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1.
Blood Adv ; 5(17): 3407-3417, 2021 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-34495313

RESUMO

Recent compelling evidence showed that innate immune effector cells could recognize allogeneic grafts and prime an adaptive immune response. Signal regulatory protein α (SIRPα) is an immunoglobulin superfamily receptor that is expressed on myeloid cells; the interaction between SIRPα and its ubiquitously expressed ligand CD47 elicits an inhibitory signal that suppresses macrophage phagocytic function. Additional studies showed that donor-recipient mismatch in SIRPα variants might activate monocytic allorecognition, possibly as the result of non-self SIRPα-CD47 interaction. However, the frequency of SIRPα variation and its role in hematopoietic stem cell transplantation (HSCT) remains unexplored. We studied 350 patients with acute myeloid leukemia/myelodysplastic syndrome who underwent HLA-matched related HSCT and found that SIRPα allelic mismatches were present in 39% of transplantation pairs. SIRPα variant mismatch was associated with a significantly higher rate of chronic graft-versus-host disease (GVHD; hazard ratio [HR], 1.5; P = .03), especially de novo chronic GVHD (HR, 2.0; P = .01), after adjusting for other predictors. Those with mismatched SIRPα had a lower relapse rate (HR, 0.6; P = .05) and significantly longer relapse-free survival (RFS; HR, 0.6; P = .04). Notably, the effect of SIRPα variant mismatch on relapse protection was most pronounced early after HSCT and in patients who were not in remission at HSCT (cumulative incidence, 73% vs 54%; HR, 0.5; P = .01). These findings show that SIRPα variant mismatch is associated with HSCT outcomes, possibly owing to innate allorecognition. SIRPα variant matching could provide valuable information for donor selection and risk stratification in HSCT.


Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Imunidade Inata
2.
Haematologica ; 2021 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-34435482

RESUMO

HLA-DPB1 mismatches between donor and recipient are commonly seen in allogeneic hematopoietic stem cell transplantation (HSCT) from an unrelated donor. HLA-DPB1 mismatch, conventionally determined by the similarity of the T-cell epitope (TCE), is associated with an increased risk of acute graft-versus-host disease (aGVHD) and a decreased risk of disease relapse. We investigated the clinical impact of HLA-DPB1 molecular mismatch quantified by mismatched eplets (ME) and Predicted Indirectly Recognizable HLA Epitopes score (PS) in a cohort of 1,514 patients receiving HSCT from unrelated donors matched at HLA-A, -B, -C, -DRB1/3/4/5, and -DQB1 loci. HLA-DPB1 alloimmunity in the GVH direction determined by high GVH ME/PS was associated with a reduced risk of relapse (HR 0.83, P= .05 for ME) and increased risk of grade 2-4 aGVHD (HR 1.44, P< .001 for ME), whereas high HVG ME/PS was only associated with an increased risk of grade 2-4 aGVHD (HR 1.26, P= .004 for ME). Notably, in the permissive mismatch subgroup classified by TCE grouping, high HVG ME/PS was associated with an increased risk of relapse (HR 1.36, P= .026 for ME) and grade 2-4 aGVHD (HR 1.43, P= .003 for PS-II). Decision curve analysis showed GVH ME outperformed other models and provided the best clinical net benefit for the modification of aGVHD prophylaxis regimen in patients with high risk of developing clinically significant aGVHD. In conclusion, molecular assessment of HLA-DPB1 mismatch enables separate prediction of HVG or GVH alloresponse quantitatively and allows further refinement of HLA-DPB1 permissiveness as defined by conventional TCE grouping.

3.
Blood Adv ; 4(15): 3474-3485, 2020 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-32726398

RESUMO

Haploidentical donors are increasingly used for patients requiring hematopoietic stem cell transplantation (HSCT). Although several factors have been associated with transplant outcomes, the impact of HLA disparity in haploidentical HSCT (haplo-HSCT) remains unclear. We investigated the impact of HLA disparity quantified by mismatched eplets (ME) load of each HLA locus on the clinical outcome of 278 consecutive haploidentical transplants. Here, we demonstrated that the degree of HLA molecular mismatches, at individual HLA loci, may be relevant to clinical outcome in the haplo-HSCT. A significantly better overall survival was associated with higher ME load from HLA-A (hazard ratio [HR], 0.97; 95% confidence interval [CI], 0.95-0.99; P = .003) and class I loci (HR, 0.99; 95% CI, 0.97-0.99; P = .045) in the host-versus-graft direction. The apparent survival advantage of HLA-A ME was primarily attributed to reduced risk in relapse associated with an increase in HLA-A ME load (subdistribution HR, 0.95; 95% CI, 0.92-0.98; P = .004). Furthermore, we have identified an association between the risk of grade 3-4 acute graft-versus-host disease (GVHD) and a higher ME load at HLA-B and class I loci in graft-versus-host (GVH) direction. Additionally, GVH nonpermissive HLA-DPB1 mismatch defined by T-cell epitope grouping was significantly associated with relapse protection (subdistribution HR, 0.19; 95% CI, 0.06-0.59; P = .004) without a concurrent increase in GVHD. These findings indicate that alloreactivity generated by HLA disparity at certain HLA loci is associated with transplant outcomes, and ME analysis of individual HLA loci might assist donor selection and risk stratification in haplo-HSCT.


Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Seleção do Doador , Doença Enxerto-Hospedeiro/etiologia , Antígenos HLA/genética , Humanos , Modelos de Riscos Proporcionais
4.
Blood ; 131(11): 1248-1257, 2018 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-29386198

RESUMO

We investigated the impact of donor-recipient HLA-DPB1 matching on outcomes of allogeneic hematopoietic stem cell transplantation with in vivo T-cell depletion using antithymocyte globulin (ATG) for patients with hematological malignancies. All donor-recipient pairs had high-resolution typing for HLA-A, HLA-B, HLA-C, HLA-DRB1, HLA-DQB1, HLA-DPB1, and HLA-DRB3/4/5 and were matched at HLA-A, HLA-B, HLA-C, and HLA-DRB1. HLA-DPB1 mismatches were categorized by immunogenicity of the DPB1 matching using the DPB T-cell epitope tool. Of 1004 donor-recipient pairs, 210 (21%) were DPB1 matched, 443 (44%) had permissive mismatches, 184 (18%) had nonpermissive mismatches, in graft-versus-host (GVH) direction, and 167 (17%) had nonpermissive mismatches in host-versus-graft (HVG) direction. Compared with HLA-DPB1 permissive mismatched pairs, nonpermissive GVH mismatched pairs had the highest risk for grade II to IV acute graft-versus-host disease (aGVHD) (hazard ratio [HR], 1.4; P = .01) whereas matched pairs had the lowest risk (HR, 0.5; P < .001). Grade III to IV aGVHD was only increased with HLA-DPB1 nonpermissive GVH mismatched pairs (HR, 2.3; P = .005). The risk for disease progression was lower with any HLA-DPB1 mismatches, permissive or nonpermissive. However, the favorable prognosis of HLA-DPB1 mismatches on disease progression was observed only in peripheral blood stem cell recipients who were in the intermediate-risk group by the Disease Risk Index (HR, 0.4; P = .001) but no other risk groups. Our results suggest avoidance of nonpermissive GVH HLA-DPB1 mismatches for lowering the risk for grade II to IV and III to IV aGVHD. Permissive or nonpermissive HVG HLA-DPB1 mismatches may be preferred over HLA-DPB1 matches in the intermediate-risk patients to decrease the risk for disease progression.


Assuntos
Cadeias HLA-DRB1 , Neoplasias Hematológicas , Transplante de Células-Tronco Hematopoéticas , Teste de Histocompatibilidade , Depleção Linfocítica , Linfócitos T , Doença Aguda , Adulto , Idoso , Aloenxertos , Intervalo Livre de Doença , Feminino , Doença Enxerto-Hospedeiro/metabolismo , Doença Enxerto-Hospedeiro/mortalidade , Doença Enxerto-Hospedeiro/patologia , Doença Enxerto-Hospedeiro/prevenção & controle , Neoplasias Hematológicas/metabolismo , Neoplasias Hematológicas/mortalidade , Neoplasias Hematológicas/patologia , Neoplasias Hematológicas/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Taxa de Sobrevida
5.
Haematologica ; 100(10): 1361-70, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26250579

RESUMO

Cord blood transplant requires less stringent human leukocyte antigen matching than unrelated donors. In 133 patients with hematologic malignancies who engrafted after double cord blood transplantation with a dominant unit, we studied the effect of high resolution testing at 4 loci (-A, -B, -C, -DRB1) for its impact on 2-year transplant-related mortality. Ten percent of the dominant cord blood units were matched at 7-8/8 alleles using HLA-A, -B, -C, and -DRB1; 25% were matched at 6/8, 40% at 5/8, and 25% at 4/8 or less allele. High resolution typing at 4 loci showed that there was no 2-year transplant-related mortality in 7-8/8 matched patients. Patients with 5-6/8 matched dominant cord blood units had 2-year transplant-related mortality of 39% while patients with 4/8 or less matched units had 60%. Multivariate regression analyses confirmed the independent effect of high resolution typing on the outcome when adjusted for age, diagnosis, CD34(+) cell dose infused, graft manipulation and cord to cord matching. The worst prognostic group included patients aged over 32 years with 4/8 or less matched cord blood units compared with patients who were either younger than 32 years old independent of allele-level matching, or aged over 32 years but with 5-6/8 matched cord blood units (Hazard Ratio 2.2; 95% confidence interval: 1.3-3.7; P<0.001). Patients with 7-8/8 matched units remained the group with the best prognosis. Our data suggest that high resolution typing at 4 loci and selecting cord blood units matched at at least 5/8 alleles may reduce transplant-related mortality after double cord blood transplantation.


Assuntos
Alelos , Transplante de Células-Tronco de Sangue do Cordão Umbilical , Histocompatibilidade/genética , Histocompatibilidade/imunologia , Mortalidade , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Transplante de Células-Tronco de Sangue do Cordão Umbilical/efeitos adversos , Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Feminino , Sangue Fetal/citologia , Seguimentos , Doença Enxerto-Hospedeiro/etiologia , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/imunologia , Neoplasias Hematológicas/mortalidade , Neoplasias Hematológicas/terapia , Antígenos de Histocompatibilidade/genética , Antígenos de Histocompatibilidade/imunologia , Teste de Histocompatibilidade , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Retratamento , Análise de Sobrevida , Resultado do Tratamento , Adulto Jovem
6.
Biol Blood Marrow Transplant ; 21(8): 1392-8, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25985919

RESUMO

Detection of donor-specific anti-HLA antibodies (DSA) has been associated with graft rejection in all forms of transplantation. The mechanism by which DSA increase the risk of graft failure remains unclear. We hypothesized that complement-binding DSA are associated with engraftment failure in hematopoietic stem cell transplantation (HSCT) and analyzed 122 haploidentical transplant recipients tested prospectively for DSA. Retrospective analysis to detect C1q binding DSA (C1q+DSA) was performed on 22 allosensitized recipients. Twenty-two of 122 patients (18%) had DSA, 19 of which were women (86%). Seven patients with DSA (32%) rejected the graft. Median DSA level at transplant for patients who failed to engraft was 10,055 mean fluorescence intensity (MFI) versus 2065 MFI for those who engrafted (P = .007). Nine patients with DSA were C1q positive in the initial samples with median DSA levels of 15,279 MFI (range, 1554 to 28,615), compared with 7 C1q-negative patients with median DSA levels of 2471 MFI (range, 665 to 12,254) (P = .016). Of 9 patients who were C1q positive in the initial samples, 5 patients remained C1q positive at time of transplant (all with high DSA levels [median, 15,279; range, 6487 to 22,944]) and experienced engraftment failure, whereas 4 patients became C1q negative pretransplant and all engrafted the donor cells (P = .008). In conclusion, patients with high DSA levels (>5000 MFI) and complement-binding DSA antibodies (C1q positive) appear to be at much higher risk of primary graft failure. The presence of C1q+DSA should be assessed in allosensitized patients before HSCT. Reduction of C1q+DSA levels might prevent engraftment failure in HSCT.


Assuntos
Rejeição de Enxerto/imunologia , Sobrevivência de Enxerto/imunologia , Antígenos HLA/imunologia , Transplante de Células-Tronco Hematopoéticas/métodos , Teste de Histocompatibilidade/métodos , Isoanticorpos/sangue , Condicionamento Pré-Transplante/métodos , Adolescente , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto Jovem
7.
Int J Radiat Oncol Biol Phys ; 85(4): 1024-30, 2013 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-23092727

RESUMO

PURPOSE: C4, a cobalt dichloride-N-acetyl cysteine complex, is being developed as a positive-signal magnetic resonance imaging (MRI) marker to localize implanted radioactive seeds in prostate brachytherapy. We evaluated the toxicity and biodistribution of C4 in rats with the goal of simulating the systemic effects of potential leakage from C4 MRI markers within the prostate. METHODS AND MATERIALS: 9-µL doses (equivalent to leakage from 120 markers in a human) of control solution (0.9% sodium chloride), 1% (proposed for clinical use), and 10% C4 solution were injected into the prostates of male Sprague-Dawley rats via laparotomy. Organ toxicity and cobalt disposition in plasma, tissues, feces, and urine were evaluated. RESULTS: No C4-related morbidity or mortality was observed in the biodistribution arm (60 rats). Biodistribution was measurable after 10% C4 injection: cobalt was cleared rapidly from periprostatic tissue; mean concentrations in prostate were 163 µg/g and 268 µg/g at 5 and 30 minutes but were undetectable by 60 minutes. Expected dual renal-hepatic elimination was observed, with percentages of injected dose recovered in tissues of 39.0 ± 5.6% (liver), >11.8 ± 6.5% (prostate), and >5.3 ± 0.9% (kidney), with low plasma concentrations detected up to 1 hour (1.40 µg/mL at 5-60 minutes). Excretion in urine was 13.1 ± 4.6%, with 3.1 ± 0.54% recovered in feces by 24 hours. In the toxicity arm, 3 animals died in the control group and 1 each in the 1% and 10% groups from surgical or anesthesia-related complications; all others survived to scheduled termination at 14 days. No C4-related adverse clinical signs or organ toxicity were observed. CONCLUSION: C4-related toxicity was not observed at exposures at least 10-fold the exposure proposed for use in humans. These data demonstrating lack of systemic toxicity with dual routes of elimination in the event of in situ rupture suggest that C4 warrants further investigation as an MRI marker for prostate brachytherapy.


Assuntos
Acetilcisteína/análogos & derivados , Acetilcisteína/farmacocinética , Imageamento por Ressonância Magnética/métodos , Próstata/metabolismo , Acetilcisteína/toxicidade , Animais , Braquiterapia/métodos , Humanos , Rim/metabolismo , Fígado/metabolismo , Masculino , Neoplasias da Próstata/radioterapia , Ratos , Distribuição Tecidual
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