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1.
Am J Transplant ; 18(9): 2274-2284, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29464832

RESUMO

The presence of donor-specific anti-HLA antibodies (DSAs) is associated with increased risk of graft failure after kidney transplant. We hypothesized that DSAs against HLA class I, class II, or both classes indicate a different risk for graft loss between deceased and living donor transplant. In this study, we investigated the impact of pretransplant DSAs, by using single antigen bead assays, on long-term graft survival in 3237 deceased and 1487 living donor kidney transplants with a negative complement-dependent crossmatch. In living donor transplants, we found a limited effect on graft survival of DSAs against class I or II antigens after transplant. Class I and II DSAs combined resulted in decreased 10-year graft survival (84% to 75%). In contrast, after deceased donor transplant, patients with class I or class II DSAs had a 10-year graft survival of 59% and 60%, respectively, both significantly lower than the survival for patients without DSAs (76%). The combination of class I and II DSAs resulted in a 10-year survival of 54% in deceased donor transplants. In conclusion, class I and II DSAs are a clear risk factor for graft loss in deceased donor transplants, while in living donor transplants, class I and II DSAs seem to be associated with an increased risk for graft failure, but this could not be assessed due to their low prevalence.


Assuntos
Seleção do Doador , Rejeição de Enxerto/mortalidade , Antígenos HLA/imunologia , Isoanticorpos/efeitos adversos , Falência Renal Crônica/cirurgia , Transplante de Rim/mortalidade , Doadores Vivos , Adulto , Cadáver , Feminino , Seguimentos , Rejeição de Enxerto/etiologia , Rejeição de Enxerto/patologia , Sobrevivência de Enxerto , Humanos , Transplante de Rim/efeitos adversos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida
2.
Int J Immunogenet ; 45(2): 41-53, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29464898

RESUMO

The predicted indirectly recognizable human leucocyte antigen (HLA) epitopes (PIRCHE) algorithm is a novel in silico algorithm to determine donor-recipient compatibility. The PIRCHE algorithm determines donor-recipient compatibility by counting the number of mismatched HLA-derived epitopes that are involved in indirect T-cell alloimmune responses; these epitopes are designated as PIRCHE. Over the last few years, the PIRCHE algorithm has been investigated in both hematopoietic stem cell transplantation and solid organ transplantation. This review describes the theory of the algorithm, its application in transplantation, and highlights the future perspectives on the clinical application of the PIRCHE algorithm.


Assuntos
Epitopos/imunologia , Antígenos HLA/imunologia , Histocompatibilidade/imunologia , Doadores de Tecidos , Transplante/métodos , Sequência de Bases , Humanos , Modelos Imunológicos , Peptídeos/imunologia , Linfócitos T/imunologia
3.
Neth J Med ; 75(6): 247-249, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28741584

RESUMO

A patient presented with recurrent episodes of fever and skin rash for eight years. DNA analysis of the NLRP3 gene revealed a mutation associated with autoinflammatory disease. After an initial positive response to the biological anakinra, the patient deteriorated. Reassessment revealed recurrent erysipelas. In conclusion, sometimes erysipelas-like skin rash is real erysipelas, and DNA results are not always the final answer.


Assuntos
Erisipela/diagnóstico , Exantema/diagnóstico , Doenças Hereditárias Autoinflamatórias/diagnóstico , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Adulto , Diagnóstico Diferencial , Erisipela/genética , Exantema/genética , Exantema/microbiologia , Doenças Hereditárias Autoinflamatórias/genética , Humanos , Masculino , Mutação , Recidiva
4.
Am J Transplant ; 17(12): 3076-3086, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28613392

RESUMO

De novo donor-specific HLA antibodies (dnDSA) are recognized as a risk factor for premature allograft failure. Determinants of DSA specificity are generated via the indirect allorecognition pathway. Here, we present supportive data for the relevance of predicted indirectly recognizable HLA epitopes (PIRCHE) to predict dnDSA following kidney transplantation. A total of 2787 consecutive kidney transplants performed between 1995 and 2015 without preformed DSA have been analyzed. De novo DSA were detected by single antigen bead assay. HLA epitope mismatches were determined by the HLAMatchmaker and PIRCHE approach and correlated in uni- and multivariate analyses with 10-year allograft survival and incidence of dnDSA. The PIRCHE-II score moderately predicted allograft survival. However, the predictive value of elevated PIRCHE-II scores >9 for the incidence of dnDSA was statistically significant (p < 0.001). In a multivariate Cox regression analysis adjusted for antigen mismatch and HLAMatchmaker epitopes, the PIRCHE-II score could be identified as an independent risk factor for dnDSA. The PIRCHE-II score independently from the antigen mismatch and HLAMatchmaker epitopes could be revealed as being a strong predictor for dnDSA. PIRCHE may help to identify acceptable mismatches with decreased risk of dnDSA and thus improve long-term renal allograft survival.


Assuntos
Antígenos/imunologia , Epitopos/imunologia , Rejeição de Enxerto/epidemiologia , Sobrevivência de Enxerto/imunologia , Antígenos HLA/imunologia , Isoanticorpos/sangue , Transplante de Rim/métodos , Doadores de Tecidos , Feminino , Seguimentos , Alemanha/epidemiologia , Taxa de Filtração Glomerular , Rejeição de Enxerto/imunologia , Teste de Histocompatibilidade , Humanos , Incidência , Isoanticorpos/imunologia , Falência Renal Crônica/cirurgia , Testes de Função Renal , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de Risco , Transplante Homólogo
5.
Bone Marrow Transplant ; 52(10): 1378-1383, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28581468

RESUMO

Allogeneic stem cell transplantation (allo-SCT) with or without donor lymphocyte infusions (DLI) is the only curative option for several hematological malignancies. Unfortunately, allo-SCT is often associated with GvHD, and patients often relapse. We therefore aim to improve the graft-versus-tumor effect, without increasing the risk of GvHD, by targeting hematopoietic lineage-restricted and tumor-associated minor histocompatibility antigens using peptide-loaded dendritic cell (DC) vaccinations. In the present multicenter study, we report the feasibility, safety and efficacy of this concept. We treated nine multiple myeloma patients with persistent or relapsed disease after allo-SCT and a previous DLI, with donor monocyte-derived mHag-peptide-loaded DC vaccinations combined with a second DLI. Vaccinations were well tolerated and no occurrence of GvHD was observed. In five out of nine patients, we were able to show the induction of mHag-specific CD8+ T cells in peripheral blood. Five out of nine patients, of which four developed mHag-specific T cells, showed stable disease (SD) for 3.5-10 months. This study shows that mHag-based donor monocyte-derived DC vaccination combined with DLI is safe, feasible and capable of inducing objective mHag-specific T-cell responses. Future research should focus on further improvement of the vaccination strategy, toward translating the observed T-cell responses into robust clinical responses.


Assuntos
Antígenos de Neoplasias/imunologia , Doadores de Sangue , Células Dendríticas , Antígenos HLA/imunologia , Imunidade Celular , Transfusão de Linfócitos , Mieloma Múltiplo , Transplante de Células-Tronco , Vacinação , Adulto , Idoso , Aloenxertos , Células Dendríticas/imunologia , Células Dendríticas/transplante , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/imunologia , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/patologia , Mieloma Múltiplo/terapia , Peptídeos/imunologia
6.
Bone Marrow Transplant ; 52(2): 228-237, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27841858

