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1.
Proc Natl Acad Sci U S A ; 117(11): 6042-6046, 2020 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-32111690

RESUMO

Induction of longstanding immunologic tolerance is essential for survival of transplanted organs and tissues. Despite recent advances in immunosuppression protocols, allograft damage inflicted by antibody specific for donor organs continues to represent a major obstacle to graft survival. Here we report that activation of regulatory CD8 T cells (CD8 Treg) that recognize the Qa-1 class Ib major histocompatibility complex (MHC), a mouse homolog of human leukocyte antigen-E (HLA-E), inhibits antibody-mediated immune rejection of heart allografts. We analyzed this response using a mouse model that harbors a point mutation in the class Ib MHC molecule Qa-1, which disrupts Qa-1 binding to the T cell receptor (TCR)-CD8 complex and impairs the CD8 Treg response. Despite administration of cytotoxic T lymphocyte antigen 4 (CTLA-4) immunoglobulin (Ig), Qa-1 mutant mice developed robust donor-specific antibody responses and accelerated heart graft rejection. We show that these allo-antibody responses reflect diminished Qa-1-restricted CD8 Treg-mediated suppression of host follicular helper T cell-dependent antibody production. These findings underscore the critical contribution of this Qa-1/HLA-E-dependent regulatory pathway to maintenance of transplanted organs and suggest therapeutic approaches to ameliorate allograft rejection.


Assuntos
Rejeição de Enxerto/imunologia , Transplante de Coração/efeitos adversos , Antígenos de Histocompatibilidade Classe I/imunologia , Linfócitos T Auxiliares-Indutores/metabolismo , Linfócitos T Reguladores/imunologia , Aloenxertos/imunologia , Aloenxertos/metabolismo , Animais , Modelos Animais de Doenças , Rejeição de Enxerto/sangue , Rejeição de Enxerto/genética , Sobrevivência de Enxerto/imunologia , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Tolerância Imunológica , Isoanticorpos/imunologia , Isoanticorpos/metabolismo , Isoantígenos/imunologia , Isoantígenos/metabolismo , Camundongos , Miocárdio/imunologia , Miocárdio/metabolismo , Mutação Puntual , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Linfócitos T Auxiliares-Indutores/imunologia , Transplante Homólogo/efeitos adversos
2.
Transfusion ; 60(4): 815-821, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32072650

RESUMO

BACKGROUND: Neutrophil specific Fcγ receptor IIIb (CD16b) is a low-affinity IgG receptor. Its polymorphic variants are associated with human neutrophil antigens (HNA). HNA-1a and HNA-1b differ in four amino acids. Immunization can lead to the production of alloantibodies. The exact contribution of four amino acid exchanges for the formation of HNA-1a, -1b epitopes is currently unknown. STUDY DESIGN AND METHODS: Permutation of each polymorphic amino acid from wild-type CD16b cDNA constructs was performed and expressed on HEK293 cells. All 16 receptor variants were produced and tested against 19 well-characterized HNA antisera in an antigen capture assay. RESULTS: Analyzing the reaction pattern revealed that anti-HNA-1a antibodies can bind whenever asparagine (N) is present in position 65, regardless of the three other positions (CD16b *N**). Anti-HNA-1b antibodies can bind when serine (S) is present in position 36 (CD16b S***), when N is present in position 82 (CD16b **N*), or both (CD16b S*N*). CD16b variants with N65 and S36 and/or N82 (such as CD16b SNN*) bind both, anti-HNA-1a and anti-HNA-1b alloantibodies. If these specific amino acids are missing (as in CD16b RSD*), no antibodies will bind. CONCLUSION: Whereas the primary structure of HNA-1a and HNA-1b usually differs in four amino acids, epitope composition is not "antithetical". N65 alone determines the presence of HNA-1a, and S36 and/or N82 determine the presence of HNA-1b. Amino acid 106 does not participate in epitope formation. Our findings are of specific relevance when a HNA-1 phenotype is predicted from a genotype.


