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1.
J Clin Invest ; 132(13)2022 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-35775481

RESUMO

Lymph node (LN) fibroblastic reticular cells (FRCs) define LN niches and regulate lymphocyte homeostasis through producing diverse extracellular matrix (ECM) components. We examined the role of ECM laminin α4 (Lama4) using FRC-Lama4 conditional KO Pdgfrb-Cre-/- × Lama4fl/fl mice. Single-cell RNA-sequencing (scRNA-Seq) data showed the promoter gene Pdgfrb was exclusively expressed in FRCs. Depleting FRC-Lama4 reduced Tregs and dendritic cells, decreased high endothelial venules, impaired the conduit system, and downregulated T cell survival factors in LNs. FRC-Lama4 depletion impaired the homing of lymphocytes to LNs in homeostasis and after allografting. Alloantigen-specific T cells proliferated, were activated to greater degrees in LNs lacking FRC-Lama4, and were more prone to differentiate into effector phenotypes relative to the Treg phenotype. In murine cardiac transplantation, tolerogenic immunosuppression was not effective in FRC-Lama4 recipients, which produced more alloantibodies than WT. After lung transplantation, FRC-Lama4-KO mice had more severe graft rejection with fewer Tregs in their LNs. Overall, FRC-Lama4 critically contributes to a tolerogenic LN niche by supporting T cell migration, constraining T cell activation and proliferation, and promoting Treg differentiation. Hence, it serves as a therapeutic target for immunoengineering.


Assuntos
Laminina , Linfonodos , Reticulina , Linfócitos T , Animais , Laminina/imunologia , Linfonodos/imunologia , Camundongos , Receptor beta de Fator de Crescimento Derivado de Plaquetas , Reticulina/imunologia , Linfócitos T/imunologia , Linfócitos T Reguladores/imunologia , Imunologia de Transplantes
2.
Sci Rep ; 12(1): 11821, 2022 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-35821240

RESUMO

T cell exhaustion refers to a dysfunctional state in which effector T cells present a decreased ability to proliferate and to produce cytokines, while the co-expression of inhibitory receptors increases. We investigated global and donor-specific T cell responses in a cohort of stable, living-donor kidney transplant patients that received similar immunosuppression. After transplantation, an increase in the ratio of TIGIT + /CD226 + in mCD4 + T cells (r = 0.47, p = 0.01), and a decrease of CD226 + TIGIT-mCD4 + T cells was observed (r = - 0.55, p = 0.001). This leads to an increase of dysfunctional T cells in patients far from transplantation. In mCD8 + T cells, a decrease of IL-2 production after mitogenic stimulation was observed far from transplantation. Phenotypic analyses revealed an increase of mCD8 + T cells co-expressing PD-1 and TIGIT over time (r = 0.51, p = 0.02). After donor-specific stimulation, the ability of CD4 + T cells to proliferate was decreased compared with third parties. CD4 + T cells expressing CD226 and TIGIT were correlated with allospecific CD4 + proliferation (r = 0.68, p = 0.04). Our study suggests that after kidney transplantation a T cell hyporesponsiveness appears over time, driven by a dysregulation of CD226/TIGIT axis in mCD4 + T cells, associated with an increase of PD1 + TIGIT + in mCD8 + T cells.


Assuntos
Antígenos de Diferenciação de Linfócitos T , Linfócitos T CD4-Positivos , Transplante de Rim , Receptores Imunológicos , Antígenos de Diferenciação de Linfócitos T/imunologia , Citocinas/imunologia , Humanos , Receptores Imunológicos/imunologia , Imunologia de Transplantes
3.
Dis Markers ; 2022: 8605621, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35756489

RESUMO

Dendritic cells (DC) initiate the immune response in the body. They can stimulate T cell activation, proliferation, and differentiation and ultimately participate in the immune response and the immune tolerance response. The purpose of this study was to coculture DCs and T cells and subcutaneously inject DCs transfected with miR-let-7i into rhesus monkey transplantations to verify the role of miR-let-7i in allograft immune tolerance. In vitro studies found that the expression of miR-let-7i was upregulated after inducing the maturation of DCs. The low expression of miR-let-7i inhibited the maturation of DCs, promoted the differentiation of T cells into T helper T cells 2 (Th2), and inhibited T helper T cell 1- (Th1-) driven rejection. In vivo studies also obtained similar results, and subcutaneous injection of DCs transfected with miR-let-7i inhibitor prolonged the survival time of allogeneic skin transplantation. Therefore, we conclude that inhibition of miR-let-7i inhibits DC maturation and improves the tolerance of grafted skin.