RESUMO

Donor lymphocyte infusions (DLI) can induce durable remissions in multiple myeloma (MM) patients, but this occurs rather infrequently. As the graft-versus-tumor (GvT) effect of DLI depends on the presence of host-dendritic cells (DCs), we tested in a phase I/II trial whether the efficacy of DLI could be improved by simultaneous vaccination with host-DCs. We also analyzed the possibility of further improving the GvT effect by loading the DCs with peptides of mismatched hematopoietic cell-specific minor histocompatibility antigens (mHags). Fifteen MM patients not responding to a first DLI were included. Eleven patients could be treated with a second equivalent dose DLI combined with DC vaccinations, generated from host monocytes (moDC). For four patients, the DC products did not meet the quality criteria. In four of the treated patients the DCs were loaded with host mHag peptides. Toxicity was limited and no acute GvHD occurred. Most patients developed objective anti-host T-cell responses and in one patient a distinct mHag-specific T-cell response accompanied a temporary clinical response. These findings confirm that DLI combined with host-DC vaccination, either unloaded or loaded with mHag peptides, is feasible, safe and capable of inducing host-specific T-cell responses. The limited clinical effects may be improved by developing more immunogenic DC products or by combining this therapy with immune potentiating modalities like checkpoint inhibitors.


Assuntos
Antígenos de Neoplasias , Células Dendríticas/transplante , Transfusão de Linfócitos , Antígenos de Histocompatibilidade Menor , Mieloma Múltiplo/terapia , Vacinação , Feminino , Humanos , Masculino , Mieloma Múltiplo/mortalidade
7.
HLA ; 88(3): 110-9, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27534609

RESUMO

Solid-phase multiplex-bead assays are widely used in transplantation to detect anti-human leukocyte antigen (HLA) antibodies. These assays enable high resolution detection of low levels of HLA antibodies. However, multiplex-bead assays are costly and yield variable measurements that limit the comparison of results between laboratories. In the context of a Dutch national Consortium study we aimed to determine the inter-assay and inter-machine variability of multiplex-bead assays, and we assessed how to reduce the assay reagents costs. Fifteen sera containing a variety of HLA antibodies were used yielding in total 7092 median fluorescence intensities (MFI) values. The inter-assay and inter-machine mean absolute relative differences (MARD) of the screening assay were 12% and 13%, respectively. The single antigen bead (SAB) inter-assay MARD was comparable, but showed a higher lot-to-lot variability. Reduction of screening assay reagents to 50% or 40% of manufacturers' recommendations resulted in MFI values comparable to 100% of the reagents, with an MARD of 12% or 14%, respectively. The MARD of the 50% and 40% SAB assay reagent reductions were 11% and 22%, respectively. From this study, we conclude that the reagents can be reliably reduced at least to 50% of manufacturers' recommendations with virtually no differences in HLA antibody assignments.


Assuntos
Automação Laboratorial/economia , Antígenos HLA/imunologia , Imunoensaio/economia , Isoanticorpos/sangue , Kit de Reagentes para Diagnóstico/economia , Alelos , Automação Laboratorial/normas , Antígenos HLA/sangue , Teste de Histocompatibilidade , Humanos , Soros Imunes/química , Imunoensaio/normas , Transplante de Rim , Variações Dependentes do Observador , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
8.
Neuroimage Clin ; 11: 588-594, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27158591

RESUMO

Despite the prevalence of migraine, the pathophysiology of the disease remains unclear. Current understanding of migraine has alluded to the possibility of a hyperexcitable brain. The aim of the current study is to investigate human brain metabolite differences in the anterior cingulate cortex (ACC) during the interictal phase in migraine patients. We hypothesized that there may be differences in levels of excitatory neurotransmitters and/or their derivatives in the migraine cohort in support of the theory of hyperexcitability in migraine. 2D J-resolved proton magnetic resonance spectroscopy ((1)H-MRS) data were acquired on a 3 Tesla (3 T) MRI from a voxel placed over the ACC of 32 migraine patients (MP; 23 females, 9 males, age 33 ± 9.6 years) and 33 healthy controls (HC; 25 females, 8 males, age 32 ± 9.6 years). Amplitude correlation matrices were constructed for each subject to evaluate metabolite discriminability. ProFit-estimated metabolite peak areas were normalized to a water reference signal to assess subject differences. The initial analysis of variance (ANOVA) was performed to test for group differences for all metabolites/creatine (Cre) ratios between healthy controls and migraineurs but showed no statistically significant differences. In addition, we used a multivariate approach to distinguish migraineurs from healthy subjects based on the metabolite/Cre ratio. A quadratic discriminant analysis (QDA) model was used to identify 3 metabolite ratios sufficient to minimize minimum classification error (MCE). The 3 selected metabolite ratios were aspartate (Asp)/Cre, N-acetyl aspartate (NAA)/Cre, and glutamine (Gln)/Cre. These findings are in support of a 'complex' of metabolite alterations, which may underlie changes in neuronal chemistry in the migraine brain. Furthermore, the parallel changes in the three-metabolite 'complex' may confer more subtle but biological processes that are ongoing. The data also support the current theory that the migraine brain is hyperexcitable even in the interictal state.


Assuntos
Ácido Aspártico/análogos & derivados , Ácido Glutâmico/metabolismo , Glutamina/metabolismo , Giro do Cíngulo/metabolismo , Transtornos de Enxaqueca/patologia , Adolescente , Adulto , Análise de Variância , Ácido Aspártico/metabolismo , Estudos de Coortes , Feminino , Giro do Cíngulo/diagnóstico por imagem , Humanos , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Transtornos de Enxaqueca/diagnóstico por imagem , Espectroscopia de Prótons por Ressonância Magnética , Adulto Jovem
9.
Artigo em Inglês | MEDLINE | ID: mdl-26613018

RESUMO

BACKGROUND: Attempts to increase compliance with infection control practices are complex and are - in part - based on attempts to change behaviour. In particular, the behaviour of significant peers (role models) has been shown to be a strong motivator. While role models within the working environment are obviously the most important, some experts suggest that media and public display cannot be ignored. The aim of this present study was to examine the display of technique recommended by current infection control guidelines including the "bare below the elbow" principle, which is considered a basic requirement for good infection control in many countries, in sets of professional stock photos. FINDINGS: From 20 random photo-stock websites we selected pictures with search terms "doctor and patient" and "nurse and patient". In all selected photos a doctor or nurse and a patient were presented, healthcare workers (HCWs) were wearing white coats or uniforms, and their arms were visible. Each photo was evaluated with regard to: closure of white coat, sleeve length, personal clothing covered, hairstyle and presence of a wristwatch, bracelet and/or ring. Overall, 1600 photos were evaluated. The most common mistakes were with regard to HCWs' white coats/uniforms. Eighty-nine percent of the photos containing doctor's images were considered incorrect while 28 % of nurse-containing photos were incorrect. CONCLUSIONS: The results seem to reflect the real world with only 40 % displaying correct behaviour with doctors being worse than nurses. It seems that the stereotypical image of a doctor does not agree with the current infection control guidelines. If we aim for higher compliance rates of HCWs, we need to change the social image of doctors and improve production, selection and display of stock photo images.

10.
Am J Transplant ; 15(12): 3112-22, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26512793

RESUMO

Pregnancy can prime maternal immune responses against inherited paternal HLA of the fetus, leading to the production of child-specific HLA antibodies. We previously demonstrated that donor-specific HLA antibody formation after kidney transplantation is associated with donor-derived HLA epitopes presented by recipient HLA class II (predicted indirectly recognizable HLA epitopes presented by HLA class II [PIRCHE-II]). In the present study, we evaluated the role of PIRCHE-II in child-specific HLA antibody formation during pregnancy. A total of 229 mother-child pairs were HLA typed. For all mismatched HLA class I molecules of the child, we subsequently predicted the number of HLA epitopes that could be presented by maternal HLA class II molecules. Child-specific antigens were classified as either immunogenic or nonimmunogenic HLA based on the presence of specific antibodies and correlated to PIRCHE-II numbers. Immunogenic HLA contained higher PIRCHE-II numbers than nonimmunogenic HLA. Moreover, the probability of antibody production during pregnancy increased with the number of PIRCHE-II. In conclusion, our data suggest that the number of PIRCHE-II is related to the formation of child-specific HLA antibodies during pregnancy. Present confirmation of the role of PIRCHE-II in antibody formation outside the transplantation setting suggests the PIRCHE-II concept is universal.


Assuntos
Formação de Anticorpos/imunologia , Epitopos/imunologia , Cadeias HLA-DRB1/imunologia , Isoanticorpos/imunologia , Doadores de Tecidos , Criança , Estudos de Coortes , Feminino , Seguimentos , Teste de Histocompatibilidade , Humanos , Gravidez , Prognóstico
11.
Leukemia ; 29(9): 1839-46, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25836589

RESUMO

We performed a prospective phase II study to evaluate clinical safety and outcome in 48 patients with steroid-refractory grade II-IV acute graft-versus-host disease (aGVHD) treated with mesenchymal stromal cells (MSCs). Clinical outcomes were correlated to comprehensive analyses of soluble and cellular biomarkers. Complete resolution (CR) of aGVHD at day 28 (CR-28) occurred in 12 (25%) patients, CR lasting >1 month (CR-B) occurred in 24 (50%) patients. One-year overall survival was significantly improved in CR-28 (75 versus 33%, P=0.020) and CR-B (79 versus 8%, P<0.001) versus non-CR patients. A six soluble biomarker-panel was predictive for mortality (HR 2.924; CI 1.485-5.758) when measured before MSC-administration. Suppression of tumorigenicity 2 (ST2) was only predictive for mortality 2 weeks after but not before MSC-administration (HR 2.389; CI 1.144-4.989). In addition, an increase in immature myeloid dendritic cells associated with decreased mortality (HR 0.554, CI 0.389-0.790). Patients had persisting T-cell responses against defined virus- and leukemia-associated antigens. In conclusion, our data emphasize the need to carefully assess biomarkers in cohorts with homogeneous GVHD treatments. Biomarkers might become an additional valuable component of composite end points for the rapid and efficient testing of novel compounds to decrease lifecycle of clinical testing and improve the success rate of phase II/III trials.


Assuntos
Resistência a Medicamentos , Doença Enxerto-Hospedeiro/metabolismo , Doença Enxerto-Hospedeiro/terapia , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/metabolismo , Doença Aguda , Adolescente , Adulto , Idoso , Antígenos de Neoplasias/imunologia , Biomarcadores/sangue , Biomarcadores/metabolismo , Criança , Pré-Escolar , Ciclosporina/uso terapêutico , Citocinas/sangue , Citocinas/metabolismo , Feminino , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/mortalidade , Humanos , Imunofenotipagem , Imunossupressores/uso terapêutico , Lactente , Linfócitos/imunologia , Linfócitos/metabolismo , Masculino , Pessoa de Meia-Idade , Prednisona/uso terapêutico , Prognóstico , Esteroides/uso terapêutico , Resultado do Tratamento , Adulto Jovem
12.
Transpl Immunol ; 31(4): 184-90, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25258025

RESUMO

Kidney transplantation is the best treatment option for patients with end-stage renal failure. At present, approximately 800 Dutch patients are registered on the active waiting list of Eurotransplant. The waiting time in the Netherlands for a kidney from a deceased donor is on average between 3 and 4 years. During this period, patients are fully dependent on dialysis, which replaces only partly the renal function, whereas the quality of life is limited. Mortality among patients on the waiting list is high. In order to increase the number of kidney donors, several initiatives have been undertaken by the Dutch Kidney Foundation including national calls for donor registration and providing information on organ donation and kidney transplantation. The aim of the national PROCARE consortium is to develop improved matching algorithms that will lead to a prolonged survival of transplanted donor kidneys and a reduced HLA immunization. The latter will positively affect the waiting time for a retransplantation. The present algorithm for allocation is among others based on matching for HLA antigens, which were originally defined by antibodies using serological typing techniques. However, several studies suggest that this algorithm needs adaptation and that other immune parameters which are currently not included may assist in improving graft survival rates. We will employ a multicenter-based evaluation on 5429 patients transplanted between 1995 and 2005 in the Netherlands. The association between key clinical endpoints and selected laboratory defined parameters will be examined, including Luminex-defined HLA antibody specificities, T and B cell epitopes recognized on the mismatched HLA antigens, non-HLA antibodies, and also polymorphisms in complement and Fc receptors functionally associated with effector functions of anti-graft antibodies. From these data, key parameters determining the success of kidney transplantation will be identified which will lead to the identification of additional parameters to be included in future matching algorithms aiming to extend survival of transplanted kidneys and to diminish HLA immunization. Computer simulation studies will reveal the number of patients having a direct benefit from improved matching, the effect on shortening of the waiting list, and the decrease in waiting time.


Assuntos
Teste de Histocompatibilidade/métodos , Falência Renal Crônica/cirurgia , Transplante de Rim/mortalidade , Obtenção de Tecidos e Órgãos/métodos , Listas de Espera , Epitopos de Linfócito B/imunologia , Epitopos de Linfócito T/imunologia , Rejeição de Enxerto/imunologia , Sobrevivência de Enxerto/imunologia , Antígenos HLA/imunologia , Humanos , Rim/imunologia , Rim/cirurgia , Qualidade de Vida , Diálise Renal
13.
Tissue Antigens ; 82(5): 312-6, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24116658

RESUMO

Studies of the effect of minor H antigen mismatching on the outcome of renal transplantation are scarce and concern mainly single center studies. The International Histocompatibility and Immunogenetics Workshops (IHIW) provide a collaborative platform to execute crucial large studies. In collaboration with 16 laboratories of the IHIW, the role of 15 autosomal, 10 Y-chromosome encoded minor H antigens and 3 CD31 polymorphisms, was investigated in relation to the incidence of renal graft rejection and graft loss in 444 human leukocyte antigens (HLA)-identical sibling renal transplantations. Recipient and donor DNA samples were genotyped for the minor H antigens HA-1, HA-2, HA-3, HA-8, HB-1, ACC-1, ACC-2, SP110, PANE1, UGT2B17, C19Orf48, LB-ECGF-1, CTSH, LRH-1, LB-ADIR and HY. The correlation between minor H antigen mismatch and the primary outcome graft rejection or graft loss was statistically analyzed. The incidence of rejection was very low and no correlation was observed between one or more minor H antigen mismatch(es) and a rejection episode (n = 36), of which only eight resulted in graft loss. In summary, in our study cohort of 444 renal transplants, mismatching for neither autosomal nor HY minor H antigens correlate with rejection episodes or with graft loss.


Assuntos
Antígenos HLA/imunologia , Teste de Histocompatibilidade , Transplante de Rim/efeitos adversos , Antígenos de Histocompatibilidade Menor/imunologia , Irmãos , Estudos de Coortes , Rejeição de Enxerto/imunologia , Humanos
15.
Tissue Antigens ; 81(4): 230-1, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23510421

RESUMO

The HLA-B*44:02:27 allele strongly resembles the HLA-B*44:02:01:01 allele with respect to HLA-C association and haplotype constitution.


Assuntos
Alelos , Antígenos HLA-B/genética , Mutação Puntual , Sequência de Bases , Éxons , Antígenos HLA-B/imunologia , Teste de Histocompatibilidade , Humanos , Dados de Sequência Molecular , Transplante de Células-Tronco , Doadores de Tecidos
16.
Int J Immunogenet ; 40(1): 2-10, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23279968

RESUMO

The International Histocompatibility Working Group is a collaborative international effort to understand the HLA and non-HLA genetics of the transplantation barrier. The Working Group is comprised of experts in the fields of histocompatibility and immunogenetics, hematopoietic cell transplantation and outcomes research. Data for 25 855 unrelated donor transplants were submitted in support of research studies for the 16th International Histocompatibility Workshop. Active investigation is in progress in seven key areas: the impact of HLA matching, role of race and ethnicity, identification of permissible HLA mismatches, haplotype-associated determinants, minor histocompatibility antigens, immune response genes and KIR genetics. New hypotheses for the 16th workshop were developed for immunogenetic studies in cord blood and haploidentical-related donor transplantation.


Assuntos
Doença Enxerto-Hospedeiro , Antígenos HLA , Transplante de Células-Tronco Hematopoéticas , Histocompatibilidade , Doença Enxerto-Hospedeiro/genética , Doença Enxerto-Hospedeiro/imunologia , Antígenos HLA/genética , Antígenos HLA/imunologia , Humanos , Imunogenética
17.
Leukemia ; 27(3): 642-9, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23079962

RESUMO

Donor T cells directed at hematopoietic system-specific minor histocompatibility antigens (mHags) are considered important cellular tools to induce therapeutic graft-versus-tumor (GvT) effects with low risk of graft-versus-host disease after allogeneic stem cell transplantation. To enable the clinical evaluation of the concept of mHag-based immunotherapy and subsequent broad implementation, the identification of more hematopoietic mHags with broad applicability is imperative. Here we describe novel mHag UTA2-1 with ideal characteristics for this purpose. We identified this antigen using genome-wide zygosity-genotype correlation analysis of a mHag-specific CD8(+) cytotoxic T lymphocyte (CTL) clone derived from a multiple myeloma patient who achieved a long-lasting complete remission after donor lymphocyte infusion from an human leukocyte antigen (HLA)-matched sibling. UTA2-1 is a polymorphic peptide presented by the common HLA molecule HLA-A*02:01, which is encoded by the bi-allelic hematopoietic-specific gene C12orf35. Tetramer analyses demonstrated an expansion of UTA2-1-directed T cells in patient blood samples after several donor T-cell infusions that mediated clinical GvT responses. More importantly, UTA2-1-specific CTL effectively lysed mHag(+) hematopoietic cells, including patient myeloma cells, without affecting non-hematopoietic cells. Thus, with the capacity to induce relevant immunotherapeutic CTLs, it's HLA-A*02 restriction and equally balanced phenotype frequency, UTA2-1 is a highly valuable mHag to facilitate clinical application of mHag-based immunotherapy.


Assuntos
Doença Enxerto-Hospedeiro/imunologia , Efeito Enxerto vs Leucemia/imunologia , Transplante de Células-Tronco Hematopoéticas , Imunoterapia , Antígenos de Histocompatibilidade Menor/imunologia , Mieloma Múltiplo/imunologia , Linfócitos T Citotóxicos/imunologia , Apoptose , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Western Blotting , Proliferação de Células , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Perfilação da Expressão Gênica , Doença Enxerto-Hospedeiro/genética , Doença Enxerto-Hospedeiro/terapia , Antígenos HLA/imunologia , Antígenos HLA/metabolismo , Humanos , Técnicas Imunoenzimáticas , Masculino , Pessoa de Meia-Idade , Antígenos de Histocompatibilidade Menor/genética , Antígenos de Histocompatibilidade Menor/metabolismo , Mieloma Múltiplo/genética , Mieloma Múltiplo/terapia , Análise de Sequência com Séries de Oligonucleotídeos , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transplante Homólogo
18.
Leukemia ; 25(10): 1548-54, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21606965

RESUMO

Many parameters predict for outcome after unrelated donor (URD) allogeneic hematopoietic stem cell transplantation (alloSCT). High-resolution HLA-matching significantly impacts outcome and also the European Group of Blood and Marrow Transplantation (EBMT) risk score, based on patient age, disease stage, donor type, time from diagnosis to SCT and gender combination, may predict for non-relapse mortality and overall survival (OS). We evaluated the individual and combined effects of allele-matching and the EBMT risk score in 327 patients with poor-risk acute leukemia or myelodysplasia, who received a T-cell depleted URD alloSCT. Matching for HLA-A, -B, -C and -DRB1 alleles (8/8 match) was associated with a 5-year OS of 40% compared with 30% for mismatched (≤7/8) pairs (P=0.02). Patients with EBMT risk scores of 1-2, 3, 4 and 5-7 had 5-year OS estimates of 53, 43, 30 and 20%, respectively (P<0.001). The favorable prognostic impact of an 8/8 donor was most pronounced if the EBMT risk score was low (1-2). Five-year OS was 74±8% vs 39±11% for fully matched patients with a low-risk EBMT score as compared with EBMT low-risk patients with ≤7/8 donors. These data underscore the importance of incorporating both the EBMT risk score and the degree of high-resolution HLA-matching in the risk assessment prior to URD alloSCT.


Assuntos
Alelos , Transplante de Medula Óssea , Leucemia/cirurgia , Síndromes Mielodisplásicas/cirurgia , Linfócitos T/citologia , Doença Aguda , Adulto , Feminino , Teste de Histocompatibilidade , Humanos , Leucemia/genética , Masculino , Síndromes Mielodisplásicas/genética , Recidiva , Risco
19.
Hum Reprod ; 25(11): 2745-52, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20823116

RESUMO

BACKGROUND: The birth of a boy is significantly more common than a girl prior to secondary recurrent miscarriage (SRM) and is associated with a poorer chance of a subsequent live birth. Children born after SRM are more likely to be girls. High-titer antisera specific for male antigens (H-Y) have been shown to arrest development of male bovine embryos efficiently. We consequently questioned the role of H-Y antibodies in women with SRM. METHODS: Serum samples from patients with unexplained SRM (n = 84), unexplained primary recurrent miscarriage (PRM) (n = 12) and healthy women (n = 37) were obtained. The samples were taken during pregnancy (gestational weeks 4-5) for 77 (80%) of the patients. Enzyme-linked immunosorbent assay was used to detect immunoglobulin G antibodies that specifically recognized any of the five recombinant H-Y proteins (EIF1AY, RPS4Y1, ZFY, DDX3Y and UTY) and their H-X homologs. RESULTS: H-Y-specific antibodies were more frequent in SRM patients (46%) compared with female controls (19%, P = 0.004) and PRM patients (8%, P = 0.01). The presence of H-Y antibodies in early pregnancy was associated with a low male: female birth ratio among the subsequent live births, as only 12% of children born to H-Y antibody-positive patients were boys compared with 44% boys born to H-Y antibody negative patients (P = 0.03). CONCLUSIONS: The high frequency of H-Y antibody-positive SRM patients and the association between the presence of these antibodies in early pregnancy and the low number of male offspring, suggest that maternal immune responses against H-Y antigens can cause pregnancy losses. Further exploring these mechanisms may increase our understanding of unexplained SRM.


Assuntos
Aborto Habitual/imunologia , Antígeno H-Y/imunologia , Isoanticorpos/análise , Resultado da Gravidez , Adolescente , Adulto , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Masculino , Gravidez , Primeiro Trimestre da Gravidez , Razão de Masculinidade
20.
Int J Immunogenet ; 35(4-5): 363-6, 2008 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-18976439

RESUMO

Minor histocompatibility (H) antigens are allogeneic targets of T-cell mediated immune reactivity following allogeneic haematopoietic stem cell transplantation. Depending on the tissue expression profile of the minor H antigens this immune reactivity clinically results in graft-vs-host disease or in graft-vs-leukaemia effects. Targeting haematopoietic-specific minor H antigens by adoptive immunotherapy will evoke leukaemia-specific allo-immune responses, thereby enhancing graft-vs-leukaemia effects. Recently, a novel alternative role for minor H antigens in transplantation has been described; minor H antigen-specific T cells appear to be able to regulate allo-immune responses after solid organ transplantation. This diversity in immune reactivity suggests a broad clinical potential of minor H antigens, both in haematopoietic stem cell transplantation and in solid organ transplantation.


Assuntos
Imunoterapia , Antígenos de Histocompatibilidade Menor/imunologia , Antígenos de Histocompatibilidade Menor/uso terapêutico , Neoplasias/terapia , Tolerância ao Transplante/imunologia , Cromossomos Humanos/genética , Cromossomos Humanos Y/genética , Feminino , Doença Enxerto-Hospedeiro/imunologia , Transplante de Células-Tronco Hematopoéticas , Humanos , Masculino
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