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1.
Malar J ; 19(1): 6, 2020 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-31906953

RESUMO

BACKGROUND: Vaccines are the most reliable alternative to elicit sterile immunity against malaria but their development has been hindered by polymorphisms and strain-specificity in previously studied antigens. New vaccine candidates are therefore urgently needed. Highly conserved Plasmodium falciparum reticulocyte-binding protein homologue-5 (PfRH5) has been identified as a potential candidate for anti-disease vaccine development. PfRH5 is essential for erythrocyte invasion by merozoites and crucial for parasite survival. However, there is paucity of data on the extent of genetic variations on PfRH5 in field isolates of Plasmodium falciparum. This study described genetic polymorphisms at the high affinity binding polypeptides (HABPs) 36718, 36727, 36728 of PfRH5 in Nigerian isolates of P. falciparum. This study tested the hypothesis that only specific conserved B and T cell epitopes on PfRH5 HABPs are crucial for vaccine development. METHODS: One hundred and ninety-five microscopically confirmed P. falciparum samples collected in a prospective cross-sectional study of three different populations in Lagos, Nigeria. Genetic diversity and haplotype construct of Pfrh5 gene were determined using bi-directional sequencing approach. Tajima's D and the ratio of nonsynonymous vs synonymous mutations were utilized to estimate the extent of balancing and directional selection in the pfrh5 gene. RESULTS: Sequence analysis revealed three haplotypes of PfRH5 with negative Tajima's D and dN/dS value of - 1.717 and 0.011 ± 0.020, respectively. A single nucleotide polymorphism, SNP (G → A) at position 608 was observed, which resulted in a change of the amino acid cysteine at position 203 to tyrosine. Haplotype and nucleotide diversities were 0.318 ± 0.016 and 0.0046 ± 0.0001 while inter-population genetic differentiation ranged from 0.007 to 0.037. Five polypeptide variants were identified, the most frequent being KTKYH with a frequency of 51.3%. One B-cell epitope, 151 major histocompatibility complex (MHC) class II T-cell epitopes, four intrinsically unstructured regions (IURs) and six MHC class I T-cell epitopes were observed in the study. Phylogenetic analysis of the sequences showed clustering and evidence of evolutionary relationship with 3D7, PAS-2 and FCB-2 RH5 sequences. CONCLUSIONS: This study has revealed low level of genetic polymorphisms in PfRH5 antigen with B- and T-cell epitopes in intrinsically unstructured regions along the PfRH5 gene in Lagos, Nigeria. A broader investigation is however required in other parts of the country to support the possible inclusion of PfRH5 in a cross-protective multi-component vaccine.


Assuntos
Proteínas de Transporte/genética , Proteínas de Transporte/imunologia , Vacinas Antimaláricas/genética , Vacinas Antimaláricas/imunologia , Polimorfismo de Nucleotídeo Único , Anticorpos Antiprotozoários/imunologia , Antígenos de Protozoários/genética , Antígenos de Protozoários/imunologia , Estudos Transversais , Epitopos de Linfócito B , Epitopos de Linfócito T , Eritrócitos/parasitologia , Fluxo Gênico , Haplótipos , Histocompatibilidade , Malária Falciparum/imunologia , Malária Falciparum/parasitologia , Malária Falciparum/prevenção & controle , Merozoítos/imunologia , Nigéria , Filogenia , Plasmodium falciparum/genética , Plasmodium falciparum/isolamento & purificação , Estudos Prospectivos , Análise de Sequência
2.
Am J Kidney Dis ; 75(1): 114-123, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31255336

RESUMO

With implementation of the Kidney Allocation System, the growth of kidney paired donation programs, and advances in desensitization and immunosuppression, the outlook for "untransplantable" kidney transplantation candidates has never been more promising. The Kidney Allocation System prioritized compatible matches for candidates with calculated panel-reactive antibody levels of 98%, 99%, or 100% and broadened allocation of non-A1 and non-A1-B subgroup kidneys to blood group type B candidates. Concurrently, the growth of kidney paired donation programs and use of incompatible transplantation as part of kidney paired donation to achieve "more compatible" kidney transplantation has improved options for candidates with an incompatible living donor. Finally, advances in desensitization and immunosuppression have strengthened the ability to manage donor-specific antibodies and antibody-mediated rejection. Although no patient should be labeled "untransplantable" due to blood group type or donor-specific antibody, all candidates should be provided with individualized and realistic counseling regarding their anticipated wait times for deceased donor or kidney paired donation matching, with early referral to expert centers when needed. In this Perspective, we consider blood group type ABO incompatibility, HLA antigen incompatibility, antibody-mediated rejection, kidney paired donation, and recent developments in incompatible transplantation in more depth and recommend an approach to the sensitized candidate.


