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1.
Cells ; 10(9)2021 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-34571859

RESUMO

The kinetics of antigen-presenting cells (APCs) vary depending on their resident tissues and the manner of immunization. We investigated the long-term changes in mature APC and T-cell subsets over 4 weeks in the ocular surface in murine models of corneal quiescent or potent sterile inflammation, and allosensitization using partial (PT), syngeneic (Syn), and allogeneic (Allo) corneal transplantation. In PT, CD11bintCD11chiMHCIIhiCD86hi cells increased until 4 weeks with an increase in IFNγhi T cells. In Syn, both CD11bintCD11chiMHCIIhiCD86hi and CD11bhiCD11chiMHCIIhiCD86hi APC subsets increased until 4 weeks with a brief increase in CD69hi T cells at 2 weeks. In Allo, CD11bintCD11chiMHCIIhiCD86hi and CD11bhiCD11chiMHCIIhiCD86hi APC subsets increased until 4 weeks, and an early increase in CD69hi T cells was observed at 2 weeks followed by a late increase in IFNγhi T cells at 4 weeks. The frequency of the IFNγhi T cell subset was positively correlated with the frequency of the CD11bintCD11chiMHCIIhiCD86hi subset, indicating the existence of APC-T cell interaction in the ocular surface. Together, the results indicate that allosensitization in mature APCs leads to T-cell activation in the ocular surface, whereas sterile inflammation merely induces a brief and non-specific T-cell activation in the ocular surface.


Assuntos
Células Apresentadoras de Antígenos/imunologia , Células Apresentadoras de Antígenos/metabolismo , Córnea/imunologia , Aloenxertos/imunologia , Animais , Células Apresentadoras de Antígenos/fisiologia , Movimento Celular , Transplante de Córnea/métodos , Células Dendríticas/imunologia , Feminino , Inflamação/metabolismo , Ativação Linfocitária/imunologia , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
2.
Biomed Res Int ; 2021: 9933136, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34368360

RESUMO

Kidney transplantation is the promising treatment of choice for chronic kidney disease and end-stage kidney disease and can effectively improve the quality of life and survival rates of patients. However, the allograft rejection following kidney transplantation has a negative impact on transplant success. Therefore, the present study is aimed at screening novel biomarkers for the diagnosis and treatment of allograft rejection following kidney transplantation for improving long-term transplant outcome. In the study, a total of 8 modules and 3065 genes were identified by WGCNA based on the GSE46474 and GSE15296 dataset from the Gene Expression Omnibus (GEO) database. Moreover, the results of Gene Ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis showed that these genes were mainly involved in the immune-related biological processes and pathways. Thus, 317 immune-related genes were selected for further analysis. Finally, 5 genes (including CD200R1, VAV2, FASLG, SH2D1B, and RAP2B) were identified as the candidate biomarkers based on the ROC and difference analysis. Furthermore, we also found that in the 5 biomarkers an interaction might exist among each other in the protein and transcription level. Taken together, our study identified CD200R1, VAV2, FASLG, SH2D1B, and RAP2B as the candidate diagnostic biomarkers, which might contribute to the prevention and treatment of allograft rejection following kidney transplantation.


Assuntos
Aloenxertos/patologia , Biomarcadores/metabolismo , Redes Reguladoras de Genes , Rejeição de Enxerto/diagnóstico , Rejeição de Enxerto/genética , Transplante de Rim/efeitos adversos , Aloenxertos/imunologia , Bases de Dados Genéticas , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Ontologia Genética , Rejeição de Enxerto/imunologia , Humanos , Anotação de Sequência Molecular , Mapas de Interação de Proteínas/genética , Curva ROC
3.
Nat Commun ; 12(1): 4372, 2021 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-34272370

RESUMO

Intrarenal B cells in human renal allografts indicate transplant recipients with a poor prognosis, but how these cells contribute to rejection is unclear. Here we show using single-cell RNA sequencing that intrarenal class-switched B cells have an innate cell transcriptional state resembling mouse peritoneal B1 or B-innate (Bin) cells. Antibodies generated by Bin cells do not bind donor-specific antigens nor are they enriched for reactivity to ubiquitously expressed self-antigens. Rather, Bin cells frequently express antibodies reactive with either renal-specific or inflammation-associated antigens. Furthermore, local antigens can drive Bin cell proliferation and differentiation into plasma cells expressing self-reactive antibodies. These data show a mechanism of human inflammation in which a breach in organ-restricted tolerance by infiltrating innate-like B cells drives local tissue destruction.


