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1.
Rev Med Liege ; 77(10): 586-592, 2022 Oct.
Artigo em Francês | MEDLINE | ID: mdl-36226395

RESUMO

The evaluation of anti-HLA immunization in organ transplantation has evolved dramatically since the first lymphocytotoxic crossmatch between donor and recipient was described. The same is true for HLA typing, which can now be performed by high-resolution sequencing. Nevertheless, the transplantation of a totally compatible organ remains an exception and the appearance of anti-HLA antibodies during the transplantation is inevitable, which conditions the long-term survival of the graft. New computer tools are currently being developed to evaluate and quantify the degree of incompatibility between donor and recipient, with a view to predicting the risk of rejection and adapting immunosuppressive therapy in a targeted manner for each patient.


L'évaluation de l'immunisation anti-HLA dans la transplantation d'organe a évolué de façon spectaculaire depuis la description des premiers crossmatchs par lymphocytotoxicité entre donneur et receveur. Il en est de même pour le typage HLA, qui peut maintenant être réalisé par séquençage en haute résolution. Néanmoins, la greffe d'organe totalement compatible reste une exception et l'apparition d'anticorps anti-HLA dans le décours de la greffe est inévitable, ce qui conditionne la survie du greffon à long terme. De nouveaux outils informatiques sont actuellement développés pour évaluer et quantifier le degré d'incompatibilité entre donneur et receveur, dans la perspective de prédire le risque de rejet et adapter la thérapie immunosuppressive de façon ciblée pour chaque patient.


Assuntos
Antígenos HLA , Transplante de Órgãos , Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto , Antígenos HLA/genética , Histocompatibilidade , Humanos
2.
Genet Res (Camb) ; 2022: 7067743, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36262249

RESUMO

Among primary liver carcinoma cases, the proportion of liver hepatocellular carcinoma (LIHC) cases is 75%-85%. Current treatments for LIHC include chemotherapy, surgical excision, and liver transplantation, which are effective for early LIHC treatment. Nevertheless, the early symptoms of liver carcinoma are atypical, so a large proportion of LIHC patients are diagnosed at an advanced stage. Histocompatibility minor 13 (HM13), located in the endoplasmic reticulum, is responsible for catalysing the hydrolysis of some signal peptides after cleavage from the precursor protein. Here, we studied the role of HM13 in LIHC development through bioinformatics analysis. Database analysis showed that HM13 was of great significance for LIHC tumorigenesis. Compared to normal liver tissues, HM13 expression was increased to a greater extent in LIHC tissues. After analysis of Kaplan‒Meier plotter and Gene Expression Profiling Interactive Analysis (GEPIA) datasets, we discovered that highly expressed HM13 exhibited an association with shorter overall survival (OS), disease-free survival (DFS), and disease-specific survival (DSS). We conducted Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses to analyse HM13-related genes, and the data indicated that these genes obviously participated in rRNA processing, ribosome biogenesis, spliceosome, Huntington's disease, and ATP-dependent helicase activity. The Cell Counting Kit-8 (CCK-8) assay and Transwell assay showed that reducing HM13 expression hindered LIHC cell proliferation, migration, and invasion. In conclusion, these findings indicate that HM13 is a biomarker and is related to the poor prognosis of LIHC. Our results are conducive to discovering new targets for LIHC treatment.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Sincalida , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Prognóstico , Sinais Direcionadores de Proteínas , Histocompatibilidade , Trifosfato de Adenosina
4.
Front Immunol ; 13: 895157, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36016958

RESUMO

The transcriptional regulation of B-cell response to antigen stimulation is complex and involves an intricate network of dynamic signals from cytokines and transcription factors propagated from T-cell interaction. Long-term alloimmunity, in the setting of organ transplantation, is dependent on this B-cell response, which does not appear to be halted by current immunosuppressive regimens which are targeted at T cells. There is emerging evidence that shows that B cells have a diverse response to solid organ transplantation that extends beyond plasma cell antibody production. In this review, we discuss the mechanistic pathways of B-cell activation and differentiation as they relate to the transcriptional regulation of germinal center B cells, plasma cells, and memory B cells in the setting of solid organ transplantation.