Assuntos
Incompatibilidade de Grupos Sanguíneos/imunologia , Antígenos HLA/imunologia , Histocompatibilidade/imunologia , Transplante de Rim/métodos , Sistema ABO de Grupos Sanguíneos/imunologia , Dessensibilização Imunológica/métodos , Doação Dirigida de Tecido , Seleção do Doador , Humanos , Doadores Vivos , Obtenção de Tecidos e Órgãos
3.
Immunogenetics ; 72(1-2): 119-129, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31741009

RESUMO

Human leukocyte antigen (HLA) mismatches between donors and recipients may lead to alloreactivity after solid organ transplantation. Over the last few decades, our knowledge of the complexity of the HLA system has dramatically increased, as numerous new HLA alleles have been identified. As a result, the likelihood of alloreactive responses towards HLA mismatches after solid organ transplantation cannot easily be assessed. Algorithms are promising solutions to estimate the risk for alloreactivity after solid organ transplantation. In this review, we show that the recently developed PIRCHE-II (Predicted Indirectly ReCognizable HLA Epitopes) algorithm can be used to minimize alloreactivity towards HLA mismatches. Together with the use of other algorithms and simulation approaches, the PIRCHE-II algorithm aims for a better estimated alloreactive risk for individual patients and eventually an improved graft survival after solid organ transplantation.


Assuntos
Epitopos/imunologia , Antígenos HLA/imunologia , Histocompatibilidade/imunologia , Algoritmos , Biologia Computacional/métodos , Rejeição de Enxerto/imunologia , Sobrevivência de Enxerto/imunologia , Antígenos HLA/genética , Teste de Histocompatibilidade/métodos , Humanos , Transplante de Órgãos/métodos , Fatores de Risco , Doadores de Tecidos , Obtenção de Tecidos e Órgãos
4.
Bull Cancer ; 107(1S): S94-S103, 2020 Jan.
Artigo em Francês | MEDLINE | ID: mdl-31006487

RESUMO

Since 2010 there has been an exponential increase of the number of transplants performed from related donors. The development of haploidentical transplants increases the resort to related-donation, which presents two main advantages: a less important financial cost and a faster availability of the graft. Standards for mandatory accreditation exist, but the adherence to these recommendations is not optimal: currently, different practices regarding the organizational modalities of care, recruitment criteria, qualification and follow-up of related donors have been observed among French transplant centers. The Francophone Society of Marrow Transplant and Cellular Therapy (SFGM-TC) has developed guidelines for the consent and the non-eligibility criteria for hematopoietic stem cell donors. A multidisciplinary group has devised a booklet as a medium to inform donors about hematopoietic cell donation and transplantation in a clear and accessible language. This paper provides recommendations on post-donation follow-up, taking into account both medical standards and organizational constraints of French centers. Some tools are proposed.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Doadores de Tecidos , Aloenxertos , Família , Haplótipos/genética , Histocompatibilidade , Humanos , Consentimento Livre e Esclarecido , Comunicação Interdisciplinar , Doadores Vivos , Obtenção de Tecidos e Órgãos/métodos , Obtenção de Tecidos e Órgãos/normas
5.
Lancet Haematol ; 7(1): e50-e60, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31669248