Assuntos
Aloenxertos/imunologia , Linfócitos B/metabolismo , Rejeição de Enxerto/imunologia , Inflamação/metabolismo , Transplante de Rim/efeitos adversos , Animais , Autoanticorpos/imunologia , Linfócitos B/imunologia , Linfócitos B/patologia , Regulação da Expressão Gênica/genética , Regulação da Expressão Gênica/imunologia , Ontologia Genética , Antígenos de Histocompatibilidade Classe I/imunologia , Antígenos de Histocompatibilidade Classe II/imunologia , Humanos , Imunoglobulina G/imunologia , Rim/imunologia , Rim/metabolismo , Camundongos , Tonsila Palatina/imunologia , Tonsila Palatina/metabolismo , RNA-Seq , Análise de Célula Única , Transplante Homólogo
4.
Mol Immunol ; 137: 67-74, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34225136

RESUMO

The purpose of this study was to study the effect of inhibiting NLRC5 expression and function on CD4 + T cells, and islet and skin transplantation in mice. A murine skin graft model and islet cell transplantation model were established, and the expression of NLRC5 was compared in rejection and immune tolerance groups. Mice spleen-derived CD4 + T cells were cultured, purified, and enriched in vitro, and transfected with the shRNA lentiviral vector NLRC5-RNAi-GFP. Changes in cytokine secretion were detected to understand changes in immunological function. Murine islet and skin transplantation models were injected with CD4 + T cells transfected with the lentivirus, and the survival time of the grafts and the levels of IFN-γ and IL-10 were compared between groups. The expression of NLRC5 mRNA in islet and skin grafts was significantly increased. In vitro experiments showed that the expression of IL-4 and IL-10 was up-regulated in CD4 + T cells, and T cells differentiation turned to Th2 after inhibition of NLRC5. In vivo experiments showed that inhibition of NLRC5 prolonged islet and skin graft survival. Pathological examination showed that the rejection of transplanted skin and islets in the NLRC5-RNAi group was mild, and there was a correlation between high expression of NLRC5 and rejection of mouse islet and skin grafts. In summary, inhibition of NLRC5 can prolong islet and skin graft survival induce transplant immune tolerance through induction of the secretion of Th2 cytokines by CD4 + T cells.


Assuntos
Aloenxertos/imunologia , Linfócitos T CD4-Positivos/imunologia , Citocinas/imunologia , Sobrevivência de Enxerto/imunologia , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Animais , Rejeição de Enxerto/imunologia , Tolerância Imunológica/imunologia , Interferon gama/imunologia , Interleucina-10/imunologia , Transplante das Ilhotas Pancreáticas/métodos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , RNA Mensageiro/imunologia , Transplante de Pele/métodos , Células Th2/imunologia , Tolerância ao Transplante/imunologia , Transplante Homólogo/métodos
5.
Front Immunol ; 12: 682334, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34276669

RESUMO

Both acute and chronic antibody-mediated allograft rejection (AMR), which are directly mediated by B cells, remain difficult to treat. Long-lived plasma cells (LLPCs) in bone marrow (BM) play a crucial role in the production of the antibodies that induce AMR. However, LLPCs survive through a T cell-independent mechanism and resist conventional immunosuppressive therapy. Desensitization therapy is therefore performed, although it is accompanied by severe side effects and the pathological condition may be at an irreversible stage when these antibodies, which induce AMR development, are detected in the serum. In other words, AMR control requires the development of a diagnostic method that predicts its onset before LLPC differentiation and enables therapeutic intervention and the establishment of humoral immune monitoring methods providing more detailed information, including individual differences in the susceptibility to immunosuppressive agents and the pathological conditions. In this study, we reviewed recent studies related to the direct or indirect involvement of immunocompetent cells in the differentiation of naïve-B cells into LLPCs, the limitations of conventional methods, and the possible development of novel control methods in the context of AMR. This information will significantly contribute to the development of clinical applications for AMR and improve the prognosis of patients who undergo organ transplantation.


Assuntos
Citotoxicidade Celular Dependente de Anticorpos/imunologia , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Rejeição de Enxerto/tratamento farmacológico , Rejeição de Enxerto/etiologia , Imunossupressores/uso terapêutico , Aloenxertos/imunologia , Animais , Linfócitos B/metabolismo , Biomarcadores , Ativação do Complemento/efeitos dos fármacos , Ativação do Complemento/imunologia , Proteínas do Sistema Complemento/imunologia , Citocinas/genética , Citocinas/metabolismo , Regulação da Expressão Gênica , Centro Germinativo/imunologia , Centro Germinativo/metabolismo , Rejeição de Enxerto/diagnóstico , Rejeição de Enxerto/metabolismo , Humanos , Memória Imunológica/efeitos dos fármacos , Imunossupressores/farmacologia , Imunoterapia , Técnicas de Diagnóstico Molecular/métodos , Terapia de Alvo Molecular/métodos , Plasmócitos/efeitos dos fármacos , Plasmócitos/imunologia , Plasmócitos/metabolismo , Transdução de Sinais
6.
Front Immunol ; 12: 666531, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34305898