Assuntos
Isoantígenos/imunologia , Receptores de IgG/imunologia , Sequência de Aminoácidos , Complexo Antígeno-Anticorpo/genética , Sítios de Ligação de Anticorpos/genética , DNA Complementar , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/imunologia , Variação Genética , Células HEK293 , Humanos , Isoanticorpos/metabolismo , Isoantígenos/química , Receptores de IgG/genética
3.
Cell Immunol ; 349: 104063, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32087929

RESUMO

Extracellular vesicles (EVs), including exosomes, ectosomes and apoptotic vesicles, play an essential role in communication between cells of the innate and adaptive immune systems. Recent studies showed that EVs released after transplantation of allogeneic tissues and organs are involved in the immune recognition and response leading to rejection or tolerance in mice. After skin, pancreatic islet, and solid organ transplantation, donor-derived EVs were shown to initiate direct inflammatory alloresponses by T cells leading to acute rejection. This occurred through presentation of intact allogeneic MHC molecules on recipient antigen presenting cells (MHC cross-dressing) and subsequent activation of T cells via semi-direct allorecognition. On the other hand, some studies have documented the role of EVs in maternal tolerance of fetal alloantigens during pregnancy and immune privilege associated with spontaneous tolerance of liver allografts in laboratory rodents. The precise nature of the EVs, which are involved in rejection or tolerance, and the cells which produce them, is still unclear. Nevertheless, several reports showed that EVs released in the blood and urine by allografts can be used as biomarkers of rejection. This article reviews current knowledge on the contribution of EVs in allorecognition by T cells and discusses some mechanisms underlying their influence on T cell alloimmunity in allograft rejection or tolerance.


Assuntos
Aloenxertos/imunologia , Vesículas Extracelulares/imunologia , Rejeição de Enxerto/imunologia , Tolerância ao Transplante/imunologia , Imunidade Adaptativa , Animais , Apresentação do Antígeno , Células Apresentadoras de Antígenos/imunologia , Biomarcadores , Quimerismo , Vesículas Extracelulares/metabolismo , Feminino , Xenoenxertos/imunologia , Humanos , Imunidade Inata , Isoantígenos/imunologia , Masculino , Troca Materno-Fetal/imunologia , Camundongos , Gravidez
5.
Am J Clin Pathol ; 153(4): 554-565, 2020 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-32011681

RESUMO

OBJECTIVES: Previously we demonstrated that a decreased percentage of CD177-positive granulocytes detected by flow cytometry (FCM) was associated with myelodysplastic syndrome (MDS). Here we expand on those findings to more rigorously evaluate the utility of CD177 for the detection of MDS. METHODS: Two hundred patient samples (100 MDS and 100 controls) were evaluated for granulocyte expression of CD177 and 11 other flow cytometric parameters known to be associated with MDS. RESULTS: We show that CD177, as a single analyte, is highly correlated with MDS with a receiver operating characteristic area under curve value of 0.8. CD177 expression below 30% demonstrated a sensitivity of 51% and a specificity of 94% for detecting MDS with a positive predictive value of 89.5%. In multivariate analysis of 12 MDS-associated FCM metrics, CD177 and the Ogata parameters were significant indicators of MDS, and CD177 increased sensitivity of the Ogata score by 16% (63%-79%) for predicting MDS. Finally, diagnostic criteria incorporating these parameters with a 1% blast cutoff level and CD177 resulted in a sensitivity of 90% and specificity of 91% for detecting MDS. CONCLUSIONS: The findings indicate CD177 is a useful FCM marker for MDS.


Assuntos
Granulócitos/metabolismo , Isoantígenos/metabolismo , Síndromes Mielodisplásicas/diagnóstico , Receptores de Superfície Celular/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Citometria de Fluxo , Proteínas Ligadas por GPI/metabolismo , Humanos , Imunofenotipagem , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/metabolismo
6.
Cell Immunol ; 349: 104061, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32059816

RESUMO

Transplantation of fully allogeneic organs into immunocompetent recipients invariably elicits T cell and B cell responses that lead to the production of donor-specific antibodies (DSA). When immunosuppression is inadequate donor-specific T cell and B cell responses escape, leading to T cell-mediated rejection (TCMR), antibody mediated (ABMR) rejection, or mixed rejection (MR) exhibiting features of both TCMR and ABMR. Current literature suggests that ABMR is a major cause of late graft loss, and that new therapies to curtail the donor-specific humoral response are necessary. The majority of research into B cell responses elicited by allogeneic allografts in both preclinical models and clinical studies, has focused on the function of B cells as antibody-secreting cells and the pathogenic effects of DSA as mediators of ABMR. However, it has long been recognized that the DSA response to allografts is T cell-dependent, and that B cells engage in cognate interactions with T cells that provide "help" and promote B cell differentiation into antibody-secreting cells (ASCs). This review focusses the function of B cells as antigen-presenting cells (APCs) to T cells in lymphoid organs, how they may be critical APCs to T cell in the allograft, and the functional consequences of these interactions.