Assuntos
Células Dendríticas , MicroRNAs , Transplante de Pele , Linfócitos T , Diferenciação Celular/imunologia , Células Dendríticas/imunologia , Humanos , Tolerância Imunológica , MicroRNAs/antagonistas & inibidores , MicroRNAs/imunologia , Linfócitos T/imunologia , Imunologia de Transplantes
4.
Sci Rep ; 12(1): 9033, 2022 05 31.
Artigo em Inglês | MEDLINE | ID: mdl-35641781

RESUMO

Improved models of experimental diabetes are needed to develop cell therapies for diabetes. Here, we introduce the B6 RIP-DTR mouse, a model of experimental diabetes in fully immunocompetent animals. These inbred mice harbor the H2b major histocompatibility complex (MHC), selectively express high affinity human diphtheria toxin receptor (DTR) in islet ß-cells, and are homozygous for the Ptprca (CD45.1) allele rather than wild-type Ptprcb (CD45.2). 100% of B6 RIP-DTR mice rapidly became diabetic after a single dose of diphtheria toxin, and this was reversed indefinitely after transplantation with islets from congenic C57BL/6 mice. By contrast, MHC-mismatched islets were rapidly rejected, and this allotransplant response was readily monitored via blood glucose and graft histology. In peripheral blood of B6 RIP-DTR with mixed hematopoietic chimerism, CD45.2 BALB/c donor blood immune cells were readily distinguished from host CD45.1 cells by flow cytometry. Reliable diabetes induction and other properties in B6 RIP-DTR mice provide an important new tool to advance transplant-based studies of islet replacement and immunomodulation to treat diabetes.


Assuntos
Diabetes Mellitus Experimental , Transplante das Ilhotas Pancreáticas , Ilhotas Pancreáticas , Animais , Diabetes Mellitus Experimental/terapia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Imunologia de Transplantes
5.
Hepatology ; 75(3): 634-645, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34724224

RESUMO

BACKGROUND AND AIMS: The European Liver Transplant Registry (ELTR) has collected data on liver transplant procedures performed in Europe since 1968. APPROACH AND RESULTS: Over a 50-year period (1968-2017), clinical and laboratory data were collected from 133 transplant centers and analyzed retrospectively (16,641 liver transplants in 14,515 children). Data were analyzed according to three successive periods (A, before 2000; B, 2000-2009; and C, since 2010), studying donor and graft characteristics and graft outcome. The use of living donors steadily increased from A to C (A, n = 296 [7%]; B, n = 1131 [23%]; and C, n = 1985 [39%]; p = 0.0001). Overall, the 5-year graft survival rate has improved from 65% in group A to 75% in group B (p < 0.0001) and to 79% in group C (B versus C, p < 0.0001). Graft half-life was 31 years, overall; it was 41 years for children who survived the first year after transplant. The late annual graft loss rate in teenagers is higher than that in children aged <12 years and similar to that of young adults. No evidence for accelerated graft loss after age 18 years was found. CONCLUSIONS: Pediatric liver transplantation has reached a high efficacy as a cure or treatment for severe liver disease in infants and children. Grafts that survived the first year had a half-life similar to standard human half-life. Transplantation before or after puberty may be the pivot-point for lower long-term outcome in children. Further studies are necessary to revisit some old concepts regarding transplant benefit (survival time) for small children, the role of recipient pathophysiology versus graft aging, and risk at transition to adult age.


Assuntos
Rejeição de Enxerto/epidemiologia , Sobrevivência de Enxerto/fisiologia , Transplante de Fígado , Obtenção de Tecidos e Órgãos , Imunologia de Transplantes/fisiologia , Adolescente , Fatores Etários , Criança , Europa (Continente)/epidemiologia , Feminino , Humanos , Lactente , Transplante de Fígado/efeitos adversos , Transplante de Fígado/métodos , Transplante de Fígado/estatística & dados numéricos , Transplante de Fígado/tendências , Doadores Vivos/estatística & dados numéricos , Masculino , Sistema de Registros/estatística & dados numéricos , Tempo , Obtenção de Tecidos e Órgãos/organização & administração , Obtenção de Tecidos e Órgãos/estatística & dados numéricos
6.
J Immunol Res ; 2021: 7507459, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34950737

