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1.
Orphanet J Rare Dis ; 14(1): 240, 2019 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-31684987

RESUMO

Metachromatic leukodystrophy (MLD) is an autosomal recessively inherited metabolic disease characterized by deficient activity of the lysosomal enzyme arylsulfatase A. Its deficiency results in accumulation of sulfatides in neural and visceral tissues, and causes demyelination of the central and peripheral nervous system. This leads to a broad range of neurological symptoms and eventually premature death. In asymptomatic patients with juvenile and adult MLD, treatment with allogeneic hematopoietic stem cell transplantation (HCT) provides a symptomatic and survival benefit. However, this treatment mainly impacts brain white matter, whereas the peripheral neuropathy shows no or only limited response. Data about the impact of peripheral neuropathy in MLD patients are currently lacking, although in our experience peripheral neuropathy causes significant morbidity due to neuropathic pain, foot deformities and neurogenic bladder disturbances. Besides, the reasons for residual and often progressive peripheral neuropathy after HCT are not fully understood. Preliminary studies suggest that peripheral neuropathy might respond better to gene therapy due to higher enzyme levels achieved than with HCT. However, histopathological and clinical findings also suggest a role of neuroinflammation in the pathology of peripheral neuropathy in MLD. In this literature review, we discuss clinical aspects, pathological findings, distribution of mutations, and treatment approaches in MLD with particular emphasis on peripheral neuropathy. We believe that future therapies need more emphasis on the management of peripheral neuropathy, and additional research is needed to optimize care strategies.

2.
Blood Adv ; 3(17): 2525-2536, 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31471322

RESUMO

Presumably, reduced-intensity/nonmyeloablative conditioning (RIC/NMA) for allogeneic hematopoietic cell transplantation (alloHCT) results in reduced infections compared with myeloablative conditioning (MAC) regimens; however, published evidence is limited. In this Center for International Blood and Marrow Transplant Research study, 1755 patients (aged ≥40 years) with acute myeloid leukemia in first complete remission were evaluated for infections occurring within 100 days after T-cell replete alloHCT. Patients receiving RIC/NMA (n = 777) compared with those receiving MAC (n = 978) were older and underwent transplantation more recently; however, the groups were similar regarding Karnofsky performance score, HCT-comorbidity index, and cytogenetic risk. One or more infections occurred in 1045 (59.5%) patients (MAC, 595 [61%]; RIC/NMA, 450 [58%]; P = .21) by day 100. The median time to initial infection after MAC conditioning occurred earlier (MAC, 15 days [range, <1-99 days]; RIC/NMA, 21 days [range, <1-100 days]; P < .001). Patients receiving MAC were more likely to experience at least 1 bacterial infection by day 100 (MAC, 46% [95% confidence interval (CI), 43-49]; RIC/NMA, 37% [95% CI, 34-41]; P = .0004), whereas at least a single viral infection was more prevalent in the RIC/NMA cohort (MAC, 34% [95% CI, 31-37]; RIC/NMA, 39% [95% CI, 36-42]; P = .046). MAC remained a risk factor for bacterial infections in multivariable analysis (relative risk, 1.44; 95% CI, 1.23-1.67; P < .0001). Moreover, the rate of any infection per patient-days at risk in the first 100 days (infection density) after alloHCT was greater for the MAC cohort (1.21; 95% CI, 1.11-1.32; P < .0001). RIC/NMA was associated with reduced infections, especially bacterial infections, in the first 100 days after alloHCT.

3.
Artigo em Inglês | MEDLINE | ID: mdl-31344451

RESUMO

Development of autoimmune cytopenia (AIC) after allogeneic hematopoietic cell transplantation (HCT) is a serious complication requiring urgent intensification of immunosuppressive therapy. The pathophysiology and predictors of AIC are not completely understood. In this retrospective cohort analysis of 380 pediatric patients, we evaluated the incidence, outcomes, and related various variables, including immune reconstitution markers to AIC. Three hundred eighty patients (median age, 7.4 years; range, .1 to 22.7) were included, of which 30 patients (7.8%) developed AIC in 1 (n = 6), 2 (n = 6), or 3 (n = 16) cell lineages at a median of 133 days (range, 46 to 445) after HCT. Using multivariate analysis we found that chemo-naivety before HCT, acute graft-versus-host disease (aGVHD) grades II to IV, and serotherapy were associated with the development of AIC. Development of AIC was preceded by increased levels of IgM, IgA, and IgG. Immune profiles of total absolute lymphocytes were very similar between AIC patients and control subjects. However, CD3-CD16+CD56+ natural killer cells, CD3+ T cells, CD3+CD4+ T cell subset, and CD3+CD8+ T cell subset were lower in AIC patients. Overall survival was good, at 83% (similar between AIC patients and control subjects). In conclusion, we identified chemo-naivety before HCT, preceding aGVHD grades II to IV, and serotherapy as predictors for development of AIC. Increasing levels of IgM, IgA, and IgG preceded AIC development. These data provide clues to further study the biology of AIC.