Assuntos
Aloenxertos/imunologia , Células Apresentadoras de Antígenos/imunologia , Linfócitos B/imunologia , Rejeição de Enxerto/imunologia , Tolerância ao Transplante/imunologia , Animais , Especificidade de Anticorpos , Apresentação do Antígeno , Linfócitos T CD4-Positivos/imunologia , Movimento Celular , Deleção Clonal , Transplante de Coração , Humanos , Isoanticorpos/biossíntese , Isoantígenos/imunologia , Transplante de Rim , Camundongos , Baço/imunologia , Timo/imunologia
8.
Blood ; 135(8): 568-581, 2020 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-31880771

RESUMO

Gastrointestinal (GI) tract involvement is the major cause of morbidity and mortality in acute graft-versus-host disease (GVHD), and pathological damage is largely attributable to inflammatory cytokine production. Recently, granulocyte-macrophage colony stimulating factor (GM-CSF) has been identified as a cytokine that mediates inflammation in the GI tract, but the transcriptional program that governs GM-CSF production and the mechanism by which GM-CSF links adaptive to innate immunity within this tissue site have not been defined. In the current study, we identified Bhlhe40 as a key transcriptional regulator that governs GM-CSF production by CD4+ T cells and mediates pathological damage in the GI tract during GVHD. In addition, we observed that GM-CSF was not regulated by either interleukin 6 (IL-6) or IL-23, which are both potent inducers of GVHD-induced colonic pathology, indicating that GM-CSF constitutes a nonredundant inflammatory pathway in the GI tract. Mechanistically, GM-CSF had no adverse effect on regulatory T-cell reconstitution, but linked adaptive to innate immunity by enhancing the activation of donor-derived dendritic cells in the colon and subsequent accumulation of these cells in the mLNs. In addition, GM-CSF promoted indirect alloantigen presentation, resulting in the accumulation of donor-derived T cells with a proinflammatory cytokine phenotype in the colon. Thus, Bhlhe40+ GM-CSF+ CD4+ T cells constitute a colitogenic T-cell population that promotes indirect alloantigen presentation and pathological damage within the GI tract, positioning GM-CSF as a key regulator of GVHD in the colon and a potential therapeutic target for amelioration of this disease.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/imunologia , Antígenos CD4/imunologia , Linfócitos T CD4-Positivos/patologia , Doença Enxerto-Hospedeiro/patologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Proteínas de Homeodomínio/imunologia , Isoantígenos/imunologia , Animais , Linfócitos T CD4-Positivos/imunologia , Colo/imunologia , Colo/patologia , Trato Gastrointestinal/imunologia , Trato Gastrointestinal/patologia , Doença Enxerto-Hospedeiro/imunologia , Camundongos Endogâmicos C57BL
9.
Ren Fail ; 42(1): 40-47, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31875761

RESUMO

Background: De novo Donor Specific Antibodies (DSA) are considered as a risk factor for the kidney allograft outcomes in recipients after simultaneous liver-kidney transplantation (SLKT). We hypothesized that length of hospital stay (LOS) might be associated with de novo DSA development of due to the increased likelihood of receiving blood transfusions with reduced immunosuppressive regimens.Methods: This study is a single-center, retrospective cohort study consisting of 85 recipients who underwent SLKT from 2009 to 2018 in our hospital. We divided the patients into two groups according to LOS [long hospital stay (L) group (LOS >14 days) and short hospital stay (S) group (LOS ≤14 days)]. Propensity score (PS) has been created using logistic regression to predict LOS greater than median of 14 days. The association between the presence of de novo DSA and LOS was assessed by logistic regression models adjusted for PS.Results: The mean age at transplantation of the entire cohort was 55.5 ± 10.1 years. Sixty percent of the recipients were male and Caucasian. Median LOS in (L) group was three-fold longer than (S) group [L: median 30 days (IQR: 21-52), S: median 8.5 days (IQR: 7-11)]. Eight patients developed de novo DSA after SLKT (9.4%), all of them were in (L) group. Longer LOS was significantly associated with higher risk of development of de novo DSA in unadjusted (OR+ each 5 days: 1.09, 95% CI:1.02-1.16) and PS adjusted (OR+ each 5 days: 1.11, 95% CI:1.02-1.21) analysis.Conclusion: Longer hospitalization is significantly associated with the development of de novo DSA in SLKT.