RESUMO

BACKGROUND: The success of unrelated haemopoietic cell transplantation (HCT) is limited by graft-versus-host disease (GVHD), which is the main post-transplantation challenge when HLA-matched donors are unavailable. A sequence dimorphism in exon 1 of HLA-B gives rise to leader peptides containing methionine (Met; M) or threonine (Thr; T), which differentially influence natural killer and T-cell alloresponses. The main aim of the study was to evaluate the role of the leader dimorphism in GVHD after HLA-B-mismatched unrelated HCT. METHODS: We did a retrospective cohort study of 33 982 patients who received an unrelated HCT done in Australia, Europe, Japan, North America, and the UK between Jan 1, 1988, and Dec 31, 2016. Data were contributed by participants of the International Histocompatibility Working Group in Hematopoietic Cell Transplantation. All cases were included and there were no exclusion criteria. Multivariate regression models were used to assess risks associated with HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 mismatching. Among the 33 982 transplantations, the risks of GVHD associated with HLA-B M and T leaders were established in 17 100 (50·3%) HLA-matched and 1457 (4·3%) single HLA-B-mismatched transplantations using multivariate regression models. Leader frequencies were defined in 2 004 742 BeTheMatch US registry donors. FINDINGS: Between Jan 20, 2017, and March 11, 2019, we assessed 33 982 HCTs using multivariate regression models for the role of HLA mismatching on outcome. Median follow-up was 1841 days (IQR 909-2963). Mortality and GVHD increased with increasing numbers of HLA mismatches. A single HLA-B mismatch increased grade 3-4 acute GVHD (odds ratio [OR] 1·89, 95% CI 1·53-2·33; p<0·0001). Among the single HLA-B-mismatched transplantations, acute GVHD risk was higher with leader mismatching than with leader matching (OR 1·73, 1·02-2·94; p=0·042 for grade 2-4) and with an M leader shared allotype compared with a T leader shared allotype (OR 1·98, 1·39-2·81; p=0·0001 for grade 3-4). The preferred HLA-B-mismatched donor is leader-matched and shares a T leader allotype. The majority (1 836 939 [91·6%]) of the 2 004 742 US registry donors have the TT or MT genotype. INTERPRETATION: The HLA-B leader informs GVHD risk after HLA-B-mismatched unrelated HCT and differentiates high-risk HLA-B mismatches from those with lower risk. The leader of the matched allotype could be considered to be as important as the leader of the mismatched allotype for GVHD. Prospective identification of leader-matched donors is feasible for most patients in need of a HCT, and could lower GVHD and increase availability of HCT therapy. These findings are being independently validated and warrant further research in prospective trials. FUNDING: The National Institutes of Health, USA.


Assuntos
Éxons/genética , Doença Enxerto-Hospedeiro/genética , Antígenos HLA-B/genética , Transplante de Células-Tronco Hematopoéticas , Adolescente , Adulto , Feminino , Doença Enxerto-Hospedeiro/imunologia , Transplante de Células-Tronco Hematopoéticas/métodos , Histocompatibilidade , Teste de Histocompatibilidade , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estudos Retrospectivos
6.
Bull Cancer ; 107(1S): S72-S84, 2020 Jan.
Artigo em Francês | MEDLINE | ID: mdl-31586527

RESUMO

Haploidentical hematopoietic stem cell transplantation has been growing steadily since 2012. The SFGM-TC has twice published guidelines concerning T-cell repleted haploidentical grafts with high dose cyclophosphamide post-transplantation. The 2013 workshop recommended using the non-myeloablative Baltimore protocol with bone marrow and developed prospective protocols to evaluate these transplantations. The 2015 workshop reported improved results of reduced conditioning regimens in Hodgkin's lymphoma and intensive conditioning in myeloid hemopathies, and a similar outcome with 10/10 HLA matched donor with the same disease-risk score thus raising the question of the qualifier "alternative" for haploidentical transplants. The current work concerns the criteria for selecting the donor. The main criterion remains the absence of anti-HLA antibodies directed against the donor present in the recipient sera (DSA - Donor Specific Antibodies). In case of DSA and in the absence of an alternative donor, desensitization protocols exist. The other criteria are impossible to prioritize: age, sex, CMV, and blood type. The degree of relatedness and the number of HLA incompatibilities do not seem to be a criterion of choice. The 'ideal' donor would be a young man, CMV-matched, without major ABO incompatibility with a marrow transplant. There is insufficient data for the KIR-ligand and NIMA/NIPA mismatch. Peripheral stem cell grafts appear to yield more acute GVHD than bone marrow grafts after intensive conditioning, but with comparable survival rates. Based on the literature review, the comparison of haploidentical with unrelated donors encourages inclusion in existing national protocols randomizing these different donors.


Assuntos
Haplótipos , Histocompatibilidade , Doadores de Tecidos , Adulto , Fatores Etários , Aloenxertos , Transplante de Medula Óssea , Ciclofosfamida/uso terapêutico , Infecções por Citomegalovirus/complicações , Feminino , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto , Antígenos HLA/imunologia , Transplante de Células-Tronco Hematopoéticas/métodos , Teste de Histocompatibilidade , Humanos , Imunossupressores/uso terapêutico , Depleção Linfocítica , Masculino , Fatores Sexuais , Linfócitos T , Condicionamento Pré-Transplante/efeitos adversos , Condicionamento Pré-Transplante/métodos
7.
Clin Exp Immunol ; 200(1): 89-104, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31869432