RESUMO

The search for common mechanisms underlying the pathogenesis of chronic inflammatory conditions has crystalized the concept of continuous dual resetting of the immune repertoire (CDR) as a basic principle of the immune system function. Consequently, outlined was the first dynamic comprehensive picture of the immune system function. The goal of this study is to elaborate on regulation of immune responses and mechanisms of tolerance, particularly focusing on adaptive immunity. It is well established that the T/B cell repertoire is selected and maintained based on interactions with self. However, their activation also requires interaction with a self-specific major histocompatibility complex (MHC) "code," i.e., the context of MHC molecules. Therefore, not only repertoire selection and maintenance but also the T/B cell activation and function are self-centered. Thus, adaptive effectors may be primarily focused on the state of self and maintenance of integrity of the self, and only to a certain degree on elimination of the foreign. As examples of such function are used immunologically poorly understood MHC-disparate settings typical for transplantation and pregnancy. Transplantation represents an extreme setting of strong systemic compartment-level adaptive/MHC-restricted immune responses. Described are clinically identified conditions for operational tolerance of MHC-disparate tissues/living systems in allotransplantation, which are in line with the CDR-proposed self-centered regulatory role of T/B cells. In contrast, normal pregnancy is coexistence of semiallogeneic or entirely allogeneic mother and fetus, but without alloreactivity akin to transplantation settings. Presented data support the notion that maintenance of pregnancy is a process that relies predominantly on innate/MHC-independent immune mechanisms. By the inception of hemotrophic stage of pregnancy (second and third trimester), both mother and child are individual living systems, with established adaptive immune repertoires. Although mother-fetus interactions at that point become indirect systemic compartment-level communications, their interactions throughout gestation remain within the innate realm of molecular-level adaptations.


Assuntos
Imunidade Adaptativa , Tolerância Imunológica , Imunomodulação , Tolerância a Antígenos Próprios/imunologia , Linfócitos B/imunologia , Linfócitos B/metabolismo , Feminino , Humanos , Fenômenos do Sistema Imunitário , Imunidade Inata , Masculino , Troca Materno-Fetal/imunologia , Gravidez , Linfócitos T/imunologia , Linfócitos T/metabolismo , Glândula Tireoide/imunologia , Glândula Tireoide/metabolismo , Imunologia de Transplantes
7.
Sci Rep ; 11(1): 23815, 2021 12 10.
Artigo em Inglês | MEDLINE | ID: mdl-34893663

RESUMO

Allograft-specific regulatory T cells (Treg cells) are crucial for long-term graft acceptance after transplantation. Although adoptive Treg cell transfer has been proposed, major challenges include graft-specificity and stability. Thus, there is an unmet need for the direct induction of graft-specific Treg cells. We hypothesized a synergism of the immunotolerogenic effects of rapamycin (mTOR inhibition) and plerixafor (CXCR4 antagonist) for Treg cell induction. Thus, we performed fully-mismatched heart transplantations and found combination treatment to result in prolonged allograft survival. Moreover, fibrosis and myocyte lesions were reduced. Although less CD3+ T cell infiltrated, higher Treg cell numbers were observed. Noteworthy, this was accompanied by a plerixafor-dependent plasmacytoid dendritic cells-(pDCs)-mobilization. Furthermore, in vivo pDC-depletion abrogated the plerixafor-mediated Treg cell number increase and reduced allograft survival. Our pharmacological approach allowed to increase Treg cell numbers due to pDC-mediated immune regulation. Therefore pDCs can be an attractive immunotherapeutic target in addition to plerixafor treatment.


Assuntos
Células Dendríticas/imunologia , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/metabolismo , Transplante de Coração , Imunomodulação , Receptores CXCR4/antagonistas & inibidores , Aloenxertos , Animais , Benzilaminas/farmacologia , Biomarcadores , Ciclamos/farmacologia , Células Dendríticas/metabolismo , Modelos Animais de Doenças , Sinergismo Farmacológico , Rejeição de Enxerto/diagnóstico , Sobrevivência de Enxerto/efeitos dos fármacos , Sobrevivência de Enxerto/imunologia , Transplante de Coração/efeitos adversos , Transplante de Coração/métodos , Camundongos , Prognóstico , Sirolimo/farmacologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Imunologia de Transplantes , Resultado do Tratamento
8.
Front Immunol ; 12: 782152, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34868058