Assuntos
Rejeição de Enxerto/epidemiologia , Isoanticorpos/sangue , Transplante de Rim/efeitos adversos , Tempo de Internação/estatística & dados numéricos , Transplante de Fígado/efeitos adversos , Adulto , Idoso , Aloenxertos/imunologia , Transfusão de Sangue/estatística & dados numéricos , Feminino , Rejeição de Enxerto/sangue , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/prevenção & controle , Humanos , Imunossupressores/administração & dosagem , Incidência , Isoanticorpos/imunologia , Isoantígenos/imunologia , Rim/imunologia , Fígado/imunologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo
10.
Transplant Proc ; 51(10): 3456-3462, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31733792

RESUMO

OBJECTIVE: To investigate the effects of IL (interleukin) 21 on CD8+ T cells stimulated by alloantigen in the presence of IL-15 in vitro. METHODS: CD8+ T cells sorted with MicroBeads from fresh human peripheral blood mononuclear cells were cocultured with antigen-presenting cells derived from HLA-A, -B, and -DR full-mismatched individuals for 9 days without any cytokines, in the presence of IL-15, IL-21, and IL-15 combined with IL-21, respectively. The proliferation and phenotypic characteristics of CD28+ and CD28- subsets were measured after 9 days of culture. RESULTS: The proliferation of CD8+ T cells can be promoted either by IL-15 alone or in combination with IL-21 compared with IL-21. Cells expanded in the presence of IL-15 are mainly CD8+CD28- T cells, while those expanded in the presence of IL-15 combined with IL-21 are mostly CD8+CD28+ T cells. In the presence of IL-15, most CD8+CD28+ T cells shifted to CD8+CD28- T cells during the process of proliferation, but In the presence of IL-15 combined with IL-21, CD8+CD28+ T cells didn't shift to CD8+CD28- T cells during proliferation, moreover, CD8+CD28- T cells cannot transform in reverse to CD8+CD28+ T cells. IL-21 combined with IL-15 can promote the expression of granzyme B and perforin in CD8+CD28+ and/or CD8+CD28- T cells compared with IL-15 alone. CONCLUSION: IL-21 cannot promote the proliferation of CD8+ T cells under allogeneic stimulation unless combined with IL-15. IL-21 prevents the loss of CD28 molecules caused by IL-15 but cannot promote its re-expression in CD28- T cells. CD8+ T cells expanded by IL-21 combined with IL-15 is characterized by cytotoxic phenotype.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Interleucina-15/imunologia , Interleucinas/imunologia , Ativação Linfocitária/imunologia , Subpopulações de Linfócitos T/imunologia , Antígenos CD28/imunologia , Humanos , Isoantígenos/imunologia
11.
Blood ; 134(24): 2139-2148, 2019 12 12.
Artigo em Inglês | MEDLINE | ID: mdl-31697827

RESUMO

Allogeneic stem cell transplantation is a cornerstone of curative therapy for high-risk and/or advanced hematological malignancies but remains limited by graft-versus-host disease (GVHD). GVHD is initiated by the interaction between recipient antigen-presenting cells (APCs) and donor T cells, culminating in T-cell differentiation along pathogenic type-1 and type-17 paradigms at the expense of tolerogenic regulatory T-cell patterns. Type-1 and type-17 T cells secrete cytokines (eg, granulocyte-macrophage colony-stimulating factor and interferon-γ) critical to the cytokine storm that amplifies expansion of donor APCs and their alloantigen presentation. It has become increasingly clear that pathogenic donor T-cell differentiation is initiated by both professional recipient APCs (eg, dendritic cells [DCs]) and nonprofessional APCs (eg, epithelial and mesenchymal cells), particularly within the gastrointestinal (GI) tract. In the immediate peritransplantation period, these APCs are profoundly modified by pathogen-associated molecular pattern (PAMP)/damage-associated molecular pattern (DAMP) signals derived from conditioning and intestinal microbiota. Subsequently, donor DCs in the GI tract are activated by DAMP/PAMP signals in the colon that gain access to the lamina propria once the mucosal barrier mucosa is compromised by GVHD. This results in donor DC expansion and alloantigen presentation in the colon and subsequent migration into the mesenteric lymph nodes. Here, new donor T cells are primed, expanded, differentiated, and imprinted with gut-homing integrins permissive of migration into the damaged GI tract, resulting in the lethal feed-forward cascade of GVHD. These new insights into our understanding of the cellular and molecular factors initiating GVHD, both spatially and temporally, give rise to a number of logical therapeutic targets, focusing on the inhibition of APC function in the GI tract.