RESUMO

Chronic antigen stimulation can lead to immune exhaustion (a state of T cell dysfunction). Several phenotypical signatures of T cell exhaustion have been described in various pathological situations, characterized by aberrant expression of multiple inhibitory receptors (IR). This signature has been barely studied in the context of allogenic organ transplantation. We undertook a cross-sectional analysis of the expression of IR [CD244, CD279, T cell immunoreceptor with immunoglobulin (Ig) and immunoreceptor tyrosine-based inhibition motif (ITIM) domains (TIGIT) and CD57] and their correlation with cytokine-producing functions in T cells reconstituting after lymphocyte depletion in patients transplanted from living donors, with preformed donor-specific antibodies. After ABO incompatible transplantation, T cells progressively acquired a phenotype similar to healthy donors and the expression of several IR marked cells with increased functions, with the exception of TIGIT, which was associated with decreased cytokine production. In stark contrast, T cell reconstitution in patients with anti-human leukocyte antigen (HLA) antibodies was characterized with an increased co-expression of IR by T cells, and specifically by an increased expression of TIGIT. Furthermore, expression of these receptors was no longer directly correlated to cytokine production. These results suggest that T cell alloreactivity in HLA-incompatible kidney transplantation drives an aberrant T cell reconstitution with respect to IR profile, which could have an impact on the transplantation outcome.


Assuntos
Sistema ABO de Grupos Sanguíneos/imunologia , Antígenos HLA/imunologia , Transplante de Rim/métodos , Receptor de Morte Celular Programada 1/imunologia , Receptores Imunológicos/imunologia , Família de Moléculas de Sinalização da Ativação Linfocitária/imunologia , Linfócitos T/imunologia , Sistema ABO de Grupos Sanguíneos/genética , Adulto , Idoso , Incompatibilidade de Grupos Sanguíneos/genética , Incompatibilidade de Grupos Sanguíneos/imunologia , Estudos Transversais , Feminino , Perfilação da Expressão Gênica/métodos , Sobrevivência de Enxerto/genética , Sobrevivência de Enxerto/imunologia , Antígenos HLA/genética , Antígenos HLA/metabolismo , Histocompatibilidade/genética , Histocompatibilidade/imunologia , Humanos , Doadores Vivos , Depleção Linfocítica/métodos , Masculino , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/metabolismo , Receptores Imunológicos/genética , Receptores Imunológicos/metabolismo , Família de Moléculas de Sinalização da Ativação Linfocitária/genética , Família de Moléculas de Sinalização da Ativação Linfocitária/metabolismo , Linfócitos T/metabolismo
9.
Int J Immunogenet ; 47(1): 24-27, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31867873

RESUMO

This short review will be concerned with the literature that has developed connected with the immunogenetic and tissue compatibility aspects of hand transplantation and will also draw on connected work in the more general area of vascularized composite allotransplantation (VCA) which includes face, abdominal wall uterus and larynx.


Assuntos
Rejeição de Enxerto/imunologia , Sobrevivência de Enxerto/imunologia , Antígenos HLA/imunologia , Transplante de Mão , Histocompatibilidade/imunologia , Humanos , Imunização , Alotransplante de Tecidos Compostos Vascularizados
10.
Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi ; 37(11): 848-851, 2019 Nov 20.
Artigo em Chinês | MEDLINE | ID: mdl-31826553

RESUMO

Objective: To evaluate the histocompatibility and clearance of chlorpyrifos and its metabolite of activated charcoal and adsorption resin by in vitro study. Methods: Venous blood from volunteers were incubation with activated charcoal or adsorbent resins, cytometry parameters and plasma components were detected for evaluation the histocompatibility of adsorbents. Venous blood from volunteers mixed with chlorpyrifos and its metabolite were incubation with activated charcoal or adsorbent resins, plasma concentration of chlorpyrifos and its metabolite were detected for evaluation the efficacy of adsorbents. Results: Incubation tests show that the absorbents reduce the blood platelet (F=3.671, P<0.05) , serum glucose (F=10.564, P<0.05) , albumin (F=5.239, P<0.05) , uric acid (F=7.175, P<0.05) , creatinine (F=23.673, P<0.05) , T3 (F=11.161, P<0.05) and free T3 (F=10.256, P<0.05) . However, other cytometry parameters and plasma components were not influenced. Both activated charcoal and adsorbent resins could reduce the plasma concentration of chlorpyrifos (F=798.110, P<0.01) and its metabolite (F=1495.212, P<0.05) . Conclusion: In vitro test show that both activated charcoal and adsorbent resins could clear chlorpyrifos and its metabolite, however, could not influence main cytometry parameters and plasma components, the histocompatibility of adsorbents are satisfactory.