RESUMO

Minor histocompatibility antigens (mHAg) composed of peptides presented by HLA molecules can cause immune responses involved in graft-versus-host disease (GVHD) and graft-versus-leukemia effects after allogeneic hematopoietic cell transplantation (HCT). The current study was designed to identify individual graft-versus-host genomic mismatches associated with altered risks of acute or chronic GVHD or relapse after HCT between HLA-genotypically identical siblings. Our results demonstrate that in allogeneic HCT between a pair of HLA-identical siblings, a mHAg manifests as a set of peptides originating from annotated proteins and non-annotated open reading frames, which i) are encoded by a group of highly associated recipient genomic mismatches, ii) bind to HLA allotypes in the recipient, and iii) evoke a donor immune response. Attribution of the immune response and consequent clinical outcomes to individual peptide components within this set will likely differ from patient to patient according to their HLA types.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Antígenos de Histocompatibilidade Menor/imunologia , Imunologia de Transplantes , Adolescente , Adulto , Idoso , Alelos , Criança , Pré-Escolar , Suscetibilidade a Doenças/imunologia , Feminino , Predisposição Genética para Doença , Variação Genética , Doença Enxerto-Hospedeiro/epidemiologia , Doença Enxerto-Hospedeiro/etiologia , Antígenos HLA/genética , Antígenos HLA/imunologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Incidência , Lactente , Recém-Nascido , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Antígenos de Histocompatibilidade Menor/genética , Peptídeos/genética , Peptídeos/imunologia , Transplante Homólogo , Adulto Jovem
9.
Front Immunol ; 12: 667834, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34880853

RESUMO

Transplantation (Tx) remains the optimal therapy for end-stage disease (ESD) of various solid organs. Although alloimmune events remain the leading cause of long-term allograft loss, many patients develop innate and adaptive immune responses leading to graft tolerance. The focus of this review is to provide an overview of selected aspects of the effects of inflammation on this delicate balance following solid organ transplantation. Initially, we discuss the inflammatory mediators detectable in an ESD patient. Then, the specific inflammatory mediators found post-Tx are elucidated. We examine the reciprocal relationship between donor-derived passenger leukocytes (PLs) and those of the recipient, with additional emphasis on extracellular vesicles, specifically exosomes, and we examine their role in determining the balance between tolerance and rejection. The concept of recipient antigen-presenting cell "cross-dressing" by donor exosomes is detailed. Immunological consequences of the changes undergone by cell surface antigens, including HLA molecules in donor and host immune cells activated by proinflammatory cytokines, are examined. Inflammation-mediated donor endothelial cell (EC) activation is discussed along with the effect of donor-recipient EC chimerism. Finally, as an example of a specific inflammatory mediator, a detailed analysis is provided on the dynamic role of Interleukin-6 (IL-6) and its receptor post-Tx, especially given the potential for therapeutic interdiction of this axis with monoclonal antibodies. We aim to provide a holistic as well as a reductionist perspective of the inflammation-impacted immune events that precede and follow Tx. The objective is to differentiate tolerogenic inflammation from that enhancing rejection, for potential therapeutic modifications. (Words 247).


Assuntos
Rejeição de Enxerto/imunologia , Sobrevivência de Enxerto/imunologia , Inflamação/imunologia , Imunologia de Transplantes , Aloenxertos/imunologia , Animais , Citocinas/imunologia , Células Endoteliais/imunologia , Vesículas Extracelulares/imunologia , Rejeição de Enxerto/prevenção & controle , Reação Enxerto-Hospedeiro/imunologia , Reação Hospedeiro-Enxerto/imunologia , Humanos , Terapia de Imunossupressão/métodos , Imunossupressores/efeitos adversos , Infecções/imunologia , Mediadores da Inflamação/metabolismo , Isoantígenos/imunologia , Leucócitos/fisiologia , Camundongos , Complicações Pós-Operatórias/imunologia , Ativação Viral/imunologia
11.
Front Immunol ; 12: 777756, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34804070

RESUMO

Recent advances in high throughput sequencing (HTS) of T cell receptors (TCRs) and in transcriptomic analysis, particularly at the single cell level, have opened the door to a new level of understanding of human immunology and immune-related diseases. In this article, we discuss the use of HTS of TCRs to discern the factors controlling human T cell repertoire development and how this approach can be used in combination with human immune system (HIS) mouse models to understand human repertoire selection in an unprecedented manner. An exceptionally high proportion of human T cells has alloreactive potential, which can best be understood as a consequence of the processes governing thymic selection. High throughput TCR sequencing has allowed assessment of the development, magnitude and nature of the human alloresponse at a new level and has provided a tool for tracking the fate of pre-transplant-defined donor- and host-reactive TCRs following transplantation. New insights into human allograft rejection and tolerance obtained with this method in combination with single cell transcriptional analyses are reviewed here.