Assuntos
Células Apresentadoras de Antígenos/imunologia , Células Apresentadoras de Antígenos/metabolismo , Suscetibilidade a Doenças , Trato Gastrointestinal/imunologia , Trato Gastrointestinal/metabolismo , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/metabolismo , Animais , Apresentação do Antígeno/imunologia , Transplante de Medula Óssea , Trato Gastrointestinal/patologia , Estudos de Associação Genética , Doença Enxerto-Hospedeiro/mortalidade , Doença Enxerto-Hospedeiro/patologia , Transplante de Células-Tronco Hematopoéticas , Humanos , Isoantígenos/imunologia , Ativação Linfocitária , Microbiota
12.
Proc Natl Acad Sci U S A ; 116(47): 23682-23690, 2019 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-31685610

RESUMO

Following antigen stimulation, naïve T cells differentiate into memory cells that mediate antigen clearance more efficiently upon repeat encounter. Donor-specific tolerance can be achieved in a subset of transplant recipients, but some of these grafts are rejected after years of stability, often following infections. Whether T cell memory can develop from a tolerant state and whether these formerly tolerant patients develop antidonor memory is not known. Using a mouse model of cardiac transplantation in which donor-specific tolerance is induced with costimulation blockade (CoB) plus donor-specific transfusion (DST), we have previously shown that systemic infection with Listeria monocytogenes (Lm) months after transplantation can erode or transiently abrogate established tolerance. In this study, we tracked donor-reactive T cells to investigate whether memory can be induced when alloreactive T cells are activated in the setting of tolerance. We show alloreactive T cells persist after induction of cardiac transplantation tolerance, but fail to acquire a memory phenotype despite becoming antigen experienced. Instead, donor-reactive T cells develop T cell-intrinsic dysfunction evidenced when removed from the tolerant environment. Notably, Lm infection after tolerance did not rescue alloreactive T cell memory differentiation or functionality. CoB and antigen persistence were sufficient together but not separately to achieve alloreactive T cell dysfunction, and conventional immunosuppression could substitute for CoB. Antigen persistence was required, as early but not late surgical allograft removal precluded the acquisition of T cell dysfunction. Our results demonstrate transplant tolerance-associated T cell-intrinsic dysfunction that is resistant to memory development even after Lm-mediated disruption of tolerance.


Assuntos
Sobrevivência de Enxerto/imunologia , Tolerância Imunológica/imunologia , Subpopulações de Linfócitos T/imunologia , Imunologia de Transplantes , Aloenxertos , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/transplante , Fatores de Transcrição Forkhead/análise , Genes Reporter , Rejeição de Enxerto/imunologia , Antígenos H-2/imunologia , Transplante de Coração , Antígenos de Histocompatibilidade Classe II/imunologia , Memória Imunológica , Isoantígenos/imunologia , Listeria monocytogenes , Listeriose/imunologia , Transfusão de Linfócitos , Camundongos , Camundongos Congênicos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Complicações Pós-Operatórias/imunologia , Linfócitos T Reguladores/imunologia , Doadores de Tecidos
13.
Proteomics Clin Appl ; 13(6): e1900007, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31424156

RESUMO

PURPOSE: To investigate the differences in protein expression between Dpy19l2-deficient human globozoospermia and normozoospermia. EXPERIMENTAL DESIGN: Human sperm samples from three globozoospermic donors with Dpy19l2 deletion and three normal controls are subjected to TMT quantitative technology. SPESP1, HIST1H4A, and LYZL1 are randomly selected for western blotting analysis. GO annotations are performed using the Database for Annotation, Visualization, and Integrated Discovery. RESULTS: A total of 2567 proteins are identified, of which 2510 proteins are quantified, and 491 are differentially expressed (fold-change > 2), with 370 upregulated and 121 downregulated in globozoospermic patients. The levels of several important proteins, including SPACA 1, IZUMO1, ZPBP1, and PLCZ1, are decreased in globozoospermic sperm. Bioinformatics analysis indicates the Dpy19l2-deficient sperm presented molecular defects in acrosome, chromatin, sperm-egg interaction, and fertilization. CONCLUSIONS AND CLINICAL RELEVANCE: The present study is the first to analyze total globozoospermia with Dpy19l2 deletion using high-throughput proteomics. This study may provide insights into the mechanism of globozoospermia.