RESUMO

During allotransplantation, the endothelium acts as semi-professional antigen-presenting cells with the ability to activate proliferation and to promote differentiation of CD4+-T subsets. These abilities are dependent on the luminal expression of HLA class II antigens by microvascular endothelial cells, which is regulated by inflammatory cytokines. The upregulation of HLA-DR and HLA-DQ during rejection implies significant intragraft inflammation. Furthermore, the microvascular inflammation is an independent determinant for renal allograft failure. In this study, the potential of inflammation to modify endothelial regulation of peripheral CD4+ Treg cells was examined. Microvascular endothelial cells were exposed to pro-inflammatory cytokines for varying durations before co-culture with PBMC from non-HLA matched donors. Proliferation and expansion of CD4+Treg and soluble factor secretion was determined. Early interactions were detected by phosphorylation of Akt. Video microscopy was used to examine spatial and temporal endothelial-CD4+T interactions. Highly inflammatory conditions led to increased endothelial expression of HLA-DR, the adhesion molecule ICAM-1, the costimulatory molecule PD-L1 and de novo expression of HLA-DQ. Treg differentiation was impaired by exposure of endothelial cells to a high level of inflammation. Neither IL-6, IL-2 nor TGFß were implicated in reducing Treg numbers. High PD-L1 expression interfered with early endothelial cell interactions with CD4+T lymphocytes and led to modified TCR signaling. Blocking endothelial PD-L1 resulted in a partial restoration of Treg. The allogenic endothelial cell-mediated expansion of Treg depends on a critical threshold of inflammation. Manipulation of the PD-L1/PD-1 pathway or endothelial activation post-transplantation may promote or interfere with this intrinsic mechanism of allospecific Treg expansion.


Assuntos
Rejeição de Enxerto/imunologia , Antígenos HLA-DR/imunologia , Transplante de Rim/efeitos adversos , Linfócitos T Reguladores/imunologia , Aloenxertos/irrigação sanguínea , Aloenxertos/imunologia , Aloenxertos/patologia , Antígeno B7-H1/imunologia , Antígeno B7-H1/metabolismo , Comunicação Celular , Técnicas de Cultura de Células , Diferenciação Celular/imunologia , Linhagem Celular , Técnicas de Cocultura , Citocinas/imunologia , Citocinas/metabolismo , Células Endoteliais/imunologia , Células Endoteliais/patologia , Rejeição de Enxerto/sangue , Rejeição de Enxerto/patologia , Humanos , Ativação Linfocitária , Linfócitos T Reguladores/metabolismo
7.
Front Immunol ; 12: 671025, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34305900

RESUMO

Renal tubular epithelial cells (TECs) are the primary targets of ischemia-reperfusion injury (IRI) and rejection by the recipient's immune response in kidney transplantation (KTx). However, the molecular mechanism of rejection and IRI remains to be identified. Our previous study demonstrated that kynurenine 3-monooxygenase (KMO) and kynureninase were reduced in ischemia-reperfusion procedure and further decreased in rejection allografts among mismatched pig KTx. Herein, we reveal that TEC injury in acutely rejection allografts is associated with alterations of Bcl2 family proteins, reduction of tight junction protein 1 (TJP1), and TEC-specific KMO. Three cytokines, IFN γ , TNFα, and IL1ß, reported in our previous investigation were identified as triggers of TEC injury by altering the expression of Bcl2, BID, and TJP1. Allograft rejection and TEC injury were always associated with a dramatic reduction of KMO. 3HK and 3HAA, as direct and downstream products of KMO, effectively protected TEC from injury via increasing expression of Bcl-xL and TJP1. Both 3HK and 3HAA further prevented allograft rejection by inhibiting T cell proliferation and up-regulating aryl hydrocarbon receptor expression. Pig KTx with the administration of DNA nanoparticles (DNP) that induce expression of indoleamine 2,3-dioxygenase (IDO) and KMO to increase 3HK/3HAA showed an improvement of allograft rejection as well as murine skin transplant in IDO knockout mice with the injection of 3HK indicated a dramatic reduction of allograft rejection. Taken together, our data provide strong evidence that reduction of KMO in the graft is a key mediator of allograft rejection and loss. KMO can effectively improve allograft outcome by attenuating allograft rejection and maintaining graft barrier function.


Assuntos
Aloenxertos/imunologia , Células Epiteliais/fisiologia , Rejeição de Enxerto/prevenção & controle , Rim/patologia , Quinurenina 3-Mono-Oxigenase/metabolismo , Traumatismo por Reperfusão/prevenção & controle , Transplante de Pele , Animais , Células Cultivadas , Citocinas , Feminino , Humanos , Mediadores da Inflamação/metabolismo , Quinurenina 3-Mono-Oxigenase/genética , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Síndrome Respiratória e Reprodutiva Suína , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Suínos , Proteína da Zônula de Oclusão-1/metabolismo
8.
Front Immunol ; 12: 647894, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34262560

RESUMO

Acute graft-versus-host disease (aGVHD) is a lethal complication after allogeneic hematopoietic stem cell transplantation. The mechanism involves the recognition of host antigens by donor-derived T cells which induces augmented response of alloreactive T cells. In this study, we characterized the role of a previously identified novel classical secretory protein with antitumor function-LYG1 (Lysozyme G-like 1), in aGVHD. LYG1 deficiency reduced the activation of CD4+ T cells and Th1 ratio, but increased Treg ratio in vitro by MLR assay. By using major MHC mismatched aGVHD model, LYG1 deficiency in donor T cells or CD4+ T cells attenuated aGVHD severity, inhibited CD4+ T cells activation and IFN-γ expression, promoted FoxP3 expression, suppressed CXCL9 and CXCL10 expression, restrained allogeneic CD4+ T cells infiltrating in target organs. The function of LYG1 in aGVHD was also confirmed using haploidentical transplant model. Furthermore, administration of recombinant human LYG1 protein intraperitoneally aggravated aGVHD by promoting IFN-γ production and inhibiting FoxP3 expression. The effect of rhLYG1 could partially be abrogated with the absence of IFN-γ. Furthermore, LYG1 deficiency in donor T cells preserved graft-versus-tumor response. In summary, our results indicate LYG1 regulates aGVHD by the alloreactivity of CD4+ T cells and the balance of Th1 and Treg differentiation of allogeneic CD4+ T cells, targeting LYG1 maybe a novel therapeutic strategy for preventing aGVHD.


