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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.
Transplantation ; 82(11): 1524-8, 2006 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-17164726

RESUMO

BACKGROUND: We used a solid-phase assay to identify human leukocyte antigen (HLA) Class I and II specificities in highly reactive sera, and applied this information to predict crossmatch outcome with greater than 90% accuracy. METHODS: Sera from 20 highly sensitized end-stage renal disease patients reactive to 70-100% of HLA Class I and II antigen panel were analyzed by single and/or multiple antigen flow microparticle bead assay using Luminex platform (Luminex assay). These sera contained antibodies directed against high frequency public HLA class I and/or II epitopes accounting for 70-100% of serum's total reactivity. More than 2,000 complement dependent cytotoxicity (CDC) and 200 flow crossmatches (FLXM) were performed using sera from these patients and deceased donor T and B lymphocytes. RESULTS: Luminex serum analysis was able to correctly predict outcomes of 95% of T and B cell FLXM. In contrast, predictive values for the CDC T and B cell crossmatches by Luminex serum analysis were only 77% and 75%, respectively. The use of serum analysis in donor selection would have reduced the total number of required FLXM by more than 50%. The frequency of negative T cell FLXM was 56% when donors were selected randomly; however, if serum antibody analysis had been used to preselect the donors by excluding donors that were likely to be positive, the frequency of corresponding negative crossmatches would have increased up to 93%. CONCLUSION: This approach to donor selection may allow wider geographic sharing of cadaver donor organs without actually performing the crossmatch.


Assuntos
Seleção do Doador/métodos , Antígenos de Histocompatibilidade Classe II/análise , Antígenos de Histocompatibilidade Classe I/análise , Teste de Histocompatibilidade/métodos , Hipersensibilidade/imunologia , Soro/imunologia , Anticorpos/sangue , Linfócitos B/imunologia , Cadáver , Humanos , Falência Renal Crônica/sangue , Falência Renal Crônica/imunologia , Microesferas , Estudos Retrospectivos , Linfócitos T/imunologia , Doadores de Tecidos
5.
Clin Transplant ; 20(4): 461-4, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-16842522

RESUMO

BACKGROUND: In this retrospective study we compared accuracy of panel reactive antibodies (PRA) with serum soluble CD30 (sCD30) contents in predicting acute rejection crisis post-renal transplant. METHODS: Pre-transplant sera from 115 patients were evaluated for their PRA and sCD30 concentrations. All patients received calcineurin inhibitor-based immunosuppressive therapy. Objective measurements for rejection were biopsy-proven acute rejection (AR) episodes within first six months of the transplant. Post-transplant sera of patients with AR were tested for the presence of donor-specific HLA antibodies (DSA). RESULTS: Overall AR rate was 16% (18/115). Patients positive for PRA and sCD30 tests were at significantly higher risk for AVR compared with those patients negative for both the tests (36% vs. 5%, p=0.01). Among negative PRA patients risk for AR was significantly elevated if they were also tested positive for sCD30 concentrations (21% vs. 5%, p=0.04). Of the 18 patients with AR, 14 were positive for sCD30, and 13 of them (93%) developed DSA post-transplant (p=0.001). CONCLUSION: These data showed that patients positive for sCD30 contents are at high risk for the development of DSA and AR post-transplant regardless of their pre-transplant PRA.


Assuntos
Antígenos HLA/imunologia , Isoanticorpos/sangue , Antígeno Ki-1/sangue , Falência Renal Crônica/imunologia , Transplante de Rim/imunologia , Antígenos CD/sangue , Linfócitos B/imunologia , Citometria de Fluxo , Seguimentos , Rejeição de Enxerto/epidemiologia , Teste de Histocompatibilidade , Humanos , Falência Renal Crônica/sangue , Reoperação , Estudos Retrospectivos , Linfócitos T/imunologia , Resultado do Tratamento
6.
Transplantation ; 82(12): 1606-9, 2006 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-17198244

RESUMO

BACKGROUND: This study tests a hypothesis that pretransplant concentration of soluble CD30 (sCD30) is a better predictor of posttransplant development of donor-specific HLA antibodies (DSA) and acute vascular rejection (AVR) than panel reactive HLA antibodies (PRA). METHODS: Pretransplant sera from 115 patients were evaluated for their PRA and sCD30 concentrations. All patients received calcineurin-inhibitor based immunosuppressive therapy. Objective measurements for rejection were biopsy-proven AVR episodes within first 6 months of the transplant. Posttransplant sera of patients with or without AVR were tested for the presence of DSA. RESULTS: AVR rate was 16% (18/115). Patients positive for PRA and sCD30 tests were at significantly higher risk for AVR compared to those patients negative for both tests (36% versus 5%, p = 0.01). Among negative PRA patients risk for AR was significantly elevated if they were also tested positive for sCD30 concentrations (21% versus 5%, p = 0.04). Of the 18 patients with AVR, 14 were positive for sCD30, and 13 of them (93%) developed DSA posttransplant (p = 0.001) Nineteen patients without AVR were tested for DSA and sCD30 concentrations. Only two of these 19 patients were positive for sCD30 and DSA. AVR was strongly associated with the patients tested positive for both the tests: DSA and sCD30 (p = 0.00007). Furthermore, patients with AVR are more likely to produce DSA than those without AVR (p = 0.02). CONCLUSION: These data support our hypothesis that patients positive for sCD30 contents are at high risk the development of DSA and AVR posttransplant regardless of their pretransplant PRA.


Assuntos
Rejeição de Enxerto/epidemiologia , Antígeno Ki-1/sangue , Falência Renal Crônica/epidemiologia , Transplante de Rim , Adulto , Anticorpos/imunologia , Formação de Anticorpos , Vasos Sanguíneos/imunologia , Feminino , Sobrevivência de Enxerto/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Risco , Doadores de Tecidos
7.
J Miss State Med Assoc ; 45(3): 67-70, 2004 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-15054960

RESUMO

BACKGROUND: Physiologic increases in the leukocyte count and segmental neutrophil percentage during pregnancy alter the ability of these indices to predict infection. METHODS: Women with cesarean deliveries were assessed by leukocyte counts and segmented neutrophil percentage as well as clinical signs to detect postoperative infection. RESULTS: In 157 consecutive patients undergoing cesarean deliveries there was a significant physiologic increase between the preoperative and postoperative leukocyte count (12.4 +/- 3.9/uL vs. 14.8 +/- 3.4/uL, P < 0.001). The leukocyte count after delivery did not discriminate whether or not the patient would develop a postpartum infection or have significant hyperpyrexia. CONCLUSION: Due to physiologic changes associated with pregnancy, the leukocyte count and segmented neutrophil percentage do not predict infection. Therefore clinical findings are most important in diagnosing postpartum infections.


Assuntos
Cesárea , Complicações Pós-Operatórias/diagnóstico , Infecção Puerperal/diagnóstico , Adulto , Corioamnionite/diagnóstico , Diagnóstico Diferencial , Endometrite/diagnóstico , Feminino , Humanos , Contagem de Leucócitos , Neutrófilos , Complicações Pós-Operatórias/sangue , Período Pós-Parto/sangue , Valor Preditivo dos Testes , Gravidez , Infecção Puerperal/sangue , Infecção Puerperal/patologia , Infecção dos Ferimentos/diagnóstico
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