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala , Receptores de Antígenos de Linfócitos T/genética , Linfócitos T/imunologia , Linfócitos T/metabolismo , Animais , Autoimunidade , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Seleção Clonal Mediada por Antígeno , Suscetibilidade a Doenças/imunologia , Regulação da Expressão Gênica , Predisposição Genética para Doença , Rejeição de Enxerto , Sobrevivência de Enxerto/genética , Sobrevivência de Enxerto/imunologia , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Tolerância Imunológica , Imunidade , Modelos Animais , Receptores de Antígenos de Linfócitos T/metabolismo , Linfócitos T/citologia , Imunologia de Transplantes , Transplante Homólogo , Recombinação V(D)J
12.
Comput Math Methods Med ; 2021: 2725799, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34790251

RESUMO

Type 1 regulatory T (Tr1) cells play a fundamental role in maintaining and inducing immune tolerance. Our preliminary study demonstrated that an interleukin- (IL-) 10-mediated pathway is a possible regulatory mechanism underlying the xenoantigen-specific human Treg enhanced suppressive capacity. Here, we developed a feasible protocol for expanding IL-10-induced xenoantigen-specific human Tr1 cells in vitro which would be more efficient in transplantation immunotherapy efficiency. In this study, xenoantigen-specific Tr1 cells are generated from human naive CD4+ T cells expanded for two subsequent xenoantigen-stimulation cycles with recombinant human IL-10. The phenotype and suppressive capacity of xenoantigen-stimulated Tr1 cells are assessed, and the mechanism of their suppression is studied. Tr1 cells can be induced by porcine xenoantigen stimulation combined with IL-10, IL-2, and IL-15, displaying an increased expression of CD49b, CTLA-4, and LAG-3 without expressing Foxp3 which also showed an effector memory Treg phenotype and expressed high levels of CD39. After xenoantigen stimulation, the IL-10 and IL-5 gene expression in Tr1 cells increased, secreting more IL-10, and xenoantigen-stimulated Tr1 cells changed their T cell receptor (TCR) Vß repertoire, increasing the expression of TCR Vß2, TCR Vß9, and TCR Vß13. In a pig to human mixed lymphocyte reaction (MLR), xenoantigen-stimulated Tr1 cells displayed enhanced suppressive capacity via CD39 in a dose-dependent manner. Moreover, IL-5 could affect the proliferation of xenoantigen-specific Tr1 cells, but not their phenotypes' expression. This study provides a theory and feasible method for immune tolerance induction in clinical xenotransplantation.


Assuntos
Antígenos Heterófilos/administração & dosagem , Tolerância Imunológica , Linfócitos T Reguladores/imunologia , Transferência Adotiva , Adulto , Animais , Apirase/imunologia , Proliferação de Células , Técnicas de Cocultura , Biologia Computacional , Feminino , Humanos , Técnicas In Vitro , Interleucina-10/biossíntese , Interleucina-5/antagonistas & inibidores , Interleucina-5/imunologia , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , Sus scrofa , Linfócitos T Reguladores/classificação , Linfócitos T Reguladores/citologia , Imunologia de Transplantes , Tolerância ao Transplante
13.
J Hematol Oncol ; 14(1): 174, 2021 10 24.
Artigo em Inglês | MEDLINE | ID: mdl-34689821

RESUMO

BACKGROUND: Factors affecting response to SARS-CoV-2 mRNA vaccine in allogeneic hematopoietic stem cell transplantation (allo-HCT) recipients remain to be elucidated. METHODS: Forty allo-HCT recipients were included in a study of immunization with BNT162b2 mRNA vaccine at days 0 and 21. Binding antibodies (Ab) to SARS-CoV-2 receptor binding domain (RBD) were assessed at days 0, 21, 28, and 49 while neutralizing Ab against SARS-CoV-2 wild type (NT50) were assessed at days 0 and 49. Results observed in allo-HCT patients were compared to those obtained in 40 healthy adults naive of SARS-CoV-2 infection. Flow cytometry analysis of peripheral blood cells was performed before vaccination to identify potential predictors of Ab responses. RESULTS: Three patients had detectable anti-RBD Ab before vaccination. Among the 37 SARS-CoV-2 naive patients, 20 (54%) and 32 (86%) patients had detectable anti-RBD Ab 21 days and 49 days postvaccination. Comparing anti-RBD Ab levels in allo-HCT recipients and healthy adults, we observed significantly lower anti-RBD Ab levels in allo-HCT recipients at days 21, 28 and 49. Further, 49% of allo-HCT patients versus 88% of healthy adults had detectable NT50 Ab at day 49 while allo-HCT recipients had significantly lower NT50 Ab titers than healthy adults (P = 0.0004). Ongoing moderate/severe chronic GVHD (P < 0.01) as well as rituximab administration in the year prior to vaccination (P < 0.05) correlated with low anti-RBD and NT50 Ab titers at 49 days after the first vaccination in multivariate analyses. Compared to healthy adults, allo-HCT patients without chronic GVHD or rituximab therapy had comparable anti-RBD Ab levels and NT50 Ab titers at day 49. Flow cytometry analyses before vaccination indicated that Ab responses in allo-HCT patients were strongly correlated with the number of memory B cells and of naive CD4+ T cells (r > 0.5, P < 0.01) and more weakly with the number of follicular helper T cells (r = 0.4, P = 0.01). CONCLUSIONS: Chronic GVHD and rituximab administration in allo-HCT recipients are associated with reduced Ab responses to BNT162b2 vaccination. Immunological markers could help identify allo-HCT patients at risk of poor Ab response to mRNA vaccination. TRIAL REGISTRATION: The study was registered at clinicaltrialsregister.eu on 11 March 2021 (EudractCT # 2021-000673-83).