Assuntos
Clorpirifos , Hemoperfusão , Plaquetas , Carvão Vegetal/química , Carvão Vegetal/metabolismo , Clorpirifos/sangue , Clorpirifos/imunologia , Clorpirifos/metabolismo , Histocompatibilidade , Humanos
11.
J Assist Reprod Genet ; 36(12): 2583-2591, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31741257

RESUMO

PURPOSE: Transplantation of ovarian tissue is a valuable method to rescue mouse strains with fertility problems and to revitalize archived strains. The purpose of this study was to investigate the effect of (i) different sizes of transplanted ovary pieces on reproductive outcome, (ii) use of immunodeficient recipients to overcome the limitation of histocompatibility, and (iii) to compare different protocols for cryopreservation of ovarian tissue. METHODS: Halves, quarters, and eights of mouse ovaries were transplanted. Half ovaries from B6 donors were transferred into immunodeficient mice. Halves of ovaries were frozen according to four different protocols, thawed and transferred. RESULTS: Pregnancy rate after transplantation of ovarian tissue was high (90-100%) independent of the transplant size. Although, the average litter size was significantly lower for recipients of quarters and eights (4.4 and 4.6 vs. 6.5), the total number of offspring produced per donor ovary was higher compared with recipients of halves. Pregnancy rate of immunodeficient recipients was 40% (mean 4.7 offspring per litter). All four cryopreservation protocols used were able to preserve functionality of the ovarian tissue. CONCLUSIONS: Transplantation of ovarian tissue smaller than halves resulted in reduced litter sizes. The distribution of ovarian tissue of one donor female to 4 or 8 recipients will therefore yield in a higher total number of offspring in a certain time period. The use of immunodeficient recipients is an option for non-histocompatible donors. Cryopreservation of ovarian tissue is generally feasible but the function of frozen-thawed ovary halves after transplantation differs depending on the freezing protocol used.


Assuntos
Criopreservação/métodos , Fertilidade/fisiologia , Ovário/transplante , Reprodução/fisiologia , Animais , Feminino , Histocompatibilidade/fisiologia , Humanos , Camundongos , Ovariectomia , Ovário/anatomia & histologia , Ovário/cirurgia , Gravidez , Taxa de Gravidez
12.
Immunogenetics ; 71(10): 635-645, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31745606

RESUMO

It has become anticipated that regenerative medicine will extend into the field of veterinary medicine as new treatments for various disorders. Although the use of allogeneic stem cells for tissue regeneration is more attractive than that of autologous cells in emergencies, the therapeutic potential of allogeneic transplantation is often limited by allo-immune responses inducing graft rejection. Therefore, a methodology for quantifying and monitoring alloreactive T cells is necessary for evaluating allo-immune responses. The mixed lymphocyte reaction (MLR) is widely used to evaluate T cell alloreactivity. In human, flow cytometric MLR with carboxyfluorescein diacetate succinimidyl ester has been established and used as a more useful assay than conventional MLR with radioisotope labeling. However, the available information about alloreactivity based on the differences of dog major histocompatibility complex (MHC) (dog leukocyte antigen, DLA) is quite limited in dog. In this paper, we describe our established flow cytometric MLR method that can quantify the T cell alloreactivity while distinguishing cell phenotypes in dog, and T cell alloreactivity among DLA-type matched pairs was significantly lower than DLA-mismatched pairs, suggesting that our developed flow cytometric MLR method is useful for quantifying T cell alloreactivity. In addition, we demonstrated the advantage of DLA homozygous cells as a donor (stimulator) for allogeneic transplantation. We also elucidated that the frequency of alloreactive T cell precursors was almost the same as that of mouse and human (1-10%). To our knowledge, this is the first report to focus on the degree of allo-immune responses in dog based on the differences of DLA polymorphisms.