Assuntos
Aloenxertos/imunologia , Polaridade Celular/genética , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/metabolismo , Efeito Enxerto vs Tumor/imunologia , Transplante de Células-Tronco Hematopoéticas/métodos , Muramidase/deficiência , Linfócitos T Reguladores/imunologia , Animais , Linhagem Celular Tumoral , Polaridade Celular/imunologia , Modelos Animais de Doenças , Doença Enxerto-Hospedeiro/genética , Efeito Enxerto vs Tumor/genética , Humanos , Interferon gama/metabolismo , Ativação Linfocitária/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Muramidase/administração & dosagem , Muramidase/genética , Proteínas Recombinantes/administração & dosagem , Transdução de Sinais/genética , Linfócitos T Reguladores/metabolismo , Transplante Homólogo/métodos
9.
Front Immunol ; 12: 664577, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34276656

RESUMO

Over the past twenty years, significant technical strides have been made in the area of vascularized composite tissue allotransplantation (VCA). As in solid organ transplantation, the allogeneic immune response remains a significant barrier to long-term VCA survival and function. Strategies to overcome acute and chronic rejection, minimize immunosuppression and prolong VCA survival have important clinical implications. Historically, large animals have provided a valuable model for testing the clinical translatability of immune modulating approaches in transplantation, including tolerance induction, co-stimulation blockade, cellular therapies, and ex vivo perfusion. Recently, significant advancements have been made in these arenas utilizing large animal VCA models. In this comprehensive review, we highlight recent immune strategies undertaken to improve VCA outcomes with a focus on relevant preclinical large animal models.


Assuntos
Aloenxertos/imunologia , Sobrevivência de Enxerto/imunologia , Alotransplante de Tecidos Compostos Vascularizados/métodos , Animais , Biomarcadores , Terapia Baseada em Transplante de Células e Tecidos/métodos , Rejeição de Enxerto/imunologia , Tolerância Imunológica , Imunossupressão/métodos , Imunossupressores/farmacologia , Imunossupressores/uso terapêutico , Modelos Animais , Transplante de Órgãos , Perfusão , Transplante Homólogo
10.
Exp Cell Res ; 405(2): 112705, 2021 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-34166678

RESUMO

The interleukin-33 (IL-33)/suppression of tumorigenicity 2 (ST2) pathway modulates immune response and inflammation, associated with allograft dysfunction and rejection. We hypothesized that IL-33/ST2 is a marker of renal allograft rejection and IL-33/ST2 expression may differ according to rejection type. IL-33/ST2 expression was measured in sera and kidney tissues from recipients with acute antibody-mediated rejection (AAMR), acute cell-mediated rejection (ACMR), chronic antibody-mediated rejection (CAMR), and healthy controls. The soluble ST2 and IL-33/ST2 expression levels were higher in participants with all three rejection types than in controls. Although the expression levels in recipients with AAMR and ACMR were significantly higher than those with CAMR, there was no significant difference between the expression levels in AAMR and ACMR. Although IL-33, IL-8, and fibronectin expression were significantly increased after the addition of the recipients' serum in primary cultured human renal proximal tubular epithelial cells, the levels decreased after treatment with an anti-ST2 antibody. Furthermore, the anti-ST2 antibody specifically suppressed the upregulation of the mixed lymphocyte reaction. Boyden chamber assays demonstrated that anti-ST2 antibody abrogated chemotaxis induced by recombinant IL-33. Thus, IL-33 and ST2 are potent mediators of rejection. Treatment with an anti-ST2 antibody ameliorates rejection and could be a potential therapeutic strategy for renal allograft rejection.


Assuntos
Aloenxertos/imunologia , Rejeição de Enxerto/imunologia , Interleucina-33/metabolismo , Transplante de Rim , Adulto , Anticorpos/farmacologia , Biomarcadores/análise , Feminino , Humanos , Rim/imunologia , Transplante de Rim/métodos , Masculino , Pessoa de Meia-Idade , Transplante Homólogo/métodos
11.
Front Immunol ; 12: 656632, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34177898