Assuntos
Rejeição de Enxerto , Transplante de Órgãos , Linfócitos B , Centro Germinativo , Histocompatibilidade
8.
Front Immunol ; 13: 904718, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35874659

RESUMO

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative therapy for hematologic malignancies. Alloreactivity after HSCT is known to be mediated by adaptive immune cells expressing rearranging receptors. Recent studies demonstrated that the innate immune system could likewise sense the non-self signals and subsequently enhance the alloimmune response. We recently demonstrated that the donor/recipient mismatch of signal regulatory protein α (SIRPα), an immunoglobulin receptor exclusively expressed on innate cells, is associated with a higher risk of cGVHD and relapse protection in a cohort of acute myeloid leukemia patients who underwent allo-HSCT. Whether these effects also occur in other hematologic malignancies remains unclear. In the present study, we compared outcomes by SIRPα match status in a cohort of 310 patients who received allo-HSCT from an HLA matched-related donor for the treatment of lymphoid malignancies. Multivariable analysis showed that SIRPα mismatch was associated with a significantly higher rate of cGVHD (hazard ratio [HR] 1.8, P= .002), cGVHD requiring systemic immunosuppressive therapy (HR 1.9, P= .005), a lower rate of disease progression (HR 0.5, P= .003) and improved progression-free survival (HR 0.5, P= .001). Notably, the effects of SIRPα mismatch were observed only in the patients who achieved >95% of donor T-cell chimerism. The mismatch in SIRPα is associated with favorable relapse protection and concurrently increased risk of cGVHD in patients who undergo allo-HSCT for lymphoid malignancies, and the optimal donor could be selected based on the finding of the study to mitigate the risk of GVHD and relapse.


Assuntos
Doença Enxerto-Hospedeiro , Neoplasias Hematológicas , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Histocompatibilidade , Humanos , Recidiva
9.
Transplantation ; 106(12): 2325-2337, 2022 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-35876376

RESUMO

Single-cell technologies open up new opportunities to explore the behavior of cells at the individual level. For solid organ transplantation, single-cell technologies can provide in-depth insights into the underlying mechanisms of the immunological processes involved in alloimmune responses after transplantation by investigating the role of individual cells in tolerance and rejection. Here, we review the value of single-cell technologies, including cytometry by time-of-flight and single-cell RNA sequencing, in the context of solid organ transplantation research. Various applications of single-cell technologies are addressed, such as the characterization and identification of immune cell subsets involved in rejection or tolerance. In addition, we explore the opportunities for analyzing specific alloreactive T- or B-cell clones by linking phenotype data to T- or B-cell receptor data, and for distinguishing donor- from recipient-derived immune cells. Moreover, we discuss the use of single-cell technologies in biomarker identification and risk stratification, as well as the remaining challenges. Together, this review highlights that single-cell approaches contribute to a better understanding of underlying immunological mechanisms of rejection and tolerance, thereby potentially accelerating the development of new or improved therapies to avoid allograft rejection.


Assuntos
Rejeição de Enxerto , Transplante de Órgãos , Transplante de Órgãos/efeitos adversos , Histocompatibilidade , Transplante Homólogo , Tolerância Imunológica
10.
Comput Biol Med ; 148: 105856, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35863244

RESUMO

BACKGROUND: Multiple sclerosis (MS) can be induced upon successful presentation of myelin antigens by MHC I/II. Antigenic similarity between the myelin and viral proteins may worsen the immunological responses. METHODOLOGY: Antigenic regions within myelin proteins; PLP1, MBP, MOG, and MAG were analyzed using SVMTrip and EMBOSS. Homology search identified sequence similarity between the predicted host epitopes and viral proteins. NetMHCpan predicted MHC I/II binding followed by peptide-protein docking through the HPEPDOCK server. Thereafter we analyzed conformational flexibility and stability of 15 protein-peptide complexes based on high docking scores. The binding free energy was calculated using conventional (MD) and Gaussian accelerated molecular dynamics simulation. RESULTS: PLP1, MBP, MAG and MOG contained numerous antigenic epitopes. MBP and MOG epitopes had sequence similarity to HHV-6 BALF5; EBNA1 and CMV glycoprotein M (gM), and EBV LMP2B, gp350/220; HHV-8 ORFs respectively. Many herpes virus proteins like tegument, envelope glycoproteins, and ORFs of EBV, CMV, HHV-6, and HHV-8 demonstrated sequence similarity with MAG and PLP1. Some antigenic peptides were also linear B-cell epitopes and influenced cytokine production by T-cell. MHC I allele HLA-B*57:01 bound to PLP1 peptide and HLA-A*68:02 bound to a MAG peptide strongly. MHC II alleles HLA-DRB1*04:05 and HLA-DR1*01:01 associated with MAG- and MOG-derived peptides, respectively, demonstrating high HPEPDOCK scores. MD simulations established stable binding of certain peptides with the MHC namely HLA-B*51:01-MBP(DYKSAHKGFKGVDAQGTLSKIFKL), HLA-B*57:01-PLP1(PDKFVGITYALTVVWLLVFACSAVPVYIYF), HLA-DR1*01:01-MOG(VEDPFYWVSPGVLVLLAVLPVLLLQITVGLVFLCLQYR) and HLA-DRB1*04:05-MAG(TWVQVSLLHFVPTREA). CONCLUSIONS: Cross-reactivity between self-antigens and pathogen derived immunodominant epitopes may induce MS. Our study supported the role of specific MHC alleles as a contributing MS risk factor.


