similarly reflect severe IRI in cardiac transplantation ( 24 , 25 ). We analyzed biopsies from patients with DGF and EGD to test associations of Hh signaling with IRI-related injury.…”

Section: Resultsmentioning

confidence: 99%

Hedgehog-induced ZFYVE21 promotes chronic vascular inflammation by activating NLRP3 inflammasomes in T cells

et al. 2023

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The zinc finger protein ZFYVE21 is involved in immune signaling. Using humanized mouse models, primary human cells, and patient samples, we identified a T cell–autonomous role for ZFYVE21 in promoting chronic vascular inflammation associated with allograft vasculopathy. Ischemia-reperfusion injury (IRI) stimulated endothelial cells to produce Hedgehog (Hh) ligands, which in turn induced the production of ZFYVE21 in a population of T memory cells with high amounts of the Hh receptor PTCH1 (PTCH hi cells, CD3 + CD4 + CD45RO + PTCH1 hi PD-1 hi ), vigorous recruitment to injured endothelia, and increased effector responses in vivo. After priming by interferon-γ (IFN-γ), Hh-induced ZFYVE21 activated NLRP3 inflammasome activity in T cells, which potentiated IFN-γ responses. Hh-induced NLRP3 inflammasomes and T cell–specific ZFYVE21 augmented the vascular sequelae of chronic inflammation in mice engrafted with human endothelial cells or coronary arteries that had been subjected to IRI before engraftment. Moreover, the population of PTCH hi T cells producing high amounts of ZFYVE21 was expanded in patients with renal transplant–associated IRI, and sera from these patients expanded this population in control T cells in a manner that depended on Hh signaling. We conclude that Hh-induced ZFYVE21 activates NLRP3 inflammasomes in T cells, thereby promoting chronic inflammation.

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Section: Resultsmentioning

confidence: 99%

Hedgehog-induced ZFYVE21 promotes chronic vascular inflammation by activating NLRP3 inflammasomes in T cells

et al. 2023

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“…Complement activation is involved in the pathogenesis of solid organ transplant rejection 32,33 . To assess functional effects of ZFYVE21-associated signaling in vivo, we utilized a humanized mouse model of allograft vasculopathy, a T cell-mediated process exacerbated by terminal complement activation on ECs 5 .…”

Section: Resultsmentioning

confidence: 99%

ZFYVE21 is a complement-induced Rab5 effector that activates non-canonical NF-κB via phosphoinosotide remodeling of endosomes

et al. 2019

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Complement promotes vascular inflammation in transplant organ rejection and connective tissue diseases. Here we identify ZFYVE21 as a complement-induced Rab5 effector that induces non-canonical NF-κB in endothelial cells (EC). In response to membrane attack complexes (MAC), ZFYVE21 is post-translationally stabilized on MAC+Rab5+ endosomes in a Rab5- and PI(3)P-dependent manner. ZFYVE21 promotes SMURF2-mediated polyubiquitinylation and proteasome-dependent degradation of endosome-associated PTEN to induce vesicular enrichment of PI(3,4,5)P3 and sequential recruitment of activated Akt and NF-κB-inducing kinase (NIK). Pharmacologic alteration of cellular phosphoinositide content with miltefosine reduces ZFYVE21 induction, EC activation, and allograft vasculopathy in a humanized mouse model. ZFYVE21 induction distinctly occurs in response to MAC and is detected in human renal and synovial tissues. Our data identifies ZFYVE21 as a Rab5 effector, defines a Rab5-ZFYVE21-SMURF2-pAkt axis by which it mediates EC activation, and demonstrates a role for this pathway in complement-mediated conditions.

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“…During the first 2 days after cardiac xenograft transplantation, which is an important time point for HAR, Toll‐like receptor (TLR)‐mediated MYD88‐dependent ( TLR1 , TLR2 , TLR8 , NKFB1 , MYD88 , NFKB1 , and NFKB1A )/MYD88‐independent ( CD14 , TICAM1 , and IRF3 ) pathways were induced in the absence of anti‐CD154 mAb, as detected by external pathogen‐associated molecular patterns (PAMPs), resulting in activation of inflammatory cytokines ( TNF α and CXCL10 ) and costimulatory molecules ( CD86 ). Additionally, the nucleotide‐binding oligomerization domain (NOD)‐like receptor (NLR) pathway (detected by internal PAMPs) was also activated, resulting in increased CASP1 ‐ and IL18 ‐related inflammation.…”

Section: Discussionmentioning

confidence: 99%

Immune molecular profiling of whole blood drawn from a non‐human primate cardiac xenograft model treated with anti‐CD154 monoclonal antibodies

Ock

Hwang

et al. 2018

Xenotransplantation

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Most studies of xenografts have been carried out with complex immunosuppressive regimens to prevent immune rejection; however, such treatments may be fatal owing to unknown causes. Here, we performed immune molecular profiling following anti‐CD154 monoclonal antibody (mAb) treatment in heterotopic abdominal cardiac xenografts from α‐1,3‐galactosyltransferase‐knockout pigs into cynomolgus monkeys to elucidate the mechanisms mediating the undesirable fatal side effects of immunosuppressive agents. Blood samples were collected from healthy monkeys as control and then at 2 days after xenograft transplantation and just before humane euthanasia; 94 genes related to the immune system were analyzed. The basic immunosuppressive regimen included cobra venom factor, anti‐thymocyte globulin, and rituximab, with and without anti‐CD154 mAbs. The maintenance therapy was followed with tacrolimus, MMF, and methylprednisolone. The number of upregulated genes was initially decreased on Day 2 (−/+ anti‐CD154 mAb, 22/13) and then increased before euthanasia in recipients treated with anti‐CD154 mAbs (−/+ anti‐CD154 mAb, 30/37). The number of downregulated genes was not affected by anti‐CD154 mAb treatment. Additionally, the number of upregulated genes increased over time for both groups. Interestingly, treatment with anti‐CD154 mAbs upregulated coagulation inducers (CCL2/IL6) before euthanasia. In conclusion, immunosuppressive regimens used for cardiac xenografting affected upregulation of 6 inflammation genes (CXCL10, MPO, MYD88, NLRP3, TNFα, and TLR1) and downregulation of 8 genes (CCR4, CCR6, CD40, CXCR3, FOXP3, GATA3, STAT4, and TBX21).

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Innate immune mechanisms in transplant allograft vasculopathy

Cited by 11 publications

References 63 publications

Hedgehog-induced ZFYVE21 promotes chronic vascular inflammation by activating NLRP3 inflammasomes in T cells

Hedgehog-induced ZFYVE21 promotes chronic vascular inflammation by activating NLRP3 inflammasomes in T cells

ZFYVE21 is a complement-induced Rab5 effector that activates non-canonical NF-κB via phosphoinosotide remodeling of endosomes

Immune molecular profiling of whole blood drawn from a non‐human primate cardiac xenograft model treated with anti‐CD154 monoclonal antibodies

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