RESUMO

Urine has been regarded as a good resource based on the assumption that urine can directly reflect the state of the allograft or ongoing injury in kidney transplantation. Previous studies, suggesting the usefulness of urinary mRNA as a biomarker of acute rejection, imply that urinary mRNA mirrors the transcriptional activity of the kidneys. We selected 14 data-driven candidate genes through a meta-analysis and measured the candidate genes using quantitative PCR without pre-amplification in the cross-sectional specimens from Korean kidney transplant patients. Expression of 9/14 genes (CXCL9, CD3ϵ, IP-10, LCK, C1QB, PSMB9, Tim-3, Foxp3, and FAM26F) was significantly different between acute rejection and stable graft function with normal pathology and long-term graft survival in 103 training samples. CXCL9 was also distinctly expressed in allografts with acute rejection in in situ hybridization analysis. This result, consistent with the qPCR result, implies that urinary mRNA could reflect the magnitude of allograft injury. We developed an AR prediction model with the urinary mRNAs by a binary logistic regression and the AUC of the model was 0.89 in the training set. The model was validated in 391 independent samples, and the AUC value yielded 0.84 with a fixed manner. In addition, the decision curve analysis indicated a range of reasonable threshold probabilities for biopsy. Therefore, we suggest the urine mRNA signature could be used as a non-invasive monitoring tool of acute rejection for clinical application and could help determine whether to perform a biopsy in a recipient with increased creatinine.


Assuntos
Aloenxertos/imunologia , Biomarcadores , Rejeição de Enxerto/diagnóstico , Rejeição de Enxerto/etiologia , Transplante de Rim/efeitos adversos , Biópsia Líquida/métodos , RNA Mensageiro/genética , Doença Aguda , Adulto , Biomarcadores/urina , Ácidos Nucleicos Livres , Feminino , Humanos , Imuno-Histoquímica , Transplante de Rim/métodos , Masculino , Pessoa de Meia-Idade , Curva ROC , Reprodutibilidade dos Testes
12.
Curr Opin Organ Transplant ; 26(3): 314-320, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33938468

RESUMO

PURPOSE OF REVIEW: Chronic lung allograft dysfunction (CLAD) limits the success of lung transplantation. Among the risk factors associated with CLAD, we recognize pretransplant circulating antibodies against the human leukocyte antigens (HLA), acute cellular rejection (ACR) and antibody-mediated rejection (AMR). This review will summarize current data surrounding management of desensitization, ACR, AMR, and CLAD. RECENT FINDINGS: Strategies in managing in highly sensitized patients waiting for lung transplant include avoidance of specific HLA antigens and reduction of circulating anti-HLA antibodies at time of transplant. Several multimodal approaches have been studied in the treatment of AMR with a goal to clear circulating donor-specific antibodies (DSAs) and to halt the production of new antibodies. Different immunosuppressive strategies focus on influence of the host immune system, particularly T-cell responses, in order to prevent ACR and the progression of CLAD. SUMMARY: The lack of significant evidence and consensus limits to draw conclusion regarding the impact of specific immunosuppressive regimens in the management of HLA antibodies, ACR, and CLAD. Development of novel therapeutic agents and use of multicenter randomized clinical trials will allow to better define patient-specific treatments and improve the length and quality of life of lung transplant recipients.


Assuntos
Rejeição de Enxerto , Aloenxertos/imunologia , Rejeição de Enxerto/prevenção & controle , Antígenos HLA , Humanos , Isoanticorpos , Transplante de Pulmão/efeitos adversos , Estudos Multicêntricos como Assunto , Qualidade de Vida
13.
Front Immunol ; 12: 661614, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33936098

RESUMO

Chronic active antibody-mediated rejection (AMR) in renal transplantation is usually refractory to current conventional treatment with rituximab, plasmapheresis (PP), and intravenous immunoglobulins (IVIG). Splenic irradiation has been reported to be effective in the rescue of early severe acute AMR after kidney transplantation; however, its effect in chronic active AMR has not been reported to date. In order to reduce donor-specific antibody (DSA) and prevent the progression of chronic AMR, we used repetitive low-dose splenic irradiation, together with rituximab and PP/IVIG, in two living-related kidney transplant recipients with pathologically diagnosed chronic active AMR and the presence of long-term class II-de novo DSA. DSA monitoring and repeated renal biopsy revealed significantly reduced DSA levels as well as alleviated glomerulitis and peritubular capillaritis in both patients after treatment, and these therapies may have played a role in delaying the progression of chronic AMR. Although DSA levels in both patients eventually rebounded to some extent after treatment, serum creatinine increased slowly in one patient during the 16-month follow-up period and remained stable in the other during the 12-month follow-up period. Given the poor efficacy of conventional treatment at present, splenic irradiation may still be one of the treatment options for chronic active AMR.


Assuntos
Anticorpos/imunologia , Rejeição de Enxerto/imunologia , Transplante de Rim/métodos , Baço/imunologia , Doadores de Tecidos , Adulto , Aloenxertos/imunologia , Rejeição de Enxerto/prevenção & controle , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Fatores Imunológicos/uso terapêutico , Rim/efeitos dos fármacos , Rim/imunologia , Masculino , Rituximab/uso terapêutico , Baço/efeitos da radiação , Transplantados
14.
Medicine (Baltimore) ; 100(21): e25958, 2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34032705