Assuntos
Anticorpos Neutralizantes/biossíntese , Vacinas contra COVID-19/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/métodos , Adulto , Idoso , Anticorpos Neutralizantes/imunologia , Vacina BNT162 , Vacinas contra COVID-19/imunologia , Humanos , Pessoa de Meia-Idade , Condicionamento Pré-Transplante , Imunologia de Transplantes , Transplante Homólogo
14.
Eur J Immunol ; 51(10): 2373-2386, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34375446

RESUMO

Liver transplantation is the ultimate treatment option for end-stage liver disease. Breakthroughs in surgical practice and immunosuppression have seen considerable advancements in survival after transplantation. However, the intricate management of immunosuppressive regimens, balancing desired immunological quiescence while minimizing toxicity has proven challenging. Diminishing improvements in long-term morbidity and mortality have been inextricably linked with the protracted use of these medications. As such, there is now enormous interest to devise protocols that will allow us to minimize or completely withdraw immunosuppressants after transplantation. Immunosuppression withdrawal trials have proved the reality of tolerance following liver transplantation, however, without intervention will only occur after several years at the risk of potential cumulative immunosuppression-related morbidity. Focus has now been directed at accelerating this phenomenon through tolerance-inducing strategies. In this regard, efforts have seen the use of regulatory cell immunotherapy. Here we focus particularly on regulatory T cells, discussing preclinical data that propagated several clinical trials of adoptive cell therapy in liver transplantation. Furthermore, we describe efforts to further optimize the specificity and survival of regulatory cell therapy guided by concurrent immunomonitoring studies and the development of novel technologies including chimeric antigen receptors and co-administration of low-dose IL-2.


Assuntos
Transplante de Fígado/tendências , Imunologia de Transplantes , Tolerância ao Transplante/imunologia , Animais , Comunicação Celular/imunologia , Estudos Clínicos como Assunto , Ensaios Clínicos como Assunto , Terapia Combinada , Humanos , Imunomodulação , Fígado/imunologia , Fígado/metabolismo , Hepatopatias/etiologia , Hepatopatias/terapia , Transplante de Fígado/efeitos adversos , Transplante de Fígado/métodos , Modelos Animais , Especificidade de Órgãos/imunologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo
15.
Int J Hematol ; 114(6): 682-690, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34420193

RESUMO

Infection is one of the major causes of death in hematopoietic stem cell transplantation (HSCT) survivors. Precise assessments of immune function after HSCT will be critical in establishing appropriate treatment and prophylaxis, such as re-vaccination. Although several surrogate markers for prediction of clinical outcomes after HSCT have been proposed, definitive markers of immune reconstitution and data on those markers in long-term survivors are lacking. In this study, cellular response to mitogens was assessed and clinical features associated with a poor response to mitogens were investigated in long-term allogeneic HSCT survivors. Age at transplantation and age at the time of mitogen stimulation test were each identified as significant risk factors for poor response to phytohemagglutinin and concanavalin A, respectively (P < 0.001 each). However, time elapsed since transplantation was not found to be correlated with responsiveness to mitogens in this study. Prospective, in-depth studies on immune reconstitution are needed to establish appropriate prophylaxis against infections after HSCT and a schedule for re-vaccination.