Assuntos
Infecções por Citomegalovirus , Esclerose Múltipla , Epitopos de Linfócito B , Antígeno HLA-DR1 , Cadeias HLA-DRB1 , Histocompatibilidade , Humanos , Glicoproteína Mielina-Oligodendrócito , Peptídeos , Proteínas Virais
11.
Expert Rev Med Devices ; 19(4): 353-367, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35531761

RESUMO

INTRODUCTION: Biomaterials, either metallic, ceramic, or polymeric, can be used in medicine as a part of the implants, dialysis membranes, bone scaffolds, or components of artificial organs. Polymeric biomaterials cover a vast range of biomedical applications. The biocompatibility and immunocompatibility of polymeric materials are of fundamental importance for their possible therapeutic uses, as the immune system can intervene in the materials' performance. Therefore, based on application, different routes can be utilized for immunoregulation. AREAS COVERED: As different biomaterials can be modulated by different strategies, this study aims to summarize and evaluate the available methods for the immunocompatibility enhancement of more common polymeric biomaterials based on their nature. Different strategies such as surface modification, physical characterization, and drug incorporation are investigated for the immunomodulation of nanoparticles, hydrogels, sponges, and nanofibers. EXPERT OPINION: Recently, strategies for triggering appropriate immune responses by functional biomaterials have been highlighted. As most strategies correspond to the physical and surface properties of biomaterials, specific modulation can be conducted for each biomaterial system. Besides, different applications require different modulations of the immune system. In the future, the selection of novel materials and immune regulators can play a role in tuning the immune system for regenerative medicine.


Assuntos
Medicina Regenerativa , Engenharia Tecidual , Materiais Biocompatíveis/farmacologia , Materiais Biocompatíveis/uso terapêutico , Histocompatibilidade , Humanos , Polímeros , Engenharia Tecidual/métodos
12.
Semin Nephrol ; 42(1): 44-62, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-35618395

RESUMO

Human Leukocyte Antigen (HLA) diversity is the key driver of alloimmune responses. Ideally, patients would receive an allograft that is fully matched at the allelic level. However, the extensive polymorphism in the HLA loci renders this impractical. Thus, there is growing interest in determining whether HLA mismatches at the eplet/epitope level better reflects the true disparity between a donor-recipient pair, with the goal of predicting permissible mismatches versus those that should be avoided because they will elicit a strong alloimmune response. Here, we will discuss the available algorithms used to predict immunogenicity/antigenicity of mismatches and prognosticate graft outcomes.


Assuntos
Transplante de Rim , Medicina de Precisão , Antígenos HLA/genética , Histocompatibilidade , Humanos , Doadores de Tecidos
13.
Methods Mol Biol ; 2453: 533-570, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35622341

RESUMO

T-cell receptors (TR), the antigen receptors of T cells, specifically recognize peptides presented by the major histocompatibility (MH) proteins, as peptide/MH (pMH), on the cell surface. The structure characterization of the trimolecular TR/pMH complexes is crucial to the fields of immunology, vaccination, and immunotherapy. IMGT/3Dstructure-DB is the three-dimensional (3-D) structure database of IMGT®, the international ImMunoGenetics information system®. By its creation, IMGT® marks the advent of immunoinformatics, which emerged at the interface between immunogenetics and bioinformatics. The IMGT® immunoglobulin (IG) and TR gene and allele nomenclature (CLASSIFICATION axiom) and the IMGT unique numbering and IMGT/Collier-de-Perles (NUMEROTATION axiom) are the two founding breakthroughs of immunoinformatics. IMGT-ONTOLOGY concepts and IMGT Scientific chart rules generated from these axioms allowed IMGT® bridging genes, structures, and functions. IMGT/3Dstructure-DB contains 3-D structures of IG or antibodies, TR and MH proteins of the adaptive immune responses of jawed vertebrates (gnathostomata), IG or TR complexes with antigens (IG/Ag, TR/pMH), related proteins of the immune system of any species belonging to the IG and MH superfamilies, and fusion proteins for immune applications. The focus of this chapter is on the TR V domains and MH G domains and the contact analysis comparison in TR/pMH interactions. Standardized molecular characterization includes "IMGT pMH contact sites" for peptide and MH groove interactions and "IMGT paratopes and epitopes" for TR/pMH complexes. Data are available in the IMGT/3Dstructure database, at the IMGT Home page http://www.imgt.org .