Assuntos
Proteínas de Membrana/genética , Proteoma/análise , Proteômica/métodos , Teratozoospermia/metabolismo , Acrossomo/metabolismo , Adulto , Estudos de Casos e Controles , Regulação para Baixo , Genótipo , Humanos , Imunoglobulinas/genética , Isoantígenos/genética , Masculino , Proteínas de Plasma Seminal/genética , Espermatozoides/metabolismo , Espermatozoides/patologia , Teratozoospermia/patologia , Regulação para Cima , Adulto Jovem
14.
Nephrol Dial Transplant ; 34(12): 2143-2154, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31280312

RESUMO

BACKGROUND: Antigen-specific cellular response is essential in immune tolerance. We tested whether antigen-specific cellular response is differentially modulated in operational tolerance (OT) in renal transplantation with respect to critical antigenic challenges in allotransplantation-donor antigens, pathogenic antigens and self-antigens. METHODS: We analysed the profile of immunoregulatory (REG) and pro-inflammatory (INFLAMMA) cytokines for the antigen-specific response directed to these three antigen groups, by Luminex. RESULTS: We showed that, in contrast to chronic rejection and healthy individuals, OT gives rise to an immunoregulatory deviation in the cellular response to donor human leucocyte antigen DR isotype peptides, while preserving the pro-inflammatory response to pathogenic peptides. Cellular autoreactivity to the N6 heat shock protein 60 (Hsp60) peptide also showed a REG profile in OT, increasing IL4, IL-5, IL-10 and IL-13. CONCLUSIONS: The REG shift of donor indirect alloreactivity in OT, with inhibition of interleukin (IL)-1B, IL-8, IL-12, IL-17, granulocyte colony-stimulating factor, Interferon-γ and monocyte chemoattractant protein-1, indicates that this may be an important mechanism in OT. In addition, the differential REG profile of cellular response to the Hsp60 peptide in OT suggests that REG autoimmunity may also play a role in human transplantation tolerance. Despite cross-reactivity of antigen-specific T cell responses, a systemic functional antigen-specific discrimination takes place in OT.


Assuntos
Autoantígenos/imunologia , Autoimunidade/imunologia , Citocinas/imunologia , Tolerância Imunológica/imunologia , Inflamação/imunologia , Isoantígenos/imunologia , Tolerância ao Transplante/imunologia , Citocinas/metabolismo , Feminino , Humanos , Inflamação/metabolismo , Inflamação/patologia , Isoantígenos/metabolismo , Transplante de Rim/métodos , Masculino
15.
Immunohematology ; 35(2): 48-50, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31246487

RESUMO

CONCLUSIONS: This update of the Scianna blood group system (Brunker PA, Flegel WA. Scianna: the lucky 13th blood group system. Immunohematology 2011;27:41-57) provides the recent work on the genetic variation of ERMAP across more world populations, the elucidation of the molecular basis of an historical serologic case, new cases of antibodies in the system, the development of new serologic reagents, and new discoveries in the biology of the erythroid membrane associated protein (ERMAP). Although genetic variation in ERMAP has been extensively cataloged, nonsynonymous variants associated with alloantigens have remained limited, and no new antigens have been identified. The first case of a severe hemolytic transfusion reaction to anti-Sc2 has recently been reported, highlighting the importance of pursuing the possibility of antibodies to low-prevalence antigens via indirect antiglobulin testing as a routine component of all transfusion reaction investigations. The expanding use of molecular testing in blood centers and transfusion services has uncovered a wider population distribution of Scianna antigens and heightened the awareness of this blood group system. The International Society of Blood Transfusion recognizes seven antigens in the Scianna blood group system 13.


Assuntos
Antígenos de Grupos Sanguíneos/análise , Reação Transfusional , Transfusão de Sangue , Humanos , Isoantígenos
16.
J Immunol Res ; 2019: 5763430, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31179346