4.
Clin Infect Dis ; 69(10): 1771-1779, 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-30649224

RESUMO

BACKGROUND: We examined the impact of vancomycin-resistant Enterococcus (VRE) bloodstream infection (BSI) on outcomes of allogeneic hematopoietic cell transplantation (HCT) utilizing the Center for International Blood and Marrow Transplant Research database. METHODS: Adult and pediatric patients (N = 7128) who underwent first HCT for acute leukemia or myelodysplastic syndrome from 2008 through 2012 were analyzed as 3 groups-VRE BSI, non-VRE BSI, without BSI-according to BSI status at 100 days (D100) after allogeneic HCT. Multivariable models examined the effect of VRE BSI for overall survival (OS) and nonrelapse mortality (NRM) at 1 year. RESULTS: Of 7128 patients, 258 (3.2%) had VRE BSI, 2398 (33.6%) had non-VRE BSI, and 4472 (63%) had no BSI. The median time to VRE BSI and non-VRE BSI were D11 and D15, respectively. Compared with non-VRE BSI patients, VRE BSI patients were older, had advanced-stage acute leukemia, and received umbilical cord blood (UCB) allografts. In multivariable models, VRE BSI was associated with lower OS (relative risk [RR], 2.9;(99% confidence interval [CI], 2.2-3.7) and increased NRM (RR, 4.7; 99% CI, 3.6-6.2) (P < .0001) for both. Other predictors for worse OS and increased NRM were non-VRE BSI, older age, advanced disease stage, UCB allograft, - mismatch, comorbidity index ≥3, and cytomegalovirus seropositivity (P < .001 for all variables). CONCLUSIONS: VRE BSI is associated with lowest OS and highest NRM compared with patients without BSI or non-VRE BSI. Novel interventions that address the pathophysiology of VRE BSI have the potential of improving survival after HCT.

5.
Bone Marrow Transplant ; 54(8): 1354-1360, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30696997

RESUMO

Limited data exist on characteristics of central nervous system viruses (CNS-V) in allogeneic hematopoietic stem cell transplant (HCT) recipients. Between 2007 and 2015, the Center for International Blood and Marrow Transplant Research (CIBMTR) received information on 27,532 patients undergoing HCT. Of these, centers reported 165 HCT recipients with CNS-V detected in cerebrospinal fluid within 6 months after HCT. CNS viruses predominantly included human herpes virus 6 (HHV-6) (73%), followed by Epstein-Barr Virus (10%), cytomegalovirus (3%), varicella zoster virus (3%), herpes simplex virus (3%) and Adenovirus (3%). Median time of viral detection in CNS was 31 days after HCT; and viral detection was earlier in patients with CNS HHV-6. Concurrent viremia occurred in 52% of patients. Cord blood transplant recipients (CBT) accounted for the majority (53%) of patients with CNS-V. Myeloablative conditioning (65%), use of fludarabine (63%), or use of anti-thymocyte globulin (61%) were also predominant. Overall survival from the time of detection of CNS-V was 50% at 6 months and 30% at 5 years. Infections were the leading cause of death (32%). In summary, CBT recipients predominated in the population with CNS-V. Outcomes after CNS-V were poor with significant mortality seen in the first 6 months.