Assuntos
Anticorpos , Receptores de Antígenos de Linfócitos T , Animais , Sítios de Ligação de Anticorpos , Proteínas de Transporte , Epitopos , Histocompatibilidade , Peptídeos , Receptores de Antígenos de Linfócitos T/química , Receptores de Antígenos de Linfócitos T/genética
14.
Nanoscale ; 14(17): 6656-6669, 2022 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-35438701

RESUMO

Nanocarriers have emerged as one of the most promising approaches for drug delivery. Although several nanomaterials have been approved for clinical use, the translation from lab to clinic remains challenging. However, by implementing rational design strategies and using relevant models for their validation, these challenges are being addressed. This work describes the design of novel immunocompatible polymer nanocarriers made of melanin-mimetic polydopamine and Pluronic F127 units. The nanocarrier preparation was conducted under mild conditions, using a highly reproducible method that was tuned to provide a range of particle sizes (<100 nm) without changing the composition of the carrier. A set of in vitro studies were conducted to provide a comprehensive assessment of the effect of carrier size (40, 60 and 100 nm) on immunocompatibility, viability and uptake into different pancreatic cancer cells varying in morphological and phenotypic characteristics. Pancreatic cancer is characterised by poor treatment efficacy and no improvement in patient survival in the last 40 years due to the complex biology of the solid tumour. High intra- and inter-tumoral heterogeneity and a dense tumour microenvironment limit diffusion and therapeutic response. The Pluronic-polydopamine nanocarriers were employed for the delivery of irinotecan active metabolite SN38, which is used in the treatment of pancreatic cancer. Increased antiproliferative effect was observed in all tested cell lines after administration of the drug encapsulated within the carrier, indicating the system's potential as a therapeutic agent for this hard-to-treat cancer.


Assuntos
Nanopartículas , Neoplasias Pancreáticas , Portadores de Fármacos/metabolismo , Sistemas de Liberação de Medicamentos , Histocompatibilidade , Humanos , Neoplasias Pancreáticas/tratamento farmacológico , Polímeros , Microambiente Tumoral
15.
Kidney Int ; 102(2): 355-369, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35483526

RESUMO

B cells play crucial roles in cell-mediated alloimmune responses. In vitro, B cells can support or regulate indirect T-cell alloreactivity in response to donor antigens on ELISpot and these patterns associate with clinical outcome. Previous reports of associations between B-cell phenotype and function have examined global phenotypes and responses to polyclonal stimuli. We hypothesized that studying antigen-specific B cells, using samples from sensitized patients, would inform further study to identify novel targets for intervention. Using biotinylated HLA proteins, which bind HLA-specific B cells via the B-cell receptor in a dose-dependent fashion, we report the specific phenotype of HLA-binding B cells and define how they associated with patterns of anti-HLA response in interferon-γ ELISpot. HLA-binding class-switched and IgM+CD27+ memory cells associated strongly with B-dependent interferon-γ production and appeared not suppressible by endogenous Tregs. When the predominant HLA-binding phenotype was naïve B cells, the associated functional ELISpot phenotype was determined by other cells present. High numbers of non-HLA-binding transitional cells associated with B-suppressed interferon-γ production, especially if Tregs were present. However, high frequencies of HLA-binding marginal-zone precursors associated with B-dependent interferon-γ production that appeared suppressible by Tregs. Finally, non-HLA-binding marginal zone precursors may also suppress interferon-γ production, though this association only emerged when Tregs were absent from the ELISpot. Thus, our novel data provide a foundation on which to further define the complexities of interactions between HLA-specific T and B cells and identify new targets for intervention in new therapies for chronic rejection.