Assuntos
Citometria de Fluxo/métodos , Histocompatibilidade , Teste de Cultura Mista de Linfócitos/métodos , Complexo Principal de Histocompatibilidade/genética , Complexo Principal de Histocompatibilidade/imunologia , Polimorfismo Genético , Linfócitos T/imunologia , Animais , Cães , Haplótipos , Ativação Linfocitária/imunologia
13.
Transplant Proc ; 51(10): 3286-3292, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31732216

RESUMO

The 2017 Banff meeting provided specific criteria for the diagnosis of tubulointerstitial changes in chronic active T cell-mediated rejection (CATCR), with an emphasis on inflammation in areas of interstitial fibrosis and tubular atrophy, which was thought to reflect an ongoing T cell-mediated alloimmunity. CATCR is considered to occur as a consequence of persistent or recurrent acute T cell-mediated rejection. Acute T cell-mediated rejection is an acute cytotoxic T-cell reaction to HLA antigens on the donor kidneys and causes tubulitis, interstitial inflammation, and intimal arteries. However, unlike early T-cell transplant damage, CATCR can sometimes be difficult to diagnose because the subsequent chronic T-cell damage can become more complex from the accumulation of previous immune and nonimmune injuries. Furthermore, scoring inflammation in areas of interstitial fibrosis and tubular atrophy has potential problems because other diseases and not even native kidneys can have scattered inflammatory cells. Therefore, detailed insights on the pathogenesis of CATCR are indispensable for appropriate diagnosis and further treatment. In this study, the pathologic characteristics and possible factors involved in the interstitial lesions in both typical and complex cases of CATCR are discussed.


Assuntos
Rejeição de Enxerto/complicações , Transplante de Rim/efeitos adversos , Túbulos Renais/patologia , Rim/patologia , Nefrite Intersticial/patologia , Complicações Pós-Operatórias/patologia , Adulto , Idoso , Atrofia/imunologia , Atrofia/patologia , Feminino , Fibrose , Rejeição de Enxerto/imunologia , Antígenos HLA , Histocompatibilidade , Humanos , Inflamação , Masculino , Pessoa de Meia-Idade , Nefrite Intersticial/imunologia , Complicações Pós-Operatórias/imunologia
14.
Hum Immunol ; 80(12): 966-975, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31604581

RESUMO

BACKGROUND: HLA mismatching is a well known risk factor for worst outcomes in kidney transplantation. METHODS: In the present study, HLA antigen and eplet mismatches were determined in 151 living donor-recipient pairs transplanted between 2007 and 2014 and rejection episodes and graft survival were evaluated. RESULTS: We found that high HLA-II eplet mismatch load (EpMM ≥ 13, versus low EpMM ≤ 5), was an independent predictor of AMR (adjusted HR = 14.839; P = 0.011), while HLA-II AgMM was not. We also showed that HLA-II EpMM load was a significant better predictor of AMR than AgMM (c-statistic = 0.064; P = 0.023). After discriminating HLA-II into HLA-DR and HLA-DQ loci we demonstrated that high versus low eplet mismatch load for HLA-DR (T3 ≥ 6 versus T = 0-1, p = 0.013) and HLA-DQ (T3 ≥ 7 versus T = 0-1, p = 0.009) are independent predictors for AMR. HLA-II EpMM increased discrimination performance of the classical HLA-II AgMM risk model (IDI, 0.061, 95%CI: 0.005-0.195) for AMR. Compared with AgMM, HLA-II eplet model adequately reclassified 13 of 17 patients (76.5%) with AMR and 92 of 134 patients (68.7%) without AMR (cfNRI, 0.785, 95%CI: 0.300-1.426). CONCLUSIONS: Our study evidences that eplet-based matching is a refinement of the classical HLA antigen mismatch analysis in LDKT and is a potential biomarker for personalized assessment of alloimmune risk.


Assuntos
Rejeição de Enxerto/genética , Antígenos HLA-DQ/genética , Antígenos HLA-DR/genética , Isoanticorpos/metabolismo , Transplante de Rim , Doença Aguda , Idoso , Idoso de 80 Anos ou mais , Seguimentos , Rejeição de Enxerto/diagnóstico , Antígenos HLA-DQ/imunologia , Antígenos HLA-DR/imunologia , Histocompatibilidade/genética , Teste de Histocompatibilidade , Humanos , Imunidade Humoral , Doadores Vivos , Pessoa de Meia-Idade , Medicina de Precisão , Prognóstico , Risco
15.
Hum Immunol ; 80(11): 943-947, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31521393