RESUMO

RATIONALE: Anti-angiotensin II type 1 receptor antibodies (AT1R-Abs) have been demonstrated to increase the risk of antibody-mediated rejection. We report a case of AT1R-Ab mediated rejection which caused early critical cortical infarction. PATIENT CONCERNS: A 52-year-old man with end-stage kidney disease underwent preemptive kidney transplantation (KT) from his wife. He had no immunologic risk except ABO incompatibility. Proper desensitization treatment were applied prior to KT. On postoperative day 1, he showed stable clinical course with adequate urine output, but there was no decrease in serum creatinine level and imaging studies showed hypoperfusion in the transplanted kidney. DIAGNOSES: Allograft biopsy revealed total cortical infarction with severe necrotizing vasculitis, but the medullary area was preserved. Serum AT1R-Ab concentration was elevated from 10.9 U/mL before KT to 19.1 U/mL on 7 days after KT. INTERVENTIONS: He was treated with plasmapheresis, intravenous immunoglobulin, rituximab, high-dose methylprednisolone, and bortezomib. OUTCOMES: The treatment showed a partial response, and he was discharged with 7.3 mg/dL creatinine level. At 4 months, his creatinine plateaued at 5.5 mg/dL and AT1R-Ab decreased to 3.6 U/mL. LESSONS: This case highlights the risk of early active antibody-mediated rejection by preformed AT1R-Ab, suggesting its ability to exhibit atypical histopathologic findings, such as total cortical infarction.


Assuntos
Rejeição de Enxerto/imunologia , Infarto/imunologia , Isoanticorpos/sangue , Necrose do Córtex Renal/imunologia , Transplante de Rim/efeitos adversos , Receptor Tipo 1 de Angiotensina/imunologia , Aloenxertos/irrigação sanguínea , Aloenxertos/imunologia , Aloenxertos/patologia , Feminino , Rejeição de Enxerto/sangue , Rejeição de Enxerto/diagnóstico , Rejeição de Enxerto/terapia , Teste de Histocompatibilidade , Humanos , Fatores Imunológicos/administração & dosagem , Infarto/sangue , Infarto/diagnóstico , Infarto/terapia , Isoanticorpos/imunologia , Córtex Renal/irrigação sanguínea , Córtex Renal/imunologia , Córtex Renal/patologia , Necrose do Córtex Renal/sangue , Necrose do Córtex Renal/diagnóstico , Necrose do Córtex Renal/terapia , Falência Renal Crônica/cirurgia , Doadores Vivos , Masculino , Pessoa de Meia-Idade , Plasmaferese , Cônjuges , Fatores de Tempo
15.
Exp Biol Med (Maywood) ; 246(16): 1857-1868, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34038225

RESUMO

Bone allograft is widely used to treat large bone defects or complex fractures. However, processing methods can significantly compromise allograft osteogenic activity. Adjuvants that can restore the osteogenic activity of processed allograft should improve clinical outcomes. In this study, zinc was tested as an adjuvant to increase the osteogenic activity of human allograft in a Rag2 null rat femoral defect model. Femoral defects were treated with human demineralized bone matrix (DBM) mixed with carboxy methyl cellulose containing ZnCl2 (0, 75, 150, 300 µg) or Zn stearate (347 µg). Rat femur defects treated with DBM-ZnCl2 (75 µg) and DBM-Zn stearate (347 µg) showed increased calcified tissue in the defect site compared to DBM alone. Radiograph scoring and µCT (microcomputed tomography) analysis showed an increased amount of bone formation at the defects treated with DBM-Zn stearate. Use of zinc as an adjuvant was also tested using human cancellous bone chips. The bone chips were soaked in ZnCl2 solutions before being added to defect sites. Zn adsorbed onto the chips in a time- and concentration-dependent manner. Rat femur defects treated with Zn-bound bone chips had more new bone in the defects based on µCT and histomorphometric analyses. The results indicate that zinc supplementation of human bone allograft improves allograft osteogenic activity in the rat femur defect model.


Assuntos
Aloenxertos/imunologia , Osso Esponjoso/citologia , Osteogênese/fisiologia , Zinco/metabolismo , Animais , Matriz Óssea/transplante , Transplante Ósseo/métodos , Osso Esponjoso/imunologia , Fêmur/metabolismo , Humanos , Ratos , Transplante Homólogo/métodos
16.
Front Immunol ; 12: 621935, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33912154

RESUMO

We compared the effectiveness and safety of pegylated granulocyte colony-stimulating factor (peg-G-CSF) vs. non-peg-G-CSF for hematopoietic stem cell mobilization in allogeneic hematopoietic stem cell transplantation in a real-world setting. We included 136 consecutive healthy donors treated with non-peg-G-CSF (n = 53) or peg-G-CSF (n = 83), and 125 consecutive recipients (n = 42 and 83, respectively) in this study. All harvesting was completed successfully. No significant difference in leukapheresis number and adverse events frequency was observed, nor were there severe adverse events leading to discontinuation of mobilization. The leukapheresis products mobilized by peg-G-CSF had higher total nucleated cells (p < 0.001), monocytic myeloid-derived suppressor cells (p < 0.001), granulocytic myeloid-derived suppressor cells (p = 0.004) and B cells (p = 0.019). CD34+ cells and other lymphocyte subsets (T cells, regulatory T cells, natural killer [NK] cells, etc.) were similar in both apheresis products. Patients who received grafts mobilized by peg-G-CSF exhibited a lower incidence of grade III-IV acute graft-versus-host disease (p = 0.001). The 1-year cumulative incidence of chronic graft-versus-host disease and relapse, 1-year probability of graft-versus-host disease-free relapse-free survival, and overall survival did not differ significantly between subgroups. Our results suggest that collecting allogeneic stem cells after the administration of peg-G-CSF is feasible and safe. Peg-G-CSF mobilized grafts may reduce severe acute graft-versus-host disease compared with non-peg-G-CSF mobilized grafts after allogeneic stem cell transplantation. The beneficial effects of a peg-G-CSF graft might be mediated by increased numbers of monocytic myeloid-derived suppressor cells.