6.
J Allergy Clin Immunol ; 143(6): 2238-2253, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30660643

RESUMO

BACKGROUND: CD40 ligand (CD40L) deficiency, an X-linked primary immunodeficiency, causes recurrent sinopulmonary, Pneumocystis and Cryptosporidium species infections. Long-term survival with supportive therapy is poor. Currently, the only curative treatment is hematopoietic stem cell transplantation (HSCT). OBJECTIVE: We performed an international collaborative study to improve patients' management, aiming to individualize risk factors and determine optimal HSCT characteristics. METHODS: We retrospectively collected data on 130 patients who underwent HSCT for CD40L deficiency between 1993-2015. We analyzed outcome and variables' relevance with respect to survival and cure. RESULTS: Overall survival (OS), event-free survival (EFS), and disease-free survival (DFS) were 78.2%, 58.1%, and 72.3% 5 years after HSCT. Results were better in transplantations performed in 2000 or later and in children less than 10 years old at the time of HSCT. Pre-existing organ damage negatively influenced outcome. Sclerosing cholangitis was the most important risk factor. After 2000, superior OS was achieved with matched donors. Use of myeloablative regimens and HSCT at 2 years or less from diagnosis associated with higher OS and DFS. EFS was best with matched sibling donors, myeloablative conditioning (MAC), and bone marrow-derived stem cells. Most rejections occurred after reduced-intensity or nonmyeloablative conditioning, which associated with poor donor cell engraftment. Mortality occurred mainly early after HSCT, predominantly from infections. Among survivors who ceased immunoglobulin replacement, T-lymphocyte chimerism was 50% or greater donor in 85.2%. CONCLUSION: HSCT is curative in patients with CD40L deficiency, with improved outcome if performed before organ damage development. MAC is associated with better OS, EFS, and DFS. Prospective studies are required to compare the risks of HSCT with those of lifelong supportive therapy.

7.
Bone Marrow Transplant ; 54(8): 1254-1265, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30546070

RESUMO

We analyzed CIBMTR data to evaluate the incidence of non-relapse mortality (NRM) and association with overall survival (OS) for bacterial blood stream infections (BSIs) occurring within 100 days of alloHCT in 2 different phases: pre-/peri-engraftment (BSI very early phase, BSI-VEP) and BSI post-engraftment (BSI occurring between 2 weeks after engraftment and day 100, late early phase, BSI-LEP). Of the 7128 alloHCT patients, 2656 (37%) had ≥1 BSI by day 100. BSI-VEP, BSI-LEP, and BSI-Both constituted 56% (n = 1492), 31% (n = 824), and 13% (n = 340) of total BSI, respectively. Starting in 2009, we observed a gradual decline in BSI incidence through 2012 (61-48%). Patients with BSI-VEP were more likely to receive a myeloablative conditioning (MAC) regimen with total body irradiation (TBI). NRM was significantly higher in patients with any BSI (RR 1.82 95% CI 1.63-2.04 for BSI-VEP, RR 2.46, 95% CI 2.05-2.96 for BSI-LEP, and RR 2.29, 95% CI 1.87-2.81 for BSI-Both) compared with those without BSI. OS was significantly lower in patients with any BSI compared with patients without BSI (RR 1.36, 95% CI 1.26-1.47 for BSI-VEP; RR 1.83, 95% CI 1.58-2.12 for BSI-LEP: RR 1.66, 95% CI 1.43-1.94 for BSI-Both). BSIs within day 100 after alloHCT are common and remain a risk factor for mortality.

9.
Artigo em Inglês | MEDLINE | ID: mdl-30359735

RESUMO

Innate immune cells are the first to recover after allogeneic hematopoietic cell transplantation (HCT). Nevertheless, reports of innate immune cell recovery and their relation to adaptive recovery after HCT are largely lacking. Especially predicting CD4+ T cell reconstitution is of clinical interest, because this parameter directly associates with survival chances after HCT. We evaluated whether innate recovery relates to CD4+ T cell reconstitution probability and investigated differences between innate recovery after cord blood transplantation (CBT) and bone marrow transplantation (BMT). We developed a multivariate, combined nonlinear mixed-effects model for monocytes, neutrophils, and natural killer (NK) cell recovery after transplantation. A total of 205 patients undergoing a first HCT (76 BMT, 129 CBT) between 2007 and 2016 were included. The median age was 7.3 years (range, .16 to 23). Innate recovery was highly associated with CD4+ T cell reconstitution probability (P < .001) in multivariate analysis correcting for covariates. Monocyte (P < .001), neutrophil (P < .001), and NK cell (P < .001) recovery reached higher levels during the first 200 days after CBT compared with BMT. The higher innate recovery after CBT may be explained by increased proliferation capacity (measured by Ki-67 expression) of innate cells in CB grafts compared with BM grafts (P = .041) and of innate cells in vivo after CBT compared with BMT (P = .048). At an individual level, patients with increased innate recovery after either CBT or BMT had received grafts with higher proliferating innate cells (CB; P = .004, BM; P = .01, respectively). Our findings implicate the use of early innate immune monitoring to predict the chance of CD4+ T cell reconstitution after HCT, with respect to higher innate recovery after CBT compared with BMT.