RESUMO

Chronic kidney disease (CKD) is becoming a global public health problem and usually cause End-Stage Renal Disease (ESRD) in the end of progression. To analyze the associations of HLA-A, -B, -C, -DRB1 and -DQB1 alleles at high resolution with ESRD in Jiangsu province of China, a total of 499 unrelated patients with ESRD from the First Affiliated Hospital with Nanjing Medical University and 1584 healthy controls from Jiangsu Branch of Chinese Marrow Donor Program (CMDP) were genotyped at HLA-A, -B, -C, -DRB1 and -DQB1 loci. Statistical analysis was applied to compare the differences of HLA allele frequencies between patients with ESRD and healthy controls. As results, no protective allele at A locus was found and the susceptible alleles were A*11:01 and A*31:01. At B locus, B*15:01, B*55:02 and B*39:05 emerged as susceptible alleles, whereas no protective allele was found. At C locus, C*06:02 and C*07:01 emerged as protective alleles and no susceptible allele was found. At DRB1 locus, six alleles including DRB1*03:01, DRB1*04:03, DRB1*04:04, DRB1*04:05, DRB1*11:01 and DRB1*12:02 emerged as susceptible alleles, while DRB1*15:01 emerged as a protective allele. At DQB1 locus, DQB1*02:01, DQB1*03:01, DQB1*03:02 and DQB1*04:01 emerged as susceptible alleles, while DQB1*06:02 and DQB1*06:09 emerged as protective alleles. Haplotype A*11:01-C*03:03-B*15:01-DRB1*11:01-DQB1*03:01 containing four susceptible alleles was regarded as the most susceptible haplotype. The susceptible alleles and haplotypes might be used as some important risk classification markers. Besides, in the consanguineous renal transplantation, it would be very beneficial for the long-term survival of renal transplant patients to avoid the susceptible alleles and haplotypes in selecting optimal donors.


Assuntos
Genótipo , Antígenos HLA/genética , Falência Renal Crônica/genética , Adolescente , Adulto , China/epidemiologia , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Haplótipos , Histocompatibilidade , Teste de Histocompatibilidade , Humanos , Falência Renal Crônica/epidemiologia , Falência Renal Crônica/imunologia , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Estudos Retrospectivos , Doadores de Tecidos , Adulto Jovem
16.
Int J Hematol ; 110(6): 736-742, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31560116

RESUMO

This phase I study was designed for graft-versus-host disease (GVHD) prophylaxis including bortezomib in allogeneic hematopoietic cell transplantation (allo-HCT) from human leukocyte antigen (HLA)-mismatched unrelated donors in Japanese patients. Patients were administered bortezomib on days 1, 4, and 7, with short-term methotrexate and tacrolimus. Three bortezomib dose levels were prepared (1.0, 1.3, and 1.5 mg/m2). A dose of 1.3 mg/m2 was planned for administration to the initial six patients, and was adjusted if dose-limiting toxicity developed. Five of six patients enrolled for the initial dose had bone marrow donors. Two cases had single-antigen and single-allele mismatches; four had single-antigen mismatch at the A, B, C, and/or DRB1 loci in the GVH direction. All patients achieved neutrophil engraftment and complete donor chimerism. Three patients developed grade II acute GVHD, and none developed grade III-IV GVHD or any dose-limiting toxicity attributable to bortezomib by day 100. Two patients developed late-onset acute GVHD, and two developed chronic GVHD, but all cases were manageable. All patients were alive without relapse after a median follow-up period of 52 months. The optimal dose of bortezomib was determined to be 1.3 mg/m2. Prophylaxis against GVHD using a regimen including bortezomib thus seems feasible for HLA-mismatched unrelated allo-HCT.


Assuntos
Bortezomib/uso terapêutico , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/métodos , Histocompatibilidade , Doadores não Relacionados , Adolescente , Adulto , Relação Dose-Resposta a Droga , Feminino , Doença Enxerto-Hospedeiro/etiologia , Antígenos HLA , Humanos , Japão , Masculino , Metotrexato/uso terapêutico , Pessoa de Meia-Idade , Pré-Medicação/métodos , Tacrolimo/uso terapêutico , Transplante Homólogo
17.
Eur J Haematol ; 103(4): 426-432, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31385372

RESUMO

OBJECTIVE: Planning new hematopoietic stem cell (HSC) donor recruitment strategies requires a sound understanding of the factors underlying donor selection, especially considering HLA-matching criteria. METHOD: A total of 182 consecutive workups of Swiss donors performed from 2014 to 2017 were analyzed for HLA match level, locus disparities, number of potentially 10/10 matched donors in the international database, donor ranking on the lists, donor date of registration, age, ABO, CMV, gender matching, patient genotype frequency, and country performing the search. RESULTS: Matching status of the selected donors was 10/10 for 38.5%, 10-12/12 for 35.1%, and 8-9/10 for 26.4% donors, without differences in average donor age in the three categories. HLA-A and -C mismatches were most frequent and -DRB1 very rare. 8.2% patients were matched for HLA-DPB1 (12/12). ABO matching was 46.3%, and CMV matching was 59.1%. Based on "HaploStat"-derived genotype frequencies, 50.3% patients belonged to the "good," 38.5% to the "fair," and 11.2% to the "poor" search prognosis categories. 37.9% of transplants were gender-mismatched, and 42.3% of donors were female. CONCLUSION: HLA typing quality (high resolution, all loci typed), great diversity of haplotypes and donor age are main factors impacting the selection of Swiss donors, while gender and ABO matching seem to be of secondary importance.