Assuntos
Aloenxertos/imunologia , Doença Enxerto-Hospedeiro/imunologia , Fator Estimulador de Colônias de Granulócitos/metabolismo , Transplante de Células-Tronco Hematopoéticas , Células Supressoras Mieloides/imunologia , Polietilenoglicóis/metabolismo , Doença Aguda , Adolescente , Adulto , Criança , Feminino , Doença Enxerto-Hospedeiro/epidemiologia , Doença Enxerto-Hospedeiro/mortalidade , Mobilização de Células-Tronco Hematopoéticas , Humanos , Leucaférese , Masculino , Pessoa de Meia-Idade , Monócitos/imunologia , Índice de Gravidade de Doença , Análise de Sobrevida , Resultado do Tratamento , Adulto Jovem
17.
Front Immunol ; 12: 650424, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33927720

RESUMO

Chronic renal graft dysfunction (CAD) is caused by multiple factors, including glomerular sclerosis, inflammation, interstitial fibrosis and tubular atrophy (IF/TA). However, the most prominent elements of CAD are IF/TA. Our studies have confirmed that endothelial-mesenchymal transition (EndMT) is an important source to allograft IF/TA. The characteristic of EndMT is the loss of endothelial marker and the acquisition of mesenchymal or fibroblastic phenotypes. Autophagy is an intracellular degradation pathway that is regulated by autophagy-related proteins and plays a vital role in many fibrotic conditions. However, whether or not autophagy contributes to fibrosis of renal allograft and how such mechanism occurs still remains unclear. Autophagy related 16 like gene (ATG16L) is a critical autophagy-related gene (ARG) necessary for autophagosome formation. Here, we first analyzed kidney transplant patient tissues from Gene Expression Omnibus (GEO) datasets and 60 transplant patients from our center. Recipients with stable kidney function were defined as non-CAD group and all patients in CAD group were histopathologically diagnosed with CAD. Results showed that ATG16L, as one significant differential ARG, was less expressed in CAD group compared to the non-CAD group. Furthermore, we found there were less autophagosomes and autolysosomes in transplanted kidneys of CAD patients, and downregulation of autophagy is a poor prognostic factor. In vitro, we found out that the knockdown of ATG16L enhanced the process of EndMT in human renal glomerular endothelial cells (HRGECs). In vivo, the changes of EndMT and autophagic flux were then detected in rat renal transplant models of CAD. We demonstrated the occurrence of EndMT, and indicated that abundance of ATG16L was accompanied by the dynamic autophagic flux change along different stages of kidney transplantation. Mechanistically, knockdown of ATG16L, specifically in endothelial cells, reduced of NF-κB degradation and excreted inflammatory cytokines (IL-1ß, IL-6 and TNF-α), which could facilitate EndMT. In conclusion, ATG16L-dependent autophagic flux causing by transplant showed progressive loss increase over time. Inflammatory cytokines from this process promoted EndMT, thereby leading to progression of CAD. ATG16L served as a negative regulator of EndMT and development of renal graft fibrosis, and autophagy can be explored as a potential therapeutic target for chronic renal graft dysfunction.


Assuntos
Aloenxertos/patologia , Proteínas Relacionadas à Autofagia/metabolismo , Rejeição de Enxerto/imunologia , Transplante de Rim/efeitos adversos , Rim/patologia , Adulto , Aloenxertos/imunologia , Animais , Autofagossomos/imunologia , Autofagossomos/metabolismo , Autofagia/genética , Autofagia/imunologia , Proteínas Relacionadas à Autofagia/genética , Linhagem Celular , Conjuntos de Dados como Assunto , Modelos Animais de Doenças , Regulação para Baixo/imunologia , Células Endoteliais/patologia , Transição Epitelial-Mesenquimal/imunologia , Feminino , Fibrose , Técnicas de Silenciamento de Genes , Rejeição de Enxerto/patologia , Humanos , Rim/imunologia , Masculino , NF-kappa B/metabolismo , Proteólise , Ratos , Transdução de Sinais/imunologia , Proteínas de Transporte Vesicular/metabolismo
18.
Front Immunol ; 12: 648539, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33815407

RESUMO

Allograft functional failure due to acute or chronic rejection has long been a major concern in the area of solid organ transplantation for decades. As critical component of innate immune system, the macrophages are unlikely to be exclusive for driving acute or chronic sterile inflammation against allografts. Traditionally, macrophages are classified into two types, M1 and M2 like macrophages, based on their functions. M1 macrophages are involved in acute rejection for triggering sterile inflammation thus lead to tissue damage and poor allograft survival, while M2 macrophages represent contradictory features, playing pivotal roles in both anti-inflammation and development of graft fibrosis and resulting in chronic rejection. Macrophages also contribute to allograft vasculopathy, but the phenotypes remain to be identified. Moreover, increasing evidences are challenging traditional identification and classification of macrophage in various diseases. Better understanding the role of macrophage in chronic rejection is fundamental to developing innovative strategies for preventing late graft loss. In this review, we will update the recent progress in our understanding of diversity of macrophage-dominated innate immune response, and reveal the roles of M2 macrophages in chronic allograft rejection as well.