Assuntos
Imunidade Celular , Mitógenos/imunologia , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas , Humanos , Contagem de Leucócitos , Ativação Linfocitária/imunologia , Estudos Prospectivos , Índice de Gravidade de Doença , Sobreviventes , Imunologia de Transplantes , Transplante Homólogo
16.
Front Immunol ; 12: 670956, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34386000

RESUMO

Detection of alloreactive anti-HLA antibodies is a frequent and mandatory test before and after organ transplantation to determine the antigenic targets of the antibodies. Nowadays, this test involves the measurement of fluorescent signals generated through antibody-antigen reactions on multi-beads flow cytometers. In this study, in a cohort of 1,066 patients from one country, anti-HLA class I responses were analyzed on a panel of 98 different antigens. Knowing that the immune system responds typically to "shared" antigenic targets, we studied the clustering patterns of antibody responses against HLA class I antigens without any a priori hypothesis, applying two unsupervised machine learning approaches. At first, the principal component analysis (PCA) projections of intra-locus specific responses showed that anti-HLA-A and anti-HLA-C were the most distantly projected responses in the population with the anti-HLA-B responses to be projected between them. When PCA was applied on the responses against antigens belonging to a single locus, some already known groupings were confirmed while several new cross-reactive patterns of alloreactivity were detected. Anti-HLA-A responses projected through PCA suggested that three cross-reactive groups accounted for about 70% of the variance observed in the population, while anti-HLA-B responses were mainly characterized by a distinction between previously described Bw4 and Bw6 cross-reactive groups followed by several yet undocumented or poorly described ones. Furthermore, anti-HLA-C responses could be explained by two major cross-reactive groups completely overlapping with previously described C1 and C2 allelic groups. A second feature-based analysis of all antigenic specificities, projected as a dendrogram, generated a robust measure of allelic antigenic distances depicting bead-array defined cross reactive groups. Finally, amino acid combinations explaining major population specific cross-reactive groups were described. The interpretation of the results was based on the current knowledge of the antigenic targets of the antibodies as they have been characterized either experimentally or computationally and appear at the HLA epitope registry.


Assuntos
Biologia Computacional/métodos , Antígenos HLA-A/imunologia , Antígenos HLA-B/imunologia , Antígenos HLA-C/imunologia , Transplante de Órgãos , Adulto , Idoso , Estudos de Coortes , Reações Cruzadas , Epitopos , Humanos , Isoanticorpos/sangue , Aprendizado de Máquina , Pessoa de Meia-Idade , Análise de Componente Principal , Sistema de Registros , Imunologia de Transplantes
17.
Int J Mol Sci ; 22(14)2021 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-34299243

RESUMO

(1) Background: The aim of the present study was the biocompatibility analysis of a novel xenogeneic vascular graft material (PAP) based on native collagen won from porcine aorta using the subcutaneous implantation model up to 120 days post implantationem. As a control, an already commercially available collagen-based vessel graft (XenoSure®) based on bovine pericardium was used. Another focus was to analyze the (ultra-) structure and the purification effort. (2) Methods: Established methodologies such as the histological material analysis and the conduct of the subcutaneous implantation model in Wistar rats were applied. Moreover, established methods combining histological, immunohistochemical, and histomorphometrical procedures were applied to analyze the tissue reactions to the vessel graft materials, including the induction of pro- and anti-inflammatory macrophages to test the immune response. (3) Results: The results showed that the PAP implants induced a special cellular infiltration and host tissue integration based on its three different parts based on the different layers of the donor tissue. Thereby, these material parts induced a vascularization pattern that branches to all parts of the graft and altogether a balanced immune tissue reaction in contrast to the control material. (4) Conclusions: PAP implants seemed to be advantageous in many aspects: (i) cellular infiltration and host tissue integration, (ii) vascularization pattern that branches to all parts of the graft, and (iii) balanced immune tissue reaction that can result in less scar tissue and enhanced integrative healing patterns. Moreover, the unique trans-implant vascularization can provide unprecedented anti-infection properties that can avoid material-related bacterial infections.


Assuntos
Prótese Vascular/veterinária , Transplante de Tecidos/métodos , Animais , Aorta/metabolismo , Aorta/transplante , Materiais Biocompatíveis/metabolismo , Bioprótese , Bovinos , Colágeno/metabolismo , Xenoenxertos/metabolismo , Xenoenxertos/fisiologia , Ratos , Ratos Wistar , Suínos/metabolismo , Imunologia de Transplantes/imunologia , Cicatrização/fisiologia
18.
Front Immunol ; 12: 680480, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34295330

RESUMO

Natural killer (NK) cells are innate lymphocytes that can kill diseased- or virally-infected cells, mediate antibody dependent cytotoxicity and produce type I immune-associated cytokines upon activation. NK cells also contribute to the allo-immune response upon kidney transplantation either by promoting allograft rejection through lysis of cells of the transplanted organ or by promoting alloreactive T cells. In addition, they protect against viral infections upon transplantation which may be especially relevant in patients receiving high dose immune suppression. NK cell activation is tightly regulated through the integrated balance of signaling via inhibitory- and activating receptors. HLA class I molecules are critical regulators of NK cell activation through the interaction with inhibitory- as well as activating NK cell receptors, hence, HLA molecules act as critical immune checkpoints for NK cells. In the current review, we evaluate how NK cell alloreactivity and anti-viral immunity are regulated by NK cell receptors belonging to the KIR family and interacting with classical HLA class I molecules, or by NKG2A/C and LILRB1/KIR2DL4 engaging non-classical HLA-E or -G. In addition, we provide an overview of the methods to determine genetic variation in these receptors and their HLA ligands.


