RESUMO
BACKGROUND: Patient outcomes are poor for aggressive B-cell non-Hodgkin's lymphomas not responding to or progressing within 12 months after first-line therapy. Tisagenlecleucel is an anti-CD19 chimeric antigen receptor T-cell therapy approved for diffuse large B-cell lymphoma after at least two treatment lines. METHODS: We conducted an international phase 3 trial involving patients with aggressive lymphoma that was refractory to or progressing within 12 months after first-line therapy. Patients were randomly assigned to receive tisagenlecleucel with optional bridging therapy (tisagenlecleucel group) or salvage chemotherapy and autologous hematopoietic stem-cell transplantation (HSCT) (standard-care group). The primary end point was event-free survival, defined as the time from randomization to stable or progressive disease at or after the week 12 assessment or death. Crossover to receive tisagenlecleucel was allowed if a defined event occurred at or after the week 12 assessment. Other end points included response and safety. RESULTS: A total of 322 patients underwent randomization. At baseline, the percentage of patients with high-grade lymphomas was higher in the tisagenlecleucel group than in the standard-care group (24.1% vs. 16.9%), as was the percentage with an International Prognostic Index score (range, 0 to 5, with higher scores indicating a worse prognosis) of 2 or higher (65.4% vs. 57.5%). A total of 95.7% of the patients in the tisagenlecleucel group received tisagenlecleucel; 32.5% of the patients in the standard-care group received autologous HSCT. The median time from leukapheresis to tisagenlecleucel infusion was 52 days. A total of 25.9% of the patients in the tisagenlecleucel group had lymphoma progression at week 6, as compared with 13.8% of those in the standard-care group. The median event-free survival in both groups was 3.0 months (hazard ratio for event or death in the tisagenlecleucel group, 1.07; 95% confidence interval, 0.82 to 1.40; P = 0.61). A response occurred in 46.3% of the patients in the tisagenlecleucel group and in 42.5% in the standard-care group. Ten patients in the tisagenlecleucel group and 13 in the standard-care group died from adverse events. CONCLUSIONS: Tisagenlecleucel was not superior to standard salvage therapy in this trial. Additional studies are needed to assess which patients may obtain the most benefit from each approach. (Funded by Novartis; BELINDA ClinicalTrials.gov number, NCT03570892.).
Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Imunoterapia Adotiva , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Receptores de Antígenos de Linfócitos T/uso terapêutico , Receptores de Antígenos Quiméricos/antagonistas & inibidores , Adulto , Idoso , Antineoplásicos Imunológicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Terapia Combinada , Feminino , Humanos , Linfoma Difuso de Grandes Células B/mortalidade , Linfoma Difuso de Grandes Células B/terapia , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Terapia de Salvação , Transplante AutólogoRESUMO
Allogeneic haematopoietic cell transplantation (allo-HCT) recipients show impaired antibody (Ab) response to a standard two-dose vaccination against severe acute respiratory syndrome coronavirus-2 and currently a third dose is recommended as part of the primary vaccination regimen. By assessing Ab titres 1 month after a third mRNA vaccine dose in 74 allo-HCT recipients we show sufficient neutralisation activity in 77% of the patients. Discontinuation of immunosuppression before the third vaccine led to serological responses in 50% of low responders to two vaccinations. Identifying factors that might contribute to better vaccine responses in allo-HCT recipients is critical to optimise current vaccination strategies.
Assuntos
COVID-19 , Transplante de Células-Tronco Hematopoéticas , Humanos , Vacinas contra COVID-19 , Formação de Anticorpos , COVID-19/prevenção & controle , SARS-CoV-2 , Transplantados , Vacinação , Anticorpos AntiviraisRESUMO
BACKGROUND: Influenza vaccination efficacy is reduced after hematopoietic stem cell transplantation (HSCT) and patient factors determining vaccination outcomes are still poorly understood. METHODS: We investigated the antibody response to seasonal influenza vaccination in 135 HSCT patients and 69 healthy volunteers (HVs) in a prospective observational multicenter cohort study. We identified patient factors associated with hemagglutination inhibition titers against A/California/2009/H1N1, A/Texas/2012/H3N2, and B/Massachusetts/2012 by multivariable regression on the observed titer levels and on seroconversion/seroprotection categories for comparison. RESULTS: Both regression approaches yielded consistent results but regression on titers estimated associations with higher precision. HSCT patients required 2 vaccine doses to achieve average responses comparable to a single dose in HVs. Prevaccination titers were positively associated with time after transplantation, confirming that HSCT patients can elicit potent antibody responses. However, an unrelated donor, absolute lymphocyte counts below the normal range, and treatment with calcineurin inhibitors lowered the odds of responding. CONCLUSIONS: HSCT patients show a highly heterogeneous vaccine response but, overall, patients benefited from the booster shot and can acquire seroprotective antibodies over the years after transplantation. Several common patient factors lower the odds of responding, urging identification of additional preventive strategies in the poorly responding groups. CLINICAL TRIALS REGISTRATION: NCT03467074.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Vírus da Influenza A Subtipo H1N1 , Vacinas contra Influenza , Influenza Humana , Anticorpos Antivirais , Formação de Anticorpos , Estudos de Coortes , Humanos , Vírus da Influenza A Subtipo H3N2 , Vacinas contra Influenza/efeitos adversos , Influenza Humana/prevenção & controle , Estações do Ano , VacinaçãoRESUMO