RESUMO

Organ transplantation is a life-saving strategy for patients with end-stage organ failure. Over the past few decades, organ transplantation has achieved an excellent success in short-term survival but only a marginal improvement in long-term graft outcomes. The pathophysiology of graft loss is multifactorial and remains incompletely defined. However, emerging evidence suggests macrophages as crucial mediators of acute and chronic allograft immunopathology. In this process, macrophage-mediated mobilization of first-line defenses, particularly phagocytosis and the release of acute inflammatory mediators, is important, but macrophages also launch adaptive alloimmune reactions against grafts through antigen processing and presentation, as well as providing costimulation. Additionally, crosstalk with other immune cells and graft endothelial cells causes tissue damage or fibrosis in transplanted organs, contributing to graft loss or tolerance resistance. However, some macrophages function as regulatory cells that are capable of suppressing allogeneic T cells, inhibiting DC maturation, inducing the differentiation of Tregs, and subsequently promoting transplant tolerance. This functional diversity of macrophages in organ transplantation is consistent with their heterogeneity. Although our knowledge of the detrimental or beneficial effects of macrophages on transplants has exponentially increased, the exact mechanisms controlling macrophage functions are not yet completely understood. Here, we review recent advances in our understanding of the multifaceted nature of macrophages, focusing on their evolving roles in organ transplantation and the mechanisms involved in their activation and function in allograft transplantation. We also discuss potential therapeutic options and opportunities to target macrophage to improve the outcomes of transplant recipients.


Assuntos
Rejeição de Enxerto/imunologia , Macrófagos/imunologia , Transplante de Órgãos , Animais , Rejeição de Enxerto/prevenção & controle , Humanos , Tolerância Imunológica , Imunomodulação , Isoantígenos/imunologia , Ativação de Macrófagos , Transplante Homólogo
17.
J Immunol ; 203(2): 557-568, 2019 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-31182480

RESUMO

Graft-versus-host disease (GVHD) is the most serious complication of allogeneic hematopoietic cell transplantation. Notch signals delivered during the first 48 h after transplantation drive proinflammatory cytokine production in conventional T cells (Tconv) and inhibit the expansion of regulatory T cells (Tregs). Short-term Notch inhibition induces long-term GVHD protection. However, it remains unknown whether Notch blockade blunts GVHD through its effects on Tconv, Tregs, or both and what early Notch-regulated molecular events occur in alloantigen-specific T cells. To address these questions, we engineered T cell grafts to achieve selective Notch blockade in Tconv versus Tregs and evaluated their capacity to trigger GVHD in mice. Notch blockade in Tconv was essential for GVHD protection as GVHD severity was similar in the recipients of wild-type Tconv combined with Notch-deprived versus wild-type Tregs. To identify the impact of Notch signaling on the earliest steps of T cell activation in vivo, we established a new acute GVHD model mediated by clonal alloantigen-specific 4C CD4+ Tconv. Notch-deprived 4C T cells had preserved early steps of activation, IL-2 production, proliferation, and Th cell polarization. In contrast, Notch inhibition dampened IFN-γ and IL-17 production, diminished mTORC1 and ERK1/2 activation, and impaired transcription of a subset of Myc-regulated genes. The distinct Notch-regulated signature had minimal overlap with known Notch targets in T cell leukemia and developing T cells, highlighting the specific impact of Notch signaling in mature T cells. Our findings uncover a unique molecular program associated with the pathogenic effects of Notch in T cells at the earliest stages of GVHD.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Doença Enxerto-Hospedeiro/imunologia , Isoantígenos/imunologia , Receptores Notch/imunologia , Animais , Transplante de Medula Óssea/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Transdução de Sinais/imunologia , Linfócitos T Reguladores/imunologia , Transplante Homólogo/efeitos adversos
18.
Hum Immunol ; 80(8): 614-620, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31054781

RESUMO

Anti-endothelial cell antibodies (AECAs) have been correlated with increased acute and chronic rejection across all organ types and early graft dysfunction in kidney and heart transplantation. Nevertheless, the lack of appropriate tools and clear criteria for defining injurious versus non-injurious AECAs prohibits their routine inclusion in clinical risk assessments and diagnostic algorithms for antibody mediated injury. Clinical characterization of AECAs is complicated due to the wide range of polymorphic and non-polymorphic antigens expressed across different vascular tissues and the diverse array of specificities observed between individuals. This complexity is also reflected in the broad spectrum of reported injury phenotypes. AECAs detected at time of allograft dysfunction may represent biomarkers of past vascular injury or active contributors to a current rejection process. New tools within the fields of proteomics, genomics, bioinformatics, and imaging are currently being validated and hold great promise for unraveling the AECA paradox.