Assuntos
Rejeição de Enxerto/imunologia , Sobrevivência de Enxerto/imunologia , Imunidade Inata , Macrófagos/imunologia , Transplante de Órgãos/efeitos adversos , Aloenxertos/imunologia , Animais , Matriz Extracelular/imunologia , Fibrose , Humanos , Inflamação/imunologia , Camundongos , Traumatismo por Reperfusão/imunologia , Transplante Homólogo/efeitos adversos
19.
Sci Rep ; 11(1): 7903, 2021 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-33846428

RESUMO

Natural killer (NK) cells express the Fc-gamma receptor CD16 (FCGR3A) and could therefore mediate renal endothelial cell damage in cases of chronic-active antibody mediated rejection (c-aABMR). The V/V-genotype of the FCGR3A 158 F/V polymorphism is associated with increased CD16 expression and cytotoxicity by NK cells. This study evaluated whether this genotype is associated with the diagnosis of c-aABMR and renal allograft loss. The distribution of the FGCR3A 158 F/V-genotypes was not different for c-aABMR cases (N = 133) compared to control kidney transplant recipients (N = 116, P = 0.65). The V-allele was associated with increased median fluorescence intensity (MFI) of CD16 by NK cells (MFI 3.5 × 104 versus 1.3 × 104 for V/V and F/F-genotype, P < 0.001). Increased expression of CD16 correlated with CD16-dependent degranulation of NK cells (R = 0.4; P = 0.02). Moreover, the V/V-genotype was significantly associated with a higher glomerulitis score and an independent risk factor (HR 1.98; P = 0.04) for decreased allograft survival. Death-censored graft survival in c-aABMR cases at 3 years follow-up was 33% for the FCGR3A 158 V/V-genotype versus 62% for the F/F-genotype. In conclusion, the FCGR3A V/V-genotype increases CD16-mediated NK cell cytotoxicity and is associated with a higher glomerulitis score and decreased graft survival in cases with c-aABMR.


Assuntos
Aloenxertos/imunologia , Anticorpos/imunologia , Sobrevivência de Enxerto/genética , Transplante de Rim , Receptores de IgG/genética , Alelos , Feminino , Genótipo , Sobrevivência de Enxerto/imunologia , Humanos , Inflamação/patologia , Rim/irrigação sanguínea , Células Matadoras Naturais/imunologia , Masculino , Microvasos/patologia , Pessoa de Meia-Idade , Receptores de IgG/metabolismo
20.
Cells ; 10(4)2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33916034

RESUMO

BACKGROUND: The immune mechanisms occurring during acute rejection (AR) and chronic lung allograft dysfunction are a challenge for research and the balance between effector and regulatory cells has not been defined completely. In this study, we aimed to elucidate the interaction of effector cells, mainly Th17, Th1 and Th2, and regulatory cells including (CD4+CD25+CD127low/-) T reg cells and phenotypes of B regs, CD19+CD24hiCD38hi, CD19+CD24hiCD27hi and CD19+CD5+CD1d+. METHODS: Bronchoalveolar lavage cells (BAL) and peripheral blood mononuclear cells (PBMCs) from stable lung transplanted (LTx )subjects (n = 4), AR patients (n = 6) and bronchiolitis obliterans syndrome (BOS) (n = 6) were collected at the same time. Cellular subsets were detected through flow cytometry. RESULTS: A predominance of Th17 cells subtypes in the PBMCs and BAL and a depletion of Tregs, that resulted in decrease Treg/Th17 ratio, was observed in the AR group. CD19+CD24hiCD38hi Bregs resulted increased in BAL of AR patients. Th1 cells predominance and a reduction of Tregs cells was observed in BAL from AR patients. Moreover, multivariate analysis showed interdependences within studied variables revealing that effector cells and regulatory cells can effectively discriminate patients' immunological status. CONCLUSIONS: In AR, BOS and stable lung transplant, regulatory and effector cells clearly demonstrated different pathways of activation. Understanding of the balance of T cells and T and B regulatory cells can offers insights into rejection.


Assuntos
Aloenxertos/imunologia , Aloenxertos/fisiopatologia , Rejeição de Enxerto/etiologia , Rejeição de Enxerto/imunologia , Transplante de Pulmão/efeitos adversos , Alvéolos Pulmonares/imunologia , Linfócitos T Reguladores/imunologia , Doença Aguda , Linfócitos B Reguladores/imunologia , Biomarcadores/metabolismo , Lavagem Broncoalveolar , Doença Crônica , Feminino , Rejeição de Enxerto/sangue , Humanos , Leucócitos Mononucleares/metabolismo , Subpopulações de Linfócitos/imunologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Análise de Componente Principal
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