RESUMO
Major histocompatibility complex class I polypeptide-related sequence A (MICA) is a highly polymorphic ligand of the activating NKG2D receptor on natural killer (NK) cells, γδ-T cells, and NKT cells. MICA incompatibilities have been associated with an increased graft-versus-host disease (GVHD) incidence, and the MICA-129 (met/val) dimorphism has been shown to influence NKG2D signaling in unrelated hematopoietic stem cell transplantation (uHSCT). We investigated the effect of MICA matching on survival after uHSCT. We sequenced 2172 patients and their respective donors for MICA. All patients and donors were high-resolution HLA-typed and matched for 10/10 (n = 1379), 9/10 (n = 636), or 8/10 (n = 157) HLA alleles. Within each HLA match group, cases matched and mismatched for MICA and MICA-129 were analyzed for the end points overall survival (OS), disease-free survival (DFS), nonrelapse mortality (NRM), relapse-incidence (RI), and GVHD. Mismatches at the MICA locus as well as MICA-129 increased with the number of HLA mismatches (MICA mismatched 10/10, 9.2% [n = 127]; 9/10, 22.3% [n = 142]; 8/10, 38.2% [n = 60]; MICA-129 mismatched 10/10, 3.9% [n = 54]; 9/10, 10.2% [n = 65]; 8/10, 17.2% [n = 27]). Adverse OS was observed in the 10/10 match group if MICA-129 was mismatched (10/10, hazard ratio [HR], 1.77; confidence interval [CI], 1.22-2.57; P = .003). MICA-129 mismatches correlated with a significantly worse outcome for DFS in the 10/10 HLA match group (HR, 1.77; CI, 1.26-2.50; P = .001). Higher rates of aGVHD were seen in MICA-129 mismatched cases. Our results indicate that MICA-129 matching is relevant in uHSCT. Prospective typing of patients and donors in unrelated donor search may identify mismatches for MICA-129, and compatible donor selection may improve outcome for this small but high-risk subgroup.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Antígenos de Histocompatibilidade Classe I/genética , Teste de Histocompatibilidade , Polimorfismo Genético , Adolescente , Adulto , Idoso , Feminino , Loci Gênicos , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Análise de Sobrevida , Doadores de Tecidos , Adulto JovemRESUMO
Background: Virtual reality (VR) has been used successfully and effectively in psychotherapy for a variety of disorders. In the field of depression, there are only a few VR interventions and approaches. Although simple social interactions have been successfully modeled in VR for several mental disorders, there has been no transfer to the field of depression therapy. VR may be employed for psychodynamic psychotherapy to work on interpersonal conflict patterns. In this study, we developed and evaluated a VR intervention for the simulation of roleplay situations in the context of supportive-expressive therapy. Methods: We conducted a clinical user experience (UX) study at a psychotherapeutic clinic in Düsseldorf, Germany. Eight inpatients with depression and four therapists were included. Semi-structured interviews and qualitative content analysis were used to identify UX issues of the developed VR intervention. Usability questionnaires and technical usage data were also considered. The VR intervention consisted of two therapist-controlled roleplay scenarios designed to support work on the core conflictual relationship theme by allowing patients to interact in typical problematic social situations. Recorded VR roleplays allow for therapeutic debriefing with a change of perspective. Therapists were given the option of using the roleplay in multiple sessions. Results: All therapists conducted one session per patient with the VR intervention. From the patient interviews, 26 UX issues were extracted, of which one technical malfunction and two unclarities in the interaction with the VR agent were rated as major problems. From the therapist interviews, 14 UX issues were extracted, of which five were rated as major problems related to the interface in the dialog control or the complex system setup. Conclusion: The main problem was designing a dialog structure that allows both complex conversational flows and a clear control interface. In principle, VR roleplays could be integrated well and safely into therapy. The VR intervention shows promise for providing an emotional experience of interpersonal conflict patterns in the context of psychotherapy. Additionally, other roleplay situations involving various social problem areas must be created and evaluated in terms of the fit to the patients' core conflictual relationship themes.
RESUMO
MICA polymorphisms have been associated with increased incidence of acute GvHD and adverse outcome in allogeneic haematopoietic stem cell transplantation (HSCT). MICB is another expressed member of MHC class I-related chain genes and its impact on HSCT outcome is yet to be fully defined. We typed a large cohort of patients and donors for MICB polymorphisms and investigated the impact of MICB matching on outcome after unrelated HSCT. 69.2% of the patients were 10/10 human leukocyte antigen (HLA) matched and 30.8% were 9/10 HLA matched. MICB typing was performed using a short amplicon-based NGS typing assay on the Illumina MiSeq platform. Differences in proteins were considered as mismatches. MICA polymorphisms were identified as possible confounder and were therefore included as parameter in the multivariate analyses. Due to the strong linkage disequilibrium with the classical HLA-genes, sub-stratification for HLA matching status was necessary, and no effect of MICB mismatches was seen in the 10/10 HLA matched group when compared to the MICB matched cases. However, in the 9/10 HLA matched group, MICB mismatched cases showed significantly worse disease free survival (DFS), GvHD and relapse free survival (GRFS) compared to the MICB matched cases (DFS: HR 1.24, p = 0.011; GRFS: HR 1.26, p = 0.002). MICA mismatches had no impact on any outcome parameter. According to our findings, effects previously attributed to MICA differences may have been confounded by MICB polymorphisms. We show that MICB differences contribute a small but relevant effect in 9/10 HLA-matched transplantations, which in turn highlights the possible usefulness of MICB typing in donor selection among similarly suitable 9/10 matched donors, especially when HLA-B mismatches have to be accepted.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Antígenos de Histocompatibilidade Classe I , Teste de Histocompatibilidade , Humanos , Transplante de Células-Tronco Hematopoéticas/métodos , Doença Enxerto-Hospedeiro/genética , Teste de Histocompatibilidade/métodos , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe I/imunologia , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Doadores não Relacionados , Adolescente , Transplante Homólogo/métodos , Polimorfismo Genético , Idoso , Adulto Jovem , Antígenos HLA/genética , Antígenos HLA/imunologia , Desequilíbrio de Ligação , Alelos , CriançaRESUMO
Previous studies have illustrated associations between the presence of activating killer cell immunoglobulin-like receptor (KIR) genes and lower susceptibility to hematologic malignancies in humans. In addition, favorable hematopoietic stem cell transplantation (HSCT) outcomes have been reported in patients who received transplants from donors with KIR genotypes dominant for activating KIR receptors. However, the association of activating KIR genes on an allelic level with disease and their impact on HSCT outcome has been little investigated to date. To this end, we genotyped a large transplantation cohort for KIR 2 Ig domains and short cytoplasmic tail 4 (KIR2DS4) polymorphisms and investigated their association with disease. We next investigated the impact of KIR-AA genotype donor KIR2DS4 polymorphisms (AA/KIR2DS4 versus AA/ KIR 1 Ig domain [KIR1D]) on clinical outcomes of HSCT in myeloid versus lymphoid patient subgroups. Among 2810 transplantation donor-recipient pairs, 68.8% (n = 1934) were 10/10 HLA-matched and 31.2% (n = 876) were 9/10 HLA-matched. The distribution of KIR1D was equal in patients and donors (P = .205). Multivariate analysis in 10/10 HLA-matched patients with lymphoid disease showed improved HSCT outcomes when they received grafts from AA/KIR1D donors (overall survival: hazard ratio [HR], .62, P = .002; disease free survival: HR, .70, P = .011; graft-versus-host disease-free and relapse-free survival: HR, .67, P = .002; nonrelapse mortality: HR, .55, P < .001). This effect was not seen in either 9/10 HLA-matched patients with lymphoid disease or patients with myeloid disease. Our study indicates that the presence of KIR1D alleles is not associated with disease in patients, and, interestingly, using grafts from AA/KIR1D donors translated into beneficial survival outcomes in 10/10 HLA-matched patients with lymphoid disease.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Recidiva Local de Neoplasia , Humanos , Recidiva Local de Neoplasia/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Receptores KIR/genética , Genótipo , Doadores de TecidosRESUMO
INTRODUCTION: Graft-versus-host disease (GvHD) is a major complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and is highly influenced by the degree of HLA matching between recipient and donor. The HLA-class Ib molecule HLA-G has been shown to promote tolerogenicity through its interaction with inhibitory receptors found on several immunocompetent cells. We hypothesized that in an allo-HSCT setting, HLA-G mismatches may negatively impact the HLA-G-mediated tolerogenicity either due to inefficient interaction with the inhibitory receptors of the transplanted immune cells or due to direct allorecognition of mismatched HLA-G on host cells by the immune cells of the donor. METHODS: In order to explore this hypothesis, we investigated the impact of HLA-G mismatching in 2.083 10/10 matched high resolution HLA-typed allo-HSCT transplants. RESULTS: We found that the risk of chronic GvHD was significantly higher in HLA-G-mismatched transplant cases as compared with the HLA-G-matched control group (HR: 1.46, 95%CI = 1.11-1.91, p = 0.006). Sub-analysis of the mismatch vector revealed that this effect was only detectable in the GvH (HR: 1.89, 95%CI 1.39-2.57, p < 0.001) but not the HvG direction (HR: 1.01, 95%CI = 0.63-1.63, p = 0.967). In addition, the negative impact of HLA-G mismatching on chronic GvHD was only significant in younger patients (<30y HR: 3.02, 95%CI = 1.25-7.28, p = 0.014; >29y HR: 1.28, 95%CI = 0.94-1.72, p = 0.113). DISCUSSION: Our results indicate that HLA-G mismatches may contribute to the onset of chronic GvHD, especially in younger patients and should therefore be avoided when possible.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Alelos , Antígenos HLA-G , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Estudos RetrospectivosRESUMO
A common genetic variant within the T cell receptor alpha (TCRA)-T cell receptor delta (TCRD) locus (rs2204985) has been recently found to associate with thymic function. Aim of this study was to investigate the potential impact of donor rs2204985 genotype on patient's outcome after unrelated hematopoietic stem cell transplantation (uHSCT). 2016 adult patients were retrospectively analyzed. rs2204985 genotyping was performed by next generation sequencing, p < 0.05 was considered significant and donor rs2204985 GG/AG genotypes were set as reference vs. the AA genotype. Multivariate analysis of the combined cohort regarding the impact of donor's rs2204985 genotype indicated different risk estimates in 10/10 and 9/10 HLA matched transplantations. A subanalysis on account of HLA incompatibility revealed that donor AA genotype in single HLA mismatched cases (n = 624) associated with significantly inferior overall- (HR: 1.48, p = 0.003) and disease-free survival (HR: 1.50, p = 0.001). This effect was driven by a combined higher risk of relapse incidence (HR: 1.40, p = 0.026) and non-relapse mortality (HR: 1.38, p = 0.042). This is the first study to explore the role of rs2204985 in a clinical uHSCT setting. Our data suggest that donor rs2204985 AA genotype in combination with single HLA mismatches may adversely impact post-HSCT outcome and should thus be avoided.
Assuntos
Doença Enxerto-Hospedeiro , Antígenos HLA/genética , Transplante de Células-Tronco Hematopoéticas , Adulto , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Recidiva Local de Neoplasia , Receptores de Antígenos de Linfócitos T alfa-beta , Receptores de Antígenos de Linfócitos T gama-delta , Estudos Retrospectivos , Trombopoese , Doadores de Tecidos , Doadores não RelacionadosRESUMO
The HLA-DRB3/4/5 loci are closely linked to the HLA-DRB1 gene. Mismatches in these loci occur with a frequency of about 8%-12% in otherwise 10/10 HLA-matched transplant pairs. There is preliminary evidence that these disparities may associate with increased acute graft-versus-host disease (GvHD) rates. The aim of this study was to analyze a large cohort of German patients and their donors for HLA-DRB3/4/5 compatibility and to correlate the HLA-DRB3/4/5 matching status with the outcome of unrelated hematopoietic stem cell transplantation (uHSCT). To this end, 3,410 patients and their respective donors were HLA-DRB3/4/5 and HLA-DPB1 typed by amplicon-based next-generation sequencing (NGS). All patients included received their first allogeneic transplant for malignant hematologic diseases between 2000 and 2014. Mismatches in the antigen recognition domain (ARD) of HLA-DRB3/4/5 genes were correlated with clinical outcome. HLA-DRB3/4/5 incompatibility was seen in 12.5% (n = 296) and 17.8% (n = 185) of the 10/10 and 9/10 HLA-matched cases, respectively. HLA-DRB3/4/5 mismatches in the ARD associated with a worse overall survival (OS), as shown in univariate (5-year OS: 46.1% vs. 39.8%, log-rank p = 0.038) and multivariate analyses [hazard ratio (HR) 1.25, 95% CI 1.02-1.54, p = 0.034] in the otherwise 10/10 HLA-matched subgroup. The worse outcome was mainly driven by a significantly higher non-relapse mortality (HR 1.35, 95% CI 1.05-1.73, p = 0.017). In the 9/10 HLA-matched cases, the effect was not statistically significant. Our study results suggest that mismatches within the ARD of HLA-DRB3/4/5 genes significantly impact the outcome of otherwise fully matched uHSCT and support their consideration upon donor selection in the future.
Assuntos
Cadeias HLA-DRB3/imunologia , Cadeias HLA-DRB4/imunologia , Cadeias HLA-DRB5/imunologia , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Seleção do Doador , Alemanha , Doença Enxerto-Hospedeiro , Neoplasias Hematológicas/imunologia , Neoplasias Hematológicas/mortalidade , Teste de Histocompatibilidade , Humanos , Lactente , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Sistema de Registros , Estudos Retrospectivos , Resultado do Tratamento , Doadores não Relacionados , Adulto JovemRESUMO
T-cell epitope matching according to the TCE3 algorithm classifies HLA-DPB1 mismatches in permissive and non-permissive. This classification has been shown to be predictive for mortality and acute GvHD (aGvHD) events in large international cohorts. We retrospectively genotyped HLA-DPB1 in 3523 patients transplanted in Germany between 2000 and 2014 and in their unrelated donors using an Illumina amplicon-NGS based assay. Aim of the study was to evaluate DP-compatibility beyond the established TCE3 algorithm by assessing the combined effect of several DP-mismatch parameters on post-transplant outcome. We implemented an extended DP-mismatch assessment model where TCE3, DP allotype expression with respect to rs9277534, mismatch vector and number of mismatches were conjointly taken into consideration. In this model, non-permissive HLA-DPB1 mismatches showed significantly increased aGvHD risk if they were accompanied by two HLA-DPB1 mismatches in GvH direction (HR: 1.46) or one mismatched highly expressed patient allotype (HR: 1.53). As previously reported, non-permissive HLA-DPB1 mismatches associated with a significantly higher risk of aGvHD and non-relapse mortality (HR 1.36 and 1.21, respectively), which in turn translated into worse GvHD and relapse free survival (HR 1.13). Effects on GvL and GvHD appeared strongest in GvH-directed non-permissive mismatches. Our study results support the consideration of additional HLA-DPB1 mismatch parameters along with the established TCE3 matching algorithm for refinement of future donor selection. In particular, our findings suggest that DP non-permissiveness associated with two HLA-DPB1 mismatches or at least on highly expressed mismatched patient allotype should be avoided.
Assuntos
Transplante de Medula Óssea , Epitopos de Linfócito T/imunologia , Doença Enxerto-Hospedeiro/etiologia , Cadeias beta de HLA-DP/análise , Histocompatibilidade , Modelos Imunológicos , Transplante de Células-Tronco de Sangue Periférico , Regiões 3' não Traduzidas/genética , Adolescente , Adulto , Idoso , Alelos , Aloenxertos , Criança , Pré-Escolar , Feminino , Alemanha , Doença Enxerto-Hospedeiro/epidemiologia , Doença Enxerto-Hospedeiro/imunologia , Efeito Enxerto vs Leucemia/imunologia , Cadeias beta de HLA-DP/genética , Teste de Histocompatibilidade/métodos , Humanos , Incidência , Lactente , Recém-Nascido , Estimativa de Kaplan-Meier , Depleção Linfocítica , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Estudos Retrospectivos , Risco , Doadores não Relacionados , Adulto JovemRESUMO
The positive effects of physical and sports therapy for strain dependent physical practice and improved quality of life (QoL) are well known. Nevertheless, the available capacities and problem-oriented therapies in the setting of hematopoietic stem cell transplantation (HSCT) are limited. We conducted a prospective, randomized study among 42 HSCT recipients in order to investigate the influence of exergaming on Nintendo Wii® or classical physiotherapy (PT) on physical fitness and psychological well-being. The trial included evaluation of muscle strength, endurance, physical activity, distress, QoL, anxiety, and depression. Within the first 2 weeks after HSCT endurance, muscle strength and physical well-being decreased, while the value of distress increased significantly in both groups. However, exergaming on Nintendo Wii® resulted in a decrease of anxiety and depression and improved emotional well-being, while the PT group showed a contrariwise pattern of these features. Analysis of the FACT-BMT revealed a decline of QoL domains 2 and 4 weeks after HSCT and an improvement afterwards. The decrease of functional status after HSCT was accompanied by a drop of QoL and an increase of distress in both groups. However, our prospective study demonstrates that exergaming using the Nintendo Wii® is feasible and well tolerated in HSCT recipients.
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Exercício Físico , Transplante de Células-Tronco Hematopoéticas/métodos , Jogos de Vídeo , Adulto , Idoso , Exercício Físico/fisiologia , Exercício Físico/psicologia , Terapia por Exercício/métodos , Estudos de Viabilidade , Feminino , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas/psicologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Qualidade de Vida/psicologia , Transplantados/psicologia , Jogos de Vídeo/psicologia , Adulto JovemRESUMO
When moving through a tracked immersive virtual environment, it is sometimes useful to deviate from the normal one-to-one mapping of real to virtual motion. One option is the application of rotation gain, where the virtual rotation of a user around the vertical axis is amplified or reduced by a factor. Previous research in head-mounted display environments has shown that rotation gain can go unnoticed to a certain extent, which is exploited in redirected walking techniques. Furthermore, it can be used to increase the effective field of regard in projection systems. However, rotation gain has never been studied in CAVE systems, yet. In this work, we present an experiment with 87 participants examining the effects of rotation gain in a CAVE-like virtual environment. The results show no significant effects of rotation gain on simulator sickness, presence, or user performance in a cognitive task, but indicate that there is a negative influence on spatial knowledge especially for inexperienced users. In secondary results, we could confirm results of previous work and demonstrate that they also hold for CAVE environments, showing a negative correlation between simulator sickness and presence, cognitive performance and spatial knowledge, a positive correlation between presence and spatial knowledge, a mitigating influence of experience with 3D applications and previous CAVE exposure on simulator sickness, and a higher incidence of simulator sickness in women.