Assuntos
Anticorpos/metabolismo , Biomarcadores/metabolismo , Células Endoteliais/imunologia , Rejeição de Enxerto/imunologia , Transplante de Órgãos , Animais , Autoantígenos/imunologia , Exossomos/metabolismo , Humanos , Imunização , Isoantígenos/imunologia , Especificidade de Órgãos
19.
Anal Cell Pathol (Amst) ; 2019: 9506863, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31093484

RESUMO

This study was undertaken to further investigate the CD177 expression in Helicobacter pylori- (Hp-) infected wild-type and CD177-/- C57BL/6 mice, which may be helpful to elucidate the relationship between CD177 and Hp-related gastritis. 20 WT mice were randomly assigned into the Hpss1 WT group (n = 10) and Hp49503 WT group (n = 10); 20 KO mice were randomly assigned into the Hpss1 KO group (n = 10) and Hp49503 KO group (n = 10). The remaining mice served as controls. Mice in the HpSS1 groups and Hp49503 groups were independently infected with corresponding strains. Results showed that the Hp colonization score was related to the grade of mucosal inflammation (P < 0.05). The inflammation grade was comparable between the HpSS1 group and Hp49503 group as well as between the WT group and KO group. In addition, the Hp colonization score was related to the CD177 expression score (P < 0.05). The CD177 expression in the Hp colonization group was higher than that in the non-Hp colonization group (P < 0.05). CD177 expression was positively related to the inflammation grade (P < 0.01). In conclusion, CD177 expression was similar between HP49503- and HPss1-infected WT C57BL/6 mice, and CD177 expression was undetectable in CD177-/- mice. CD177 expression in the gastric mucosa increases with the elevation of inflammation grade. In Hp-infected mice, the inflammation grade had no relationship with the type of Hp strain and the CD177 expression, but the mucosal inflammation score in Hp-infected mice was higher than that in non-Hp infected mice.


Assuntos
Antígenos CD/metabolismo , Proteínas Ligadas por GPI/metabolismo , Gastrite/metabolismo , Infecções por Helicobacter/metabolismo , Helicobacter pylori , Isoantígenos/metabolismo , Receptores de Superfície Celular/metabolismo , Animais , Mucosa Gástrica/metabolismo , Mucosa Gástrica/microbiologia , Mucosa Gástrica/fisiopatologia , Gastrite/microbiologia , Infecções por Helicobacter/fisiopatologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL
20.
Pediatr Rheumatol Online J ; 17(1): 13, 2019 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-30943984

RESUMO

BACKGROUND: Kawasaki disease (KD) is the most common acute coronary vasculitis disease to occur in children. Its incidence has been attributed to the combined effects of infection, genetics, and immunity. Although the etiopathogenesis of KD remains unknown, we have performed a survey of global genetic DNA methylation status and transcripts expression in KD patients in order to determine their contribution to the pathogenesis of KD. METHODS: We recruited 148 participants for this case-control study. The chip studies consisted of 18 KD patients that were analyzed both before undergoing intravenous immunoglobulin (IVIG) treatment and at least 3 weeks afterward, as well as 36 non-KD control subjects, using Illumina HumanMethylation450 BeadChip and Affymetrix GeneChip® Human Transcriptome Array 2.0. We then carried out real-time quantitative PCR on a separate cohort of 94 subjects for validation. RESULTS: According to our microarray study, CD177, a neutrophil surface molecule, appeared to be significantly upregulated in KD patients when compared to controls with epigenetic hypomethylation. After patients received IVIG treatment, CD177 mRNA levels decreased significantly. PCR validation indicated that the CD177 expression is consistent with the Transcriptome Array 2.0 results. Furthermore, the area under the curve values of CD177 between KD patients and controls is 0.937. We also observed significantly higher CD177 levels in typical KD than in incomplete presentation or KD with IVIG resistance. CONCLUSION: In this study, we have demonstrated the epigenetic hypomethylation and increased expression of CD177 during the acute stage of KD. Furthermore, a higher expression of CD177 in KD patients with typical presentation was associated with IVIG resistance.


Assuntos
Isoantígenos/metabolismo , Síndrome de Linfonodos Mucocutâneos/metabolismo , Receptores de Superfície Celular/metabolismo , Estudos de Casos e Controles , Criança , Pré-Escolar , Metilação de DNA , Feminino , Proteínas Ligadas por GPI/sangue , Proteínas Ligadas por GPI/metabolismo , Humanos , Imunoglobulinas Intravenosas/administração & dosagem , Isoantígenos/sangue , Masculino , Síndrome de Linfonodos Mucocutâneos/terapia , Análise de Sequência com Séries de Oligonucleotídeos , Reação em Cadeia da Polimerase em Tempo Real , Receptores de Superfície Celular/sangue , Sensibilidade e Especificidade , Transcriptoma/genética
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