Assuntos
Suscetibilidade a Doenças/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Transplante de Rim/efeitos adversos , Células Matadoras Naturais/imunologia , Viroses/etiologia , Animais , Biomarcadores , Teste de Histocompatibilidade , Humanos , Proteínas de Checkpoint Imunológico/imunologia , Proteínas de Checkpoint Imunológico/metabolismo , Isoanticorpos/imunologia , Células Matadoras Naturais/metabolismo , Ligantes , Ativação Linfocitária/imunologia , Prognóstico , Ligação Proteica , Receptores de Células Matadoras Naturais/genética , Receptores de Células Matadoras Naturais/metabolismo , Imunologia de Transplantes , Resultado do Tratamento , Viroses/metabolismo
19.
Life Sci Alliance ; 4(7)2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34112724

RESUMO

Invariant natural killer T (iNKT) cells are a conserved population of innate T lymphocytes that interact with key antigen-presenting cells to modulate adaptive T-cell responses in ways that can either promote protective immunity, or limit pathological immune activation. Understanding the immunological networks engaged by iNKT cells to mediate these opposing functions is a key pre-requisite to effectively using iNKT cells for therapeutic applications. Using a human umbilical cord blood xenotransplantation model, we show here that co-transplanted allogeneic CD4+ iNKT cells interact with monocytes and T cells in the graft to coordinate pro-hematopoietic and immunoregulatory pathways. The nexus of iNKT cells, monocytes, and cord blood T cells led to the release of cytokines (IL-3, GM-CSF) that enhance hematopoietic stem and progenitor cell activity, and concurrently induced PGE2-mediated suppression of T-cell inflammatory responses that limit hematopoietic stem and progenitor cell engraftment. This resulted in successful long-term hematopoietic engraftment without pretransplant conditioning, including multi-lineage human chimerism and colonization of the spleen by antibody-producing human B cells. These results highlight the potential for using iNKT cellular immunotherapy to improve rates of hematopoietic engraftment independently of pretransplant conditioning.


Assuntos
Células T Matadoras Naturais/imunologia , Células T Matadoras Naturais/metabolismo , Imunologia de Transplantes/imunologia , Animais , Células Apresentadoras de Antígenos/imunologia , Citocinas/imunologia , Feminino , Sangue Fetal/imunologia , Humanos , Imunidade Inata/imunologia , Imunoterapia/métodos , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos NOD , Transplante de Tecidos/métodos
20.
Front Immunol ; 12: 535012, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34093514

RESUMO

Rejection after organ transplantation is a cause of graft failure. Effectively reducing rejection and inducing tolerance is a challenge in the field of transplantation immunology. The liver, as an immunologically privileged organ, has high rates of spontaneous and operational tolerance after transplantation, allowing it to maintain its normal function for long periods. Although modern immunosuppression regimens have serious toxicity and side effects, it is very risky to discontinue immunosuppression regimens blindly. A more effective treatment to induce immune tolerance is the most sought-after goal in transplant medicine. Tregs have been shown to play a pivotal role in the regulation of immune balance, and infusion of Tregs can also effectively prevent rejection and cure autoimmune diseases without significant side effects. Given the immune characteristics of the liver, the correct use of Tregs can more effectively induce the occurrence of operational tolerance for liver transplants than for other organ transplants. This review mainly summarizes the latest research advances regarding the characteristics of the hepatic immune microenvironment, operational tolerance, Treg generation in vitro, and the application of Tregs in liver transplantation. It is hoped that this review will provide a deeper understanding of Tregs as the most effective treatment to induce and maintain operational tolerance after liver transplantation.


Assuntos
Pesquisa Biomédica/métodos , Tolerância Imunológica/imunologia , Transplante de Fígado/métodos , Linfócitos T Reguladores/imunologia , Imunologia de Transplantes/imunologia , Tolerância ao Transplante/imunologia , Pesquisa Biomédica/tendências , Previsões , Rejeição de Enxerto/imunologia , Humanos , Fígado/imunologia
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