10.
J Allergy Clin Immunol ; 141(2): 697-703.e8, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28716387

RESUMO

BACKGROUND: Alloimmune-mediated lung syndromes (allo-LSs) are life-threatening complications after hematopoietic cell transplantation (HCT). Respiratory virus (RV) has been suggested to play a role in the pathogenesis. OBJECTIVE: We studied the relation between RV DNA/RNA detection in the upper/lower airways before HCT and the occurrence of allo-LSs. METHODS: We retrospectively analyzed all HCT recipients between 2004 and 2014, in whom real-time PCR for RV was performed in nasopharyngeal aspirates (NPAs) and bronchoalveolar lavage (BAL) fluid before HCT. The main outcome of interest was the presence of an allo-LS, which was defined as idiopathic pneumonia syndrome or bronchiolitis obliterans syndrome. Other outcomes were overall survival and treatment-related mortality. We used Cox proportional hazard models, logistic regression models, and Fine-Gray competing risk regression for analyses. RESULTS: One hundred seventy-nine children (median age, 6.8 years) were included. RVs were found in 61% (41% in BAL fluid/NPAs and 20% in NPAs only). Rhinovirus was the most frequently detected RV (42%). Allo-LSs occurred in 13%. RV positivity in BAL fluid was a predictor for allo-LSs (hazard ratio, 3.8; 95% CI, 1.4-10.7; P = .01), whereas RV positivity in NPAs only was not. No other predictors were found. Grade II to IV acute graft-versus-host disease related to steroid treatment shows a trend toward a protective effect (odds ratio, 0.16; 95% CI, 0.0-1.3; P = .08). Allo-LSs significantly increased treatment-related mortality (52% ± 10% in allo-LSs and 20% ± 4% in non-allo-LSs, P = .007). CONCLUSIONS: These results show that pre-HCT BAL fluid RV positivity was a predictor for allo-LSs. Screening for RVs before HCT might identify patients at risk for allo-LSs. This could have implications for prevention and treatment and might subsequently influence the outcomes of HCT.

11.
J Allergy Clin Immunol ; 141(2): 704-717.e5, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28601685

RESUMO

BACKGROUND: Gain-of-function (GOF) mutations in signal transducer and activator of transcription 1 (STAT1) cause susceptibility to a range of infections, autoimmunity, immune dysregulation, and combined immunodeficiency. Disease manifestations can be mild or severe and life-threatening. Hematopoietic stem cell transplantation (HSCT) has been used in some patients with more severe symptoms to treat and cure the disorder. However, the outcome of HSCT for this disorder is not well established. OBJECTIVE: We sought to aggregate the worldwide experience of HSCT in patients with GOF-STAT1 mutations and to assess outcomes, including donor engraftment, overall survival, graft-versus-host disease, and transplant-related complications. METHODS: Data were collected from an international cohort of 15 patients with GOF-STAT1 mutations who had undergone HSCT using a variety of conditioning regimens and donor sources. Retrospective data collection allowed the outcome of transplantation to be assessed. In vitro functional testing was performed to confirm that each of the identified STAT1 variants was in fact a GOF mutation. RESULTS: Primary donor engraftment in this cohort of 15 patients with GOF-STAT1 mutations was 74%, and overall survival was only 40%. Secondary graft failure was common (50%), and posttransplantation event-free survival was poor (10% by 100 days). A subset of patients had hemophagocytic lymphohistiocytosis before transplant, contributing to their poor outcomes. CONCLUSION: Our data indicate that HSCT for patients with GOF-STAT1 mutations is curative but has significant risk of secondary graft failure and death.

12.
Sci Transl Med ; 9(386)2017 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-28424327

RESUMO

The molecular pathways that regulate the tissue repair function of type I interferon (IFN-I) during acute tissue damage are poorly understood. We describe a protective role for IFN-I and the RIG-I/MAVS signaling pathway during acute tissue damage in mice. Mice lacking mitochondrial antiviral-signaling protein (MAVS) were more sensitive to total body irradiation- and chemotherapy-induced intestinal barrier damage. These mice developed worse graft-versus-host disease (GVHD) in a preclinical model of allogeneic hematopoietic stem cell transplantation (allo-HSCT) than did wild-type mice. This phenotype was not associated with changes in the intestinal microbiota but was associated with reduced gut epithelial integrity. Conversely, targeted activation of the RIG-I pathway during tissue injury promoted gut barrier integrity and reduced GVHD. Recombinant IFN-I or IFN-I expression induced by RIG-I promoted growth of intestinal organoids in vitro and production of the antimicrobial peptide regenerating islet-derived protein 3 γ (RegIIIγ). Our findings were not confined to RIG-I/MAVS signaling because targeted engagement of the STING (stimulator of interferon genes) pathway also protected gut barrier function and reduced GVHD. Consistent with this, STING-deficient mice suffered worse GVHD after allo-HSCT than did wild-type mice. Overall, our data suggest that activation of either RIG-I/MAVS or STING pathways during acute intestinal tissue injury in mice resulted in IFN-I signaling that maintained gut epithelial barrier integrity and reduced GVHD severity. Targeting these pathways may help to prevent acute intestinal injury and GVHD during allogeneic transplantation.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteína DEAD-box 58/metabolismo , Mucosa Intestinal/metabolismo , Proteínas de Membrana/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Proteína DEAD-box 58/genética , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/metabolismo , Transplante de Células-Tronco Hematopoéticas , Interferon Tipo I/metabolismo , Intestinos/efeitos da radiação , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Infiltração de Neutrófilos/fisiologia , Organoides/citologia , Organoides/metabolismo , Reação em Cadeia da Polimerase , Transdução de Sinais/fisiologia , Transplante Homólogo
13.
J Allergy Clin Immunol ; 140(6): 1643-1650.e9, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28392330