CD19-directed chimeric antigen receptor T cells (CAR-T) have emerged as a highly efficacious treatment for patients with relapsed/refractory (r/r) B cell lymphoma (BCL). The value of CAR-T for these patients is indisputable, but one-off production costs are high, and little is known about the ancillary resource consumption associated with CAR-T treatment. Here, we compared the resource use and costs of CAR-T treatment with high-dose chemotherapy followed by autologous stem cell transplantation (ASCT) for patients with r/r BCL. Standard operating procedures were used to develop a process model in ClipMedPPM, which comprises all activities and processes to sustain or generate treatment components that together constitute a treatment path. The software allows a graphic representation and the use of standardized linguistic elements for comparison of different treatment paths. Detailed processes involved in CAR-T treatments (n = 1041 processes) and in ASCT (n = 1535) were analyzed for time consumption of treatment phases and personnel. Process costs were calculated using financial controlling data. CAR-T treatment required ~ 30% less staff time than ASCT (primarily nursing staff) due to fewer chemotherapy cycles, less outpatient visits, and shorter hospital stays. For CAR-T, production costs were ~ 8 × higher, but overall treatment time was shorter compared with ASCT (30 vs 48 days), and direct labor and overhead costs were 40% and 10% lower, respectively. Excluding high product costs, CAR-T uses fewer hospital resources than ASCT for r/r BCL. Fewer hospital days for CAR-T compared to ASCT treatment and the conservation of hospital resources are beneficial to patients and the healthcare system.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Linfoma de Células B , Receptores de Antígenos Quiméricos , Antígenos CD19 , Humanos , Linfoma de Células B/tratamento farmacológico , Receptores de Antígenos de Linfócitos T , Transplante Autólogo/métodosRESUMO
Outbreaks of viral infections, such as measles, are regularly observed and pose a serious threat to recipients of allogeneic hematopoietic cell transplantation (HCT). The questions of how long cellular and humoral protective host immunity persists, and whether donor immunity can be transferred has not been clarified. Here we present a retrospective analysis of humoral immunity-serial antibody titers against measles, mumps, and rubella-in 331 patients who underwent allogeneic HCT at our single center between 2002 and 2015. Associations between the loss of protective antibody levels and clinical patient characteristics and transplantation parameters were examined. In general, antibody protection against measles persisted longer, with 72% of patients maintaining sufficient titers at 5 years post-HCT even without revaccination, while at that time only 65% and 50% of patients had protective immunity against rubella and mumps, respectively. The great majority of donors were seropositive for all 3 viruses; however, it appeared that donor humoral immunity could not be transferred and had no impact on post-HCT serostatus. Rather, the most relevant factor for persistent protective antibody titers against measles and rubella was whether patients were born before the introduction of the respective vaccine and thus were immunized by the wild-type disease-inducing virus instead of the vaccine. Moreover, the presence of moderate and severe chronic graft-versus-host disease (GVHD) was associated with more rapid loss of immune protection. In contrast, underlying disease, intensity of the conditioning regimen, use of antithymocyte globulin, age, and graft source had no influence on antibody titers. Overall, our findings suggest that the majority of antibodies against measles, mumps, and rubella originate from residual host cells, whereas donor immune status appears to have no influence on antibody protection post-HCT.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Sarampo , Caxumba , Rubéola (Sarampo Alemão) , Anticorpos Antivirais , Seguimentos , Humanos , Sarampo/prevenção & controle , Vacina contra Sarampo-Caxumba-Rubéola , Caxumba/prevenção & controle , Estudos Retrospectivos , Rubéola (Sarampo Alemão)/prevenção & controleRESUMO
BACKGROUND: Infections are an important complication after allogeneic hematopoietic cell transplantation (allo-HCT). The present study aimed at determining the landscape of infections occurring in a large cohort of allo-HCT patients, as well as associated risk factors for infections and for one-year non-relapse mortality. METHODS: This is a retrospective cohort study using STCS and EBMT databases to assess the one-year incidence rate of infection, as well as risk factors for infections and for one-year non-relapse mortality among adult allo-HCT patients transplanted between 2010 and 2014 in Switzerland. Univariable and multivariable quasi-Poisson and multivariable Cox regression models were used. RESULTS: Of 553 patients included, 486 had an infection with a global incidence rate of 3.66 infections per patient-year. Among a total of 1534 infections analyzed, viral infections were predominant (n = 1138, 74.2%), followed by bacterial (n = 343, 22.4%) and fungal (n = 53, 3.5%) infections. At one year, the cumulative incidence of relapse and non-relapse mortality was 26% and 16%, respectively. 195 (35.3%) of patients had at least one episode of severe graft-versus-host-disease (GvHD). A center effect was observed, and underlying disease, donor type, cytomegalovirus serological constellation, and GvHD were also associated with the incidence rate of infections. There was an increased risk for one-year non-relapse mortality associated with all pathogens, specifically within two months of infection, and this remained true beyond 2 months of a fungal infection. CONCLUSION: Despite advances to limit infections in this population, they still occur in most allo-HCT patients with a major impact on survival at 1 year.
Assuntos
Infecções Bacterianas/epidemiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/mortalidade , Micoses/epidemiologia , Viroses/epidemiologia , Adolescente , Adulto , Idoso , Bases de Dados Factuais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Recidiva , Estudos Retrospectivos , Fatores de Risco , Suíça , Fatores de Tempo , Transplante Homólogo/efeitos adversos , Transplante Homólogo/mortalidade , Adulto JovemRESUMO
Graft-versus-host disease (GVHD) remains a major complication of allogeneic hematopoietic cell transplantation. Acute GVHD (aGVHD) results from direct damage by donor T cells, whereas the biology of chronic GVHD (cGVHD) with its autoimmune-like manifestations remains poorly understood, mainly because of the paucity of representative preclinical models. We examined over an extended time period 7 MHC-matched, minor antigen-mismatched mouse models for development of cGVHD. Development and manifestations of cGVHