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1.
Front Immunol ; 13: 827535, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35281047

RESUMO

Preclinical trials of pig-to-nonhuman primate liver xenotransplantation have recently achieved longer survival times. However, life-threatening thrombocytopenia and coagulation dysregulation continue to limit preclinical liver xenograft survival times to less than one month despite various genetic modifications in pigs and intensive pharmacological support. Transfusion of human coagulation factors and complex immunosuppressive regimens have resulted in substantial improvements in recipient survival. The fundamental biological mechanisms of thrombocytopenia and coagulation dysregulation remain incompletely understood. Current studies demonstrate that porcine von Willebrand Factor binds more tightly to human platelet GPIb receptors due to increased O-linked glycosylation, resulting in increased human platelet activation. Porcine liver sinusoidal endothelial cells and Kupffer cells phagocytose human platelets in an asialoglycoprotein receptor 1-dependent and CD40/CD154-dependent manner, respectively. Porcine Kupffer cells phagocytose human platelets via a species-incompatible SIRPα/CD47 axis. Key drivers of coagulation dysregulation include constitutive activation of the extrinsic clotting cascade due to failure of porcine tissue factor pathway inhibitor to repress recipient tissue factor. Additionally, porcine thrombomodulin fails to activate human protein C when bound by human thrombin, leading to a hypercoagulable state. Combined genetic modification of these key genes may mitigate liver xenotransplantation-induced thrombocytopenia and coagulation dysregulation, leading to greater recipient survival in pig-to-nonhuman primate liver xenotransplantation and, potentially, the first pig-to-human clinical trial.


Assuntos
Células Endoteliais , Trombocitopenia , Animais , Células Endoteliais/metabolismo , Xenoenxertos , Humanos , Fígado , Suínos , Trombocitopenia/metabolismo , Transplante Heterólogo/métodos
2.
Transplant Proc ; 2022 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-35272878

RESUMO

BACKGROUND: The objective of this prospective observational study was to determine whether a transplanted liver graft releases proinflammatory cytokines and chemokines on reperfusion and to determine the relationship between these molecules and subsequent ischemic reperfusion injury and acute kidney injury. METHODS: Blood samples from 66 consecutive patients undergoing liver transplant were analyzed for cyto- and chemokines at different time frames before and after liver transplant. Ischemic reperfusion injury was defined based on the peak levels of arginine transaminase and divided into 3 groups: mild, moderate, and severe. Acute kidney injury was defined according to the latest Kidney Disease: Improving Global Outcomes classification. RESULTS: For more than 40 different cyto/chemokines and growth factors, a certain pattern of expression was observed in all patients with ischemic reperfusion injury. G-SCF, IP10, and HSP90a were significantly elevated in all patients with ischemic reperfusion injury. On the other hand, eotaxin and MCP1 levels were markedly elevated in patients without ischemic reperfusion, suggesting a possible cytoprotective effect. We identified cold ischemia, macrosteatosis > 30%, postreperfusion syndrome, and postoperative use of 2 or more vasoactive agents as independent risk factors for ischemic reperfusion injury. CONCLUSIONS: Ischemia reperfusion injury is accompanied by distinct innate and adaptive immune cytokine signatures before and after transplant. It can be used for therapeutic intervention with goal to improve post-transplant graft outcomes.

4.
Cancers (Basel) ; 14(6)2022 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-35326593

RESUMO

The poor prognosis of cholangiocarcinoma in humans is related to several factors, such as (i) the heterogeneity of the disease, (ii) the late onset of symptoms and (iii) the limited comprehension of the carcinogenic pathways determining neoplastic changes, which all limit the pursuit of appropriate treatment. Several risk factors have been recognized, including different infective, immune-mediated, and dysmorphogenic disorders of the biliary tree. In this review, we report the details of possible mechanisms that lead a specific premalignant pathological condition to become cholangiocarcinoma. For instance, during liver fluke infection, factors secreted from the worms may play a major role in pathogenesis. In primary sclerosing cholangitis, deregulation of histamine and bile-acid signaling may determine important changes in cellular pathways. The study of these molecular events may also shed some light on the pathogenesis of sporadic (unrelated to risk factors) forms of cholangiocarcinoma, which represent the majority (nearly 75%) of cases.

5.
Hepatol Commun ; 2022 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-35271760

RESUMO

Fibroblast growth factor 1 (FGF1) belongs to a family of growth factors involved in cellular growth and division. MicroRNA 16 (miR-16) is a regulator of gene expression, which is dysregulated during liver injury and insult. However, the role of FGF1 in the progression of biliary proliferation, senescence, fibrosis, inflammation, angiogenesis, and its potential interaction with miR-16, are unknown. In vivo studies were performed in male bile duct-ligated (BDL, 12-week-old) mice, multidrug resistance 2 knockout (Mdr2-/-) mice (10-week-old), and their corresponding controls, treated with recombinant human FGF1 (rhFGF1), fibroblast growth factor receptor (FGFR) antagonist (AZD4547), or anti-FGF1 monoclonal antibody (mAb). In vitro, the human cholangiocyte cell line (H69) and human hepatic stellate cells (HSCs) were used to determine the expression of proliferation, fibrosis, angiogenesis, and inflammatory genes following rhFGF1 treatment. PSC patient and control livers were used to evaluate FGF1 and miR-16 expression. Intrahepatic bile duct mass (IBDM), along with hepatic fibrosis and inflammation, increased in BDL mice treated with rhFGF1, with a corresponding decrease in miR-16, while treatment with AZD4547 or anti-FGF1 mAb decreased hepatic fibrosis, IBDM, and inflammation in BDL and Mdr2-/- mice. In vitro, H69 and HSCs treated with rhFGF1 had increased expression of proliferation, fibrosis, and inflammatory markers. PSC samples also showed increased FGF1 and FGFRs with corresponding decreases in miR-16 compared with healthy controls. Conclusion: Our study demonstrates that suppression of FGF1 and miR-16 signaling decreases the presence of hepatic fibrosis, biliary proliferation, inflammation, senescence, and angiogenesis. Targeting the FGF1 and miR-16 axis may provide therapeutic options in treating cholangiopathies such as PSC.

6.
Transplant Direct ; 8(2): e1242, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-35018300

RESUMO

BACKGROUND: There has been a dramatic increase in obesity in the United States. Several studies have reported conflicting results for the impact of obesity on outcomes of liver transplantation (LT). This study aims to assess the impact of obesity on LT and changes in body mass index (BMI) after transplantation. METHODS: All adult LTs performed at Indiana University between 2001 and 2018 were reviewed. BMIs of recipients were subdivided into 6 categories. Survival outcomes were compared across the subgroup. BMI was followed up in a cohort of patients from 2008 to 2018. RESULTS: Among 2024 patients, 25% were in class I obesity, 9.3% were in class II obesity, and 1.1% were in class III obesity. There was no significant difference in patient and graft survival at 10-y follow-up with respect to BMI. Among 1004 patients in the subgroup, BMI of all groups except the underweight group declined in the first 3 mo postoperatively; however, the BMI of all groups except the class III obesity group returned to the pre-LT level by 2 y and reached a plateau by 5 y. In the class III obesity group, there was a significant increase in body weight at 5 y. CONCLUSIONS: Class III obesity was not associated with higher mortality in our cohort. Because our cohort is small, it may be underpowered to detect a smaller difference in outcome. From our observation, obesity should not be considered a contraindication for LT. Post-LT interventions are required to prevent significant weight gain for the class III obesity group.

7.
Hepatology ; 75(4): 797-813, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-34743371

RESUMO

BACKGROUND AND AIMS: Melatonin reduces biliary damage and liver fibrosis in cholestatic models by interaction with melatonin receptors 1A (MT1) and 1B (MT2). MT1 and MT2 can form heterodimers and homodimers, but MT1 and MT2 can heterodimerize with the orphan receptor G protein-coupled receptor 50 (GPR50). MT1/GPR50 dimerization blocks melatonin binding, but MT2/GPR50 dimerization does not affect melatonin binding. GPR50 can dimerize with TGFß receptor type I (TGFßRI) to activate this receptor. We aimed to determine the differential roles of MT1 and MT2 during cholestasis. APPROACH AND RESULTS: Wild-type (WT), MT1 knockout (KO), MT2KO, and MT1/MT2 double KO (DKO) mice underwent sham or bile duct ligation (BDL); these mice were also treated with melatonin. BDL WT and multidrug resistance 2 KO (Mdr2-/- ) mice received mismatch, MT1, or MT2 Vivo-Morpholino. Biliary expression of MT1 and GPR50 increases in cholestatic rodents and human primary sclerosing cholangitis (PSC) samples. Loss of MT1 in BDL and Mdr2-/- mice ameliorated biliary and liver damage, whereas these parameters were enhanced following loss of MT2 and in DKO mice. Interestingly, melatonin treatment alleviated BDL-induced biliary and liver injury in BDL WT and BDL MT2KO mice but not in BDL MT1KO or BDL DKO mice, demonstrating melatonin's interaction with MT1. Loss of MT2 or DKO mice exhibited enhanced GPR50/TGFßR1 signaling, which was reduced by loss of MT1. CONCLUSIONS: Melatonin ameliorates liver phenotypes through MT1, whereas down-regulation of MT2 promotes liver damage through GPR50/TGFßR1 activation. Blocking GPR50/TGFßR1 binding through modulation of melatonin signaling may be a therapeutic approach for PSC.


Assuntos
Colestase , Melatonina , Animais , Colestase/complicações , Colestase/tratamento farmacológico , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/etiologia , Melatonina/metabolismo , Melatonina/farmacologia , Melatonina/uso terapêutico , Camundongos , Camundongos Knockout , Receptor MT1 de Melatonina/genética , Receptor MT1 de Melatonina/metabolismo , Receptor MT2 de Melatonina/genética , Receptor MT2 de Melatonina/metabolismo
9.
Transplantation ; 106(1): 26-36, 2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33653996

RESUMO

In the past 20 y, the number of patients in the United States who died while waiting for a human donor liver totaled >52 000. The median national wait time for patients with acute liver failure and the most urgent liver transplant listing was 7 d in 2018. The need for a clinical "bridge" to allotransplantation is clear. Current options for supporting patients with acute liver failure include artificial liver support devices, extracorporeal liver perfusion, and hepatocyte transplantation, all of which have shown mixed results with regard to survival benefit and are largely experimental. Progress in the transplantation of genetically engineered pig liver grafts in nonhuman primates has grown steadily, with survival of the pig graft extended to almost 1 mo in 2017. Further advances may justify consideration of a pig liver transplant as a clinical bridge to allotransplantation. We provide a brief history of pig liver xenotransplantation, summarize the most recent progress in pig-to-nonhuman primate liver transplantation models, and suggest criteria that may be considered for patient selection for a clinical trial of bridging by genetically engineered pig liver xenotransplantation to liver allotransplantation.


Assuntos
Falência Hepática Aguda , Transplante de Fígado , Animais , Animais Geneticamente Modificados , Humanos , Transplante de Fígado/métodos , Doadores Vivos , Primatas , Suínos , Transplante Heterólogo
11.
Cells ; 10(11)2021 11 09.
Artigo em Inglês | MEDLINE | ID: mdl-34831316

RESUMO

Cholangiocarcinoma (CCA), or cancer of bile duct epithelial cells, is a very aggressive malignancy characterized by early lymphangiogenesis in the tumor microenvironment (TME) and lymph node (LN) metastasis which correlate with adverse patient outcome. However, the specific roles of lymphatic endothelial cells (LECs) that promote LN metastasis remains unexplored. Here we aimed to identify the dynamic molecular crosstalk between LECs and CCA cells that activate tumor-promoting pathways and enhances lymphangiogenic mechanisms. Our studies show that inflamed LECs produced high levels of chemokine CXCL5 that signals through its receptor CXCR2 on CCA cells. The CXCR2-CXCL5 signaling axis in turn activates EMT (epithelial-mesenchymal transition) inducing MMP (matrix metalloproteinase) genes such as GLI, PTCHD, and MMP2 in CCA cells that promote CCA migration and invasion. Further, rate of mitochondrial respiration and glycolysis of CCA cells was significantly upregulated by inflamed LECs and CXCL5 activation, indicating metabolic reprogramming. CXCL5 also induced lactate production, glucose uptake, and mitoROS. CXCL5 also induced LEC tube formation and increased metabolic gene expression in LECs. In vivo studies using CCA orthotopic models confirmed several of these mechanisms. Our data points to a key finding that LECs upregulate critical tumor-promoting pathways in CCA via CXCR2-CXCL5 axis, which further augments CCA metastasis.


Assuntos
Neoplasias dos Ductos Biliares/metabolismo , Quimiocina CXCL5/metabolismo , Colangiocarcinoma/metabolismo , Sistema Linfático/patologia , Receptores de Interleucina-8B/metabolismo , Transdução de Sinais , Animais , Neoplasias dos Ductos Biliares/genética , Neoplasias dos Ductos Biliares/patologia , Linhagem Celular Tumoral , Movimento Celular , Colangiocarcinoma/genética , Colangiocarcinoma/patologia , Células Endoteliais/patologia , Metabolismo Energético , Transição Epitelial-Mesenquimal/genética , Adesões Focais/metabolismo , Regulação Neoplásica da Expressão Gênica , Glucose/metabolismo , Humanos , Inflamação/genética , Inflamação/patologia , Ácido Láctico/biossíntese , Linfonodos/patologia , Linfangiogênese/genética , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Modelos Biológicos , Espécies Reativas de Oxigênio/metabolismo , Regulação para Cima
12.
Am J Pathol ; 191(12): 2052-2063, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34509441

RESUMO

Increased lymphangiogenesis and lymph node metastasis, the important prognostic indicators of aggressive hepatobiliary malignancies such as hepatocellular cancer and cholangiocarcinoma, are associated with poor patient outcome. The liver produces 25% to 50% of total lymphatic fluid in the body and has a dense network of lymphatic vessels. The lymphatic system plays critical roles in fluid homeostasis and inflammation and immune response. Yet, lymphatic vessel alterations and function are grossly understudied in the context of liver pathology. Expansion of the lymphatic network has been documented in clinical samples of liver cancer; and although largely overlooked in the liver, tumor-induced lymphangiogenesis is an important player, increasing tumor metastasis in several cancers. This review aims to provide a detailed perspective on the current knowledge of alterations in the hepatic lymphatic system during liver malignancies, as well as various molecular signaling mechanisms and growth factors that may provide future targets for therapeutic intervention. In addition, the review also addresses current mechanisms and bottlenecks for effective therapeutic targeting of tumor-associated lymphangiogenesis.


Assuntos
Carcinoma Hepatocelular/terapia , Neoplasias Hepáticas/terapia , Linfangiogênese , Metástase Linfática/terapia , Animais , Neoplasias dos Ductos Biliares/genética , Neoplasias dos Ductos Biliares/patologia , Neoplasias dos Ductos Biliares/terapia , Ductos Biliares Intra-Hepáticos/patologia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Colangiocarcinoma/genética , Colangiocarcinoma/patologia , Colangiocarcinoma/terapia , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Linfangiogênese/genética , Metástase Linfática/genética , Metástase Linfática/patologia , Vasos Linfáticos/patologia , Terapia de Alvo Molecular/métodos , Terapia de Alvo Molecular/tendências , Transdução de Sinais/genética , Transdução de Sinais/fisiologia
13.
Cells ; 10(8)2021 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-34440841

RESUMO

Fatty liver diseases, such as non-alcoholic fatty liver disease (NAFLD), are global health disparities, particularly in the United States, as a result of cultural eating habits and lifestyle. Pathological studies on NAFLD have been mostly focused on hepatocytes and other inflammatory cell types; however, the impact of other biliary epithelial cells (i.e., cholangiocytes) in the promotion of NAFLD is growing. This review article will discuss how cholestatic injury and cholangiocyte activity/ductular reaction influence NAFLD progression. Furthermore, this review will provide informative details regarding the fundamental properties of cholangiocytes and bile acid signaling that can influence NAFLD. Lastly, studies relating to the pathogenesis of NAFLD, cholangiopathies, and ductular reaction will be analyzed to help gain insight for potential therapies.


Assuntos
Ductos Biliares/metabolismo , Colestase/patologia , Hepatopatia Gordurosa não Alcoólica/patologia , Transdução de Sinais , Ácidos e Sais Biliares/metabolismo , Ductos Biliares/citologia , Canabinoides/metabolismo , Colestase/etiologia , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Humanos , Sistemas Neurossecretores/metabolismo , Hepatopatia Gordurosa não Alcoólica/complicações , Fator A de Crescimento do Endotélio Vascular/metabolismo
14.
Cells ; 10(8)2021 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-34440898

RESUMO

BACKGROUND & AIMS: Liver fibrosis is a pathological healing process resulting from hepatic stellate cell (HSC) activation and the generation of myofibroblasts from activated HSCs. The precise underlying mechanisms of liver fibrogenesis are still largely vague due to lack of understanding the functional heterogeneity of activated HSCs during liver injury. Approach and Results: In this study, to define the mechanism of HSC activation, we performed the transcriptomic analysis at single-cell resolution (scRNA-seq) on HSCs in mice treated with carbon tetrachloride (CCl4). By employing LRAT-Cre:Rosa26mT/mG mice, we were able to isolate an activated GFP-positive HSC lineage derived cell population by fluorescence-activated cell sorter (FACS). A total of 8 HSC subpopulations were identified based on an unsupervised analysis. Each HSC cluster displayed a unique transcriptomic profile, despite all clusters expressing common mouse HSC marker genes. We demonstrated that one of the HSC subpopulations expressed high levels of mitosis regulatory genes, velocity, and monocle analysis indicated that these HSCs are at transitioning and proliferating phases at the beginning of HSCs activation and will eventually give rise to several other HSC subtypes. We also demonstrated cell clusters representing HSC-derived mature myofibroblast populations that express myofibroblasts hallmark genes with unique contractile properties. Most importantly, we found a novel HSC cluster that is likely to be critical in liver regeneration, immune reaction, and vascular remodeling, in which the unique profiles of genes such as Rgs5, Angptl6, and Meg3 are highly expressed. Lastly, we demonstrated that the heterogeneity of HSCs in the injured mouse livers is closely similar to that of cirrhotic human livers. CONCLUSIONS: Collectively, our scRNA-seq data provided insight into the landscape of activated HSC populations and the dynamic transitional pathway from HSC to myofibroblasts in response to liver injury.


Assuntos
Células Estreladas do Fígado/metabolismo , Fígado/metabolismo , Animais , Células Cultivadas , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Análise de Componente Principal , Análise de Célula Única , Transcriptoma/genética
16.
Cells ; 10(7)2021 07 04.
Artigo em Inglês | MEDLINE | ID: mdl-34359861

RESUMO

Cholangiocarcinoma is a lethal disease with scarce response to current systemic therapy. The rare occurrence and large heterogeneity of this cancer, together with poor knowledge of its molecular mechanisms, are elements contributing to the difficulties in finding an appropriate cure. Cholangiocytes (and their cellular precursors) are considered the liver component giving rise to cholangiocarcinoma. These cells respond to several hormones, neuropeptides and molecular stimuli employing the cAMP/PKA system for the translation of messages in the intracellular space. For instance, in physiological conditions, stimulation of the secretin receptor determines an increase of intracellular levels of cAMP, thus activating a series of molecular events, finally determining in bicarbonate-enriched choleresis. However, activation of the same receptor during cholangiocytes' injury promotes cellular growth again, using cAMP as the second messenger. Since several scientific pieces of evidence link cAMP signaling system to cholangiocytes' proliferation, the possible changes of this pathway during cancer growth also seem relevant. In this review, we summarize the current findings regarding the cAMP pathway and its role in biliary normal and neoplastic cell proliferation. Perspectives for targeting the cAMP machinery in cholangiocarcinoma therapy are also discussed.


Assuntos
Neoplasias dos Ductos Biliares/tratamento farmacológico , Neoplasias dos Ductos Biliares/patologia , Sistema Biliar/patologia , Colangiocarcinoma/tratamento farmacológico , Colangiocarcinoma/patologia , AMP Cíclico/metabolismo , Terapia de Alvo Molecular , Transdução de Sinais , Animais , Proliferação de Células , Humanos
17.
Cancers (Basel) ; 13(13)2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34282753

RESUMO

Cholangiocarcinoma (CCA) is a type of biliary tract cancer emerging from the biliary tree. CCA is the second most common primary liver cancer after hepatocellular carcinoma and is highly aggressive resulting in poor prognosis and patient survival. Treatment options for CCA patients are limited since early diagnosis is challenging, and the efficacy of chemotherapy or radiotherapy is also limited because CCA is a heterogeneous malignancy. Basic research is important for CCA to establish novel diagnostic testing and more effective therapies. Previous studies have introduced new techniques and methodologies for animal models, in vitro models, and biomarkers. Recent experimental strategies include patient-derived xenograft, syngeneic mouse models, and CCA organoids to mimic heterogeneous CCA characteristics of each patient or three-dimensional cellular architecture in vitro. Recent studies have identified various novel CCA biomarkers, especially non-coding RNAs that were associated with poor prognosis or metastases in CCA patients. This review summarizes current advances and limitations in basic and translational studies of CCA.

18.
Surgery ; 170(4): 1240-1247, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34092375

RESUMO

BACKGROUND: Positive crossmatch (XM+) combined liver-kidney transplantation due to preformed donor-specific human leukocyte antigen antibodies has produced mixed results. We sought to understand the role of delayed kidney transplant approach in XM+ combined liver-kidney transplantations. METHODS: XM+ combined liver-kidney transplantations were retrospectively reviewed. T- and B-cell XM, complement-dependent cytotoxic crossmatch, and flow cytometric crossmatch were performed prospectively. RESULTS: Of 183 combined liver-kidney transplantations performed (2002-2019), 114 (62%) were with "delayed" kidney transplant approach and 19 (19 of 183, 10%) were XM+. Of 19 XM+ combined liver-kidney transplantations, kidney transplant was "delayed" in 14 by an average of 47 hours (range 24-64 hours) from liver transplant. There was a significant reduction in both class I (mean pre-liver transplant mean fluorescence intensity (MFI) 26,230 versus mean post-liver transplant and pre-delayed kidney transplant MFI 3,272, P = .01) and total MFI (mean pre-liver transplant MFI 27,233 vs mean post liver transplant and predelayed kidney transplant MFI 11,469, P = .01). However, there was no significant change in the MFI of class II donor-specific antibodies (mean pre-liver transplant MFI 17,899 versus post-liver transplant and pre-delayed kidney transplant MFI 14,341, P = .19). None of XM+ delayed kidney transplants had delayed graft function, and there was no antibody-mediated rejection. One-year patient survival for the XM+ combined liver-kidney transplantation with delayed kidney transplant approach was 92.9%, which is comparable to patient survival of XM- combined liver-kidney transplantation. Whereas patient survival in recipients before "delayed" approach ("simultaneous"; n = 5) was 40% when liver-kidney transplants were performed simultaneously (P = .06). CONCLUSION: In sensitized combined liver-kidney transplantation recipients, the "delayed" kidney transplant approach is associated with a significant reduction in total and class I donor-specific antibodies after liver transplant before kidney transplant, enabling therapeutic interventions such as plasmapheresis, if needed, providing optimal outcomes similar to crossmatch recipients.


Assuntos
Tipagem e Reações Cruzadas Sanguíneas/métodos , Rejeição de Enxerto/diagnóstico , Antígenos HLA/imunologia , Teste de Histocompatibilidade/métodos , Transplante de Rim , Transplante de Fígado , Tempo para o Tratamento , Adulto , Idoso , Feminino , Rejeição de Enxerto/imunologia , Sobrevivência de Enxerto , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Doadores de Tecidos , Adulto Jovem
19.
Transplant Direct ; 7(7): e714, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34131586

RESUMO

The predictors of recurrent autoimmune hepatitis (R-AIH) after liver transplantation (LT) are heterogeneous with limited data to guide immunosuppression, with little data on impact of race. AIMS: To describe the incidence, predictors, and outcomes of R-AIH. METHODS: We studied patients undergoing LT for AIH during 2000-2017 at our center. Liver biopsies were performed for clinical indications. R-AIH was defined using clinical and histologic criteria. RESULTS: Among 75 patients undergoing LT for AIH (mean age 45 ± 16, 65% female individuals, 19% Black), 71 (95%) received antithymocyte globulin induction with tacrolimus-based immunosuppression. R-AIH developed in 20 (27%) patients at a median interval of 313 d (interquartile range, 155-1205). R-AIH was associated with level 2 HLA-DR mismatch (hazard ratio, 3.6; (95% confidence interval, 1.3-9.9; P = 0.01) and Black race (hazard ratio, 4.5; 95% confidence interval, 1.8-11.8; P = 0.002)] in the multivariable analysis. R-AIH developed in 62% of patients with level 2 HLA-DR mismatch on single-agent immunosuppression but in <20% of patients with no or 1 HLA-DR mismatch regardless of maintenance immunosuppression. R-AIH developed in 8 (57%) of 14 Black patients (71% on single-agent and 43% on dual-agent maintenance immunosuppression). Patient and graft survival were not impacted by R-AIH over a median follow-up of 8.3 y (interquartile range, 3-12). CONCLUSIONS: High-level HLA-DR mismatch and Black recipient race are associated with an increased risk of R-AIH. Immunosuppression did not predict R-AIH, but higher rates of disease recurrence with single-agent maintenance immunosuppression with these risk factors were observed and may guide maintenance immunosuppression in LT for AIH.

20.
Sci Rep ; 11(1): 13131, 2021 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-34162938

RESUMO

Xenotransplantation (cross-species transplantation) using genetically-engineered pig organs offers a potential solution to address persistent organ shortage. Current evaluation of porcine genetic modifications is to monitor the nonhuman primate immune response and survival after pig organ xenotransplantation. This measure is an essential step before clinical xenotransplantation trials, but it is time-consuming, costly, and inefficient with many variables. We developed an efficient approach to quickly examine human-to-pig xeno-immune responses in vitro. A porcine endothelial cell was characterized and immortalized for genetic modification. Five genes including GGTA1, CMAH, ß4galNT2, SLA-I α chain, and ß2-microglobulin that are responsible for the production of major xenoantigens (αGal, Neu5Gc, Sda, and SLA-I) were sequentially disrupted in immortalized porcine endothelial cells using CRISPR/Cas9 technology. The elimination of αGal, Neu5Gc, Sda, and SLA-I dramatically reduced the antigenicity of the porcine cells, though the cells still retained their ability to provoke human natural killer cell activation. In summary, evaluation of human immune responses to genetically modified porcine cells in vitro provides an efficient method to identify ideal combinations of genetic modifications for improving pig-to-human compatibility, which should accelerate the application of xenotransplantation to humans.


Assuntos
Animais Geneticamente Modificados/imunologia , Antígenos Heterófilos/imunologia , Células Endoteliais/imunologia , Suínos/imunologia , Transplante Heterólogo/métodos , Animais , Anticorpos Heterófilos/imunologia , Reações Antígeno-Anticorpo , Antígenos Heterófilos/genética , Sistemas CRISPR-Cas , Degranulação Celular , Linhagem Celular Transformada , Citocinas/farmacologia , Células Endoteliais/efeitos dos fármacos , Galactosiltransferases/genética , Galactosiltransferases/imunologia , Técnicas de Inativação de Genes , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/prevenção & controle , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Células Matadoras Naturais/imunologia , Fígado/citologia , Ativação Linfocitária , Oxigenases de Função Mista/genética , Oxigenases de Função Mista/imunologia , N-Acetilgalactosaminiltransferases/genética , N-Acetilgalactosaminiltransferases/imunologia , Microglobulina beta-2/genética , Microglobulina beta-2/imunologia
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