RESUMO

BACKGROUND: Viral reactivations (VRs) after hematopoietic cell transplantation (HCT) contribute to significant morbidity and mortality. Timely immune reconstitution (IR) is suggested to prevent VR. OBJECTIVES: We studied the relation between IR (as a continuous predictor over time) and VR (as a time-varying predictor) and the relation between VR and other clinical outcomes. METHODS: In this retrospective analysis all patients receiving a first HCT between January 2004 and September 2014 were included. IR (CD3/CD4/CD8 T, natural killer, and B cells) was measured biweekly until 12 weeks and monthly thereafter. Main outcomes of interest were VR of adenovirus, EBV, human herpesvirus 6 (HHV6), cytomegalovirus (CMV), and BK virus screened weekly. Clinical outcomes included overall survival (OS), event-free-survival, nonrelapse mortality (NRM), and graft-versus-host disease. Cox proportional hazard and Fine and Gray competing risk models were used. RESULTS: Two hundred seventy-three patients (age, 0.1-22.7 years; median follow-up, 58 months) were included. Delayed CD4 reconstitution predicted reactivation of adenovirus (hazard ratio [HR], 0.995; P = .022), EBV (HR, 0.994; P = .029), and HHV6 (HR, 0.991; P = .012) but not CMV (P = .31) and BK virus (P = .27). Duration of adenovirus reactivation was shorter with timely CD4 reconstitution, which was defined as 50 × 106 cells/L or greater within 100 days. Adenovirus reactivation predicted lower OS (HR, 2.17; P = .0039) and higher NRM (HR, 2.96; P = .0008). Concomitant CD4 reconstitution abolished this negative effect of adenovirus reactivation (OS, P = .67; NRM, P = .64). EBV and HHV6 reactivations were predictors for the occurrence of graft-versus-host disease, whereas CMV and BK virus reactivation did not predict clinical outcomes. CONCLUSION: These results stress the importance of timely CD4 reconstitution. Strategies to improve CD4 reconstitution can improve HCT outcomes, including survival, and reduce the need for toxic antiviral therapies.


Assuntos
Doença Enxerto-Hospedeiro/virologia , Transplante de Células-Tronco Hematopoéticas , Reconstituição Imune , Complicações Pós-Operatórias/virologia , Ativação Viral , Adolescente , Adulto , Criança , Pré-Escolar , Seguimentos , Doença Enxerto-Hospedeiro/mortalidade , Humanos , Lactente , Complicações Pós-Operatórias/mortalidade , Estudos Retrospectivos , Análise de Sobrevida , Adulto Jovem
14.
Blood ; 128(23): 2734-2741, 2016 12 08.
Artigo em Inglês | MEDLINE | ID: mdl-27702800

RESUMO

Successful immune reconstitution (IR) is associated with improved outcomes following pediatric cord blood transplantation (CBT). Usage and timing of anti-thymocyte globulin (ATG), introduced to the conditioning to prevent graft-versus-host disease and graft failure, negatively influences T-cell IR. We studied the relationships among ATG exposure, IR, and clinical outcomes. All pediatric patients receiving a first CBT between 2004 and 2015 at the University Medical Center Utrecht were included. ATG-exposure measures were determined with a validated pharmacokinetics model. Main outcome of interest was early CD4+ IR, defined as CD4+ T-cell counts >50 × 106/L twice within 100 days after CBT. Other outcomes of interest included event-free survival (EFS). Cox proportional-hazard and Fine-Gray competing-risk models were used. A total of 137 patients, with a median age of 7.4 years (range, 0.2-22.7), were included, of whom 82% received ATG. Area under the curve (AUC) of ATG after infusion of the cord blood transplant predicted successful CD4+ IR. Adjusted probability on CD4+ IR was reduced by 26% for every 10-point increase in AUC after CBT (hazard ratio [HR], 0.974; P < .0001). The chance of EFS was higher in patients with successful CD4+ IR (HR, 0.26; P < .0001) and lower ATG exposure after CBT (HR, 1.005; P = .0071). This study stresses the importance of early CD4+ IR after CBT, which can be achieved by reducing the exposure to ATG after CBT. Individualized dosing of ATG to reach optimal exposure or, in selected patients, omission of ATG may contribute to improved outcomes in pediatric CBT.