Assuntos
Seleção do Doador , Células-Tronco Hematopoéticas , Sistema de Registros , Doadores não Relacionados , Fatores Etários , Alelos , Bases de Dados Factuais , Genótipo , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/imunologia , Células-Tronco Hematopoéticas/metabolismo , Histocompatibilidade , Teste de Histocompatibilidade , Humanos , Suíça
18.
Hum Immunol ; 80(11): 917-922, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31431297

RESUMO

Various cells from humans and animals have been established as cell lines, and their features, characteristics, and origins have been reported. Many laboratories use cell lines as model cells, which are selected to suit research purposes. We attempted to identify the ABO genotypes of 31 human leukemia and lymphoma cell lines stored in our laboratory using three methods: the PCR amplification of specific alleles (PASA), PCR-restriction fragment length polymorphism (RFLP), and the direct DNA sequencing of PCR products. We distinguished 31 human leukemia and lymphoma cell lines examined into six major ABO genotypes: A/O (A101/O01: n = 1, A101/O12: n = 4, A101/O26: n = 1, A101/O49: n = 1, A102/O01: n = 3), A/A (A101/A101: n = 1, A102/A102: n = 2), B/O (Bw29/O01: n = 1), B/B (B101/B101: n = 2), O/O (O01/O01: n = 9, O01/O02: n = 1, O01/O26: n = 1, O02/O03: n = 1), and A/B (A102/B101: n = 3). To the best of our knowledge, this is the first study to identify the ABO genotypes of various cell lines. The ABO genotypes of cell lines are important when selecting an experimental model cell for an ABO blood group study, and are essential information for cell lines. These results may be employed by research and clinical laboratories as well as in the forensic field.


Assuntos
Sistema ABO de Grupos Sanguíneos/genética , Genótipo , Leucemia/genética , Linfoma/genética , Alelos , Pesquisa Biomédica , Tipagem e Reações Cruzadas Sanguíneas , Linhagem Celular Tumoral , Transplante de Células-Tronco Hematopoéticas , Histocompatibilidade , Humanos , Reação em Cadeia da Polimerase , Polimorfismo de Fragmento de Restrição , Análise de Sequência de DNA
19.
J Immunol ; 203(5): 1392-1403, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31331971

RESUMO

Controlling portal vein pressure in living-donor liver transplantation has received increased attention owing to its potential importance for graft survival. Portal hypertension may lead to the activation of liver-resident APCs, including liver sinusoidal endothelial cells (LSECs), which have immunological tolerogenic capacity. We investigated the effects of portal hypertension on graft survival and the antidonor immune response using clinical data and a mouse model. We categorized patients (n = 136) according to their portal vein pressure values at the end of surgery. Using propensity score-matching analyses, we found that portal hypertension was significantly associated with a higher antidonor immune response and incidence of acute rejection. To investigate the mechanism, we performed an allogeneic coculture assay using a 70% hepatectomized (HTx) mouse model with or without a portosystemic shunt. Liver cells from HTx mice without a shunt exhibited a significantly greater anti-BALB/c B6 T cell response than those from sham-operated mice or HTx mice with a shunt. LSECs from sham-operated mice, but not from HTx mice, suppressed the B6 T cell alloresponse in a dose-dependent manner. Furthermore, LSECs from HTx mice without a shunt showed significantly downregulated MHC class I/II and programmed death-ligand 1 expression, and those from mice with a shunt showed recovered expression of these molecules. Postoperative portal hypertension enhances alloimmune responses in recipients after living-donor liver transplantation, likely due, in part, to the impaired immune-suppression capacity of LSECs.


Assuntos
Hipertensão Portal/imunologia , Fígado/imunologia , Animais , Modelos Animais de Doenças , Células Endoteliais/imunologia , Feminino , Histocompatibilidade/imunologia , Humanos , Tolerância Imunológica/imunologia , Transplante de Fígado/métodos , Doadores Vivos , Camundongos , Camundongos Endogâmicos BALB C , Linfócitos T/imunologia
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