Assuntos
Interferon gama , Transplante de Rim , Rejeição de Enxerto/prevenção & controle , Histocompatibilidade , Interferon gama/metabolismo , Transplante de Rim/efeitos adversos , Fenótipo , Prognóstico
18.
Front Immunol ; 13: 796456, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35173720

RESUMO

Induction of immunological tolerance has been the holy grail of transplantation immunology for decades. The only successful approach to achieve it in patients has been a combined kidney and hematopoietic stem cell transplantation from an HLA-matched or -mismatched living donor. Here, we report the first three patients in Europe included in a clinical trial aiming at the induction of tolerance by mixed lymphohematopoietic chimerism after kidney transplantation. Two female and one male patient were transplanted with a kidney and peripherally mobilized hematopoietic stem cells from their HLA-identical sibling donor. The protocol followed previous studies at Stanford University: kidney transplantation was performed on day 0 including induction with anti-thymocyte globulin followed by conditioning with 10x 1.2 Gy total lymphoid irradiation and the transfusion of CD34+ cells together with a body weight-adjusted dose of donor T cells on day 11. Immunosuppression consisted of cyclosporine A and steroids for 10 days, cyclosporine A and mycophenolate mofetil for 1 month, and then cyclosporine A monotherapy with tapering over 9-20 months. The 3 patients have been off immunosuppression for 4 years, 19 months and 8 months, respectively. No rejection or graft-versus-host disease occurred. Hematological donor chimerism was stable in the first, but slowly declining in the other two patients. A molecular microscope analysis in patient 2 revealed the genetic profile of a normal kidney. No relevant infections were observed, and the quality of life in all three patients is excellent. During the SARS-CoV-2 pandemic, all three patients were vaccinated with the mRNA vaccine BNT162b2 (Comirnaty®), and they showed excellent humoral and in 2 out 3 patients also cellular SARS-CoV-2-specific immunity. Thus, combined kidney and hematopoietic stem cell transplantation is a feasible and successful approach to induce specific immunological tolerance in the setting of HLA-matched sibling living kidney donation while maintaining immune responsiveness to an mRNA vaccine (ClinicalTrials.gov: NCT00365846).


Assuntos
Rejeição de Enxerto/prevenção & controle , Antígenos HLA/imunologia , Transplante de Células-Tronco Hematopoéticas , Histocompatibilidade , Falência Renal Crônica/cirurgia , Transplante de Rim , Doadores Vivos , Irmãos , Tolerância ao Transplante , /administração & dosagem , Estudos de Viabilidade , Feminino , Rejeição de Enxerto/imunologia , Sobrevivência de Enxerto , Humanos , Imunidade Humoral , Imunogenicidade da Vacina , Imunossupressores/uso terapêutico , Falência Renal Crônica/diagnóstico , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Fatores de Tempo , Resultado do Tratamento , Vacinação
19.
Mol Immunol ; 144: 44-48, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35184022

RESUMO

Dendritic cells (DCs) have the unique capacity to link innate to adaptive immunity. While most cells that express major histocompatibility (MHC) molecules are able to present antigens to activated T cells, DCs possess the means for presenting antigens to naïve T cells, and, as such, are able to instruct T cells to initiate immune response. There are two cascades of events necessary for DCs to start their instructive function. First, DCs enzymatically process proteins to make T cells recognize an antigen as unique peptide-MHC complexes. Second, DCs provide secretory cytokines and co-stimulatory functions for T cells to respond to this antigen. Thus, the compartments for protein degradation and for protein synthesis are central to DC function. The endoplasmic reticulum (ER), a vast network of membranes and vesicles, connects these compartments and helps modulate DC-specific performance, such as antigen capture and presentation. However, while the health of ER appears relevant for DC function, the intersection between ER stress and antigen presentation remains to be explored.


Assuntos
Apresentação de Antígeno , Estresse do Retículo Endoplasmático , Antígenos , Células Dendríticas , Histocompatibilidade
20.
Hum Immunol ; 83(3): 233-240, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35067388

RESUMO

Human Leukocyte Antigens (HLA) matching at the serological level used to serve as the measure of histocompatibility between organ donors and recipients. With advancements in HLA typing methods more precise HLA mismatch assessment tools were developed to measure dissimilarities at the molecular level, collectively referred to as Molecular Mismatch load analysis tools. Currently, several software are aimed at deciphering the dissimilarities using somewhat different immunologic rationales. Our goal, in this review is to provide a basic overview of the different computational approaches, provide clinical cases to contextualize concerns regarding the lack of assessment of immunogenicity, and present our personal view regarding the gaps and the needs of our field.


Assuntos
Sobrevivência de Enxerto , Histocompatibilidade , Antígenos HLA/genética , Teste de Histocompatibilidade/métodos , Humanos , Doadores de Tecidos
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