Assuntos
Soro Antilinfocitário/administração & dosagem , Linfócitos T CD4-Positivos , Transplante de Células-Tronco de Sangue do Cordão Umbilical , Recuperação de Função Fisiológica/efeitos dos fármacos , Condicionamento Pré-Transplante/métodos , Adolescente , Adulto , Aloenxertos , Contagem de Linfócito CD4 , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Humanos , Lactente , Masculino , Estudos Retrospectivos , Taxa de Sobrevida
16.
Biol Blood Marrow Transplant ; 22(9): 1636-1645, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27343716

RESUMO

Alternative graft sources (umbilical cord blood [UCB], matched unrelated donors [MUD], or mismatched unrelated donors [MMUD]) enable patients without a matched sibling donor to receive potentially curative hematopoietic cell transplantation (HCT). Retrospective studies demonstrate comparable outcomes among different graft sources. However, the risk and types of infections have not been compared among graft sources. Such information may influence the choice of a particular graft source. We compared the incidence of bacterial, viral, and fungal infections in 1781 adults with acute leukemia who received alternative donor HCT (UCB, n= 568; MUD, n = 930; MMUD, n = 283) between 2008 and 2011. The incidences of bacterial infection at 1 year were 72%, 59%, and 65% (P < .0001) for UCB, MUD, and MMUD, respectively. Incidences of viral infection at 1 year were 68%, 45%, and 53% (P < .0001) for UCB, MUD, and MMUD, respectively. In multivariable analysis, bacterial, fungal, and viral infections were more common after either UCB or MMUD than after MUD (P < .0001). Bacterial and viral but not fungal infections were more common after UCB than MMUD (P = .0009 and <.0001, respectively). The presence of viral infection was not associated with an increased mortality. Overall survival (OS) was comparable among UCB and MMUD patients with Karnofsky performance status (KPS) ≥ 90% but was inferior for UCB for patients with KPS < 90%. Bacterial and fungal infections were associated with poorer OS. Future strategies focusing on infection prevention and treatment are indicated to improve HCT outcomes.


Assuntos
Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Infecção/etiologia , Leucemia/complicações , Leucemia/terapia , Doença Aguda , Adolescente , Adulto , Idoso , Transplante de Células-Tronco de Sangue do Cordão Umbilical/efeitos adversos , Transplante de Células-Tronco de Sangue do Cordão Umbilical/mortalidade , Feminino , Transplante de Células-Tronco Hematopoéticas/métodos , Transplante de Células-Tronco Hematopoéticas/mortalidade , Histocompatibilidade , Humanos , Incidência , Infecção/mortalidade , Leucemia/mortalidade , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Análise de Sobrevida , Doadores não Relacionados , Adulto Jovem
17.
Nat Immunol ; 17(5): 505-513, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26998764

RESUMO

The effect of alterations in intestinal microbiota on microbial metabolites and on disease processes such as graft-versus-host disease (GVHD) is not known. Here we carried out an unbiased analysis to identify previously unidentified alterations in gastrointestinal microbiota-derived short-chain fatty acids (SCFAs) after allogeneic bone marrow transplant (allo-BMT). Alterations in the amount of only one SCFA, butyrate, were observed only in the intestinal tissue. The reduced butyrate in CD326(+) intestinal epithelial cells (IECs) after allo-BMT resulted in decreased histone acetylation, which was restored after local administration of exogenous butyrate. Butyrate restoration improved IEC junctional integrity, decreased apoptosis and mitigated GVHD. Furthermore, alteration of the indigenous microbiota with 17 rationally selected strains of high butyrate-producing Clostridia also decreased GVHD. These data demonstrate a heretofore unrecognized role of microbial metabolites and suggest that local and specific alteration of microbial metabolites has direct salutary effects on GVHD target tissues and can mitigate disease severity.


Assuntos
Células Epiteliais/imunologia , Microbioma Gastrointestinal/imunologia , Doença Enxerto-Hospedeiro/imunologia , Intestinos/imunologia , Metaboloma/imunologia , Acetilação/efeitos dos fármacos , Animais , Transplante de Medula Óssea/efeitos adversos , Transplante de Medula Óssea/métodos , Butiratos/imunologia , Butiratos/metabolismo , Butiratos/farmacologia , Células Cultivadas , Células Epiteliais/metabolismo , Células Epiteliais/microbiologia , Ácidos Graxos Voláteis/imunologia , Ácidos Graxos Voláteis/metabolismo , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Microbioma Gastrointestinal/fisiologia , Expressão Gênica/imunologia , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/microbiologia , Histona Acetiltransferases/genética , Histona Acetiltransferases/imunologia , Histona Acetiltransferases/metabolismo , Histona Desacetilases/genética , Histona Desacetilases/imunologia , Histona Desacetilases/metabolismo , Histonas/imunologia , Histonas/metabolismo , Immunoblotting , Intestinos/citologia , Intestinos/microbiologia , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Linfócitos T/imunologia , Linfócitos T/metabolismo , Transplante Homólogo
18.
Blood ; 127(20): 2427-38, 2016 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-26884374

RESUMO

Single-center studies have reported an association between early (before day 100) cytomegalovirus (CMV) reactivation and decreased incidence of relapse for acute myeloid leukemia (AML) following allogeneic hematopoietic cell transplantation. To substantiate these preliminary findings, the Center for International Blood and Marrow Transplant Research (CIBMTR) Database was interrogated to analyze the impact of CMV reactivation on hematologic disease relapse in the current era. Data from 9469 patients transplanted with bone marrow or peripheral blood between 2003 and 2010 were analyzed according to 4 disease categories: AML (n = 5310); acute lymphoblastic leukemia (ALL, n = 1883); chronic myeloid leukemia (CML, n = 1079); and myelodysplastic syndrome (MDS, n = 1197). Median time to initial CMV reactivation was 41 days (range, 1-362 days). CMV reactivation had no preventive effect on hematologic disease relapse irrespective of diagnosis. Moreover, CMV reactivation was associated with higher nonrelapse mortality [relative risk [RR] among disease categories ranged from 1.61 to 1.95 and P values from .0002 to <.0001; 95% confidence interval [CI], 1.14-2.61). As a result, CMV reactivation was associated with lower overall survival for AML (RR = 1.27; 95% CI, 1.17-1.38; P <.0001), ALL (RR = 1.46; 95% CI, 1.25-1.71; P <.0001), CML (RR = 1.49; 95% CI, 1.19-1.88; P = .0005), and MDS (RR = 1.31; 95% CI, 1.09-1.57; P = .003). In conclusion, CMV reactivation continues to remain a risk factor for poor posttransplant outcomes and does not seem to confer protection against hematologic disease relapse.


Assuntos
Transplante de Medula Óssea/efeitos adversos , Infecções por Citomegalovirus/virologia , Citomegalovirus/fisiologia , Leucemia/terapia , Síndromes Mielodisplásicas/terapia , Ativação Viral , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Aloenxertos , Anticorpos Antivirais/sangue , Antivirais/uso terapêutico , Transplante de Medula Óssea/mortalidade , Criança , Pré-Escolar , Citomegalovirus/imunologia , Infecções por Citomegalovirus/complicações , Infecções por Citomegalovirus/tratamento farmacológico , Bases de Dados Factuais , Intervalo Livre de Doença , Feminino , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/mortalidade , Humanos , Lactente , Estimativa de Kaplan-Meier , Leucemia/complicações , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/complicações , Recidiva , Sistema de Registros , Fatores de Tempo , Condicionamento Pré-Transplante/efeitos adversos , Adulto Jovem
19.
Nature ; 528(7583): 560-564, 2015 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-26649819

RESUMO

Epithelial regeneration is critical for barrier maintenance and organ function after intestinal injury. The intestinal stem cell (ISC) niche provides Wnt, Notch and epidermal growth factor (EGF) signals supporting Lgr5(+) crypt base columnar ISCs for normal epithelial maintenance. However, little is known about the regulation of the ISC compartment after tissue damage. Using ex vivo organoid cultures, here we show that innate lymphoid cells (ILCs), potent producers of interleukin-22 (IL-22) after intestinal injury, increase the growth of mouse small intestine organoids in an IL-22-dependent fashion. Recombinant IL-22 directly targeted ISCs, augmenting the growth of both mouse and human intestinal organoids, increasing proliferation and promoting ISC expansion. IL-22 induced STAT3 phosphorylation in Lgr5(+) ISCs, and STAT3 was crucial for both organoid formation and IL-22-mediated regeneration. Treatment with IL-22 in vivo after mouse allogeneic bone marrow transplantation enhanced the recovery of ISCs, increased epithelial regeneration and reduced intestinal pathology and mortality from graft-versus-host disease. ATOH1-deficient organoid culture demonstrated that IL-22 induced epithelial regeneration independently of the Paneth cell niche. Our findings reveal a fundamental mechanism by which the immune system is able to support the intestinal epithelium, activating ISCs to promote regeneration.


Assuntos
Células Epiteliais/citologia , Interleucinas/imunologia , Mucosa Intestinal/citologia , Intestino Delgado/citologia , Regeneração , Células-Tronco/citologia , Células-Tronco/metabolismo , Animais , Células Epiteliais/imunologia , Células Epiteliais/patologia , Feminino , Doença Enxerto-Hospedeiro/patologia , Humanos , Imunidade nas Mucosas , Interleucinas/deficiência , Mucosa Intestinal/imunologia , Mucosa Intestinal/patologia , Intestino Delgado/imunologia , Intestino Delgado/patologia , Camundongos , Organoides/citologia , Organoides/crescimento & desenvolvimento , Organoides/imunologia , Celulas de Paneth/citologia , Fosforilação , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Nicho de Células-Tronco
20.
Biol Blood Marrow Transplant ; 21(10): 1839-45, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26119367

RESUMO

In haploidentical (haplo)-cord blood (CB) transplantations, early haplo donor engraftment serves as a myeloid bridge to sustainable CB engraftment and is associated with early neutrophil recovery. The conditioning regimens as published for haplo-cord protocols usually contain serotherapy, such as rabbit antithymocyte globulin (ATG) (Thymoglobulin, Genzyme, Cambridge, MA). However, reducing or omitting serotherapy is an important strategy to improve early immune reconstitution after transplantation. The need for serotherapy in successful haplo-cord transplantation, defined as having a haplo-derived myeloid bridge to CB engraftment, has not been investigated before. Two consecutive cohorts of patients underwent transplantation with haplo-CB. The first group underwent transplantation with haplo-CB for active infection and/or an underlying condition with expected difficult engraftment without a conventional donor available. They received a single unit (s) CB and haplo donor cells (CD34(+) selected, 5 × 10(6) CD34(+)/kg). The second cohort included patients with poor-risk malignancies, not eligible for other treatment protocols. They received a sCB and haplo donor cells (CD19/αßTCR-depleted; 5 × 10(6) CD34(+)/kg). Retrospectively in both cohorts, active ATG (Thymoglobulin) levels were measured and post-hematopoietic cell transplantation area under the curve (AUC) was calculated. The influence of ATG exposure for having a successful haplo-myeloid bridge (early haplo donor engraftment before CB engraftment and no secondary neutropenia) and transplantation-related mortality (TRM) were analyzed as primary endpoints. Twenty patients were included (16 in the first cohort and 4 in the second cohort). In 58% of evaluable patients, there was no successful haplo-derived myeloid bridge to CB engraftment, for which a low post-transplantation ATG exposure appeared to be a predictor (P <.001). TRM in the unsuccessful haplo-bridge group was 70% ± 16% versus 12% ± 12% in the successful haplo-bridge group (P = .012). In conclusion, sufficient in vivo T depletion with ATG is required for a successful haplo-myeloid bridge to CB engraftment.


Assuntos
Soro Antilinfocitário/administração & dosagem , Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Haplótipos/imunologia , Histocompatibilidade , Imunossupressores/administração & dosagem , Linfócitos T/imunologia , Adolescente , Adulto , Alemtuzumab , Animais , Anticorpos Monoclonais Humanizados/uso terapêutico , Área Sob a Curva , Criança , Pré-Escolar , Relação Dose-Resposta Imunológica , Determinação de Ponto Final , Feminino , Rejeição de Enxerto , Sobrevivência de Enxerto , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Imunossupressores/efeitos adversos , Imunossupressores/uso terapêutico , Lactente , Recém-Nascido , Estimativa de Kaplan-Meier , Depleção Linfocítica , Masculino , Pessoa de Meia-Idade , Neutrófilos/imunologia , Neutrófilos/transplante , Coelhos , Fatores de Tempo , Resultado do Tratamento , Doadores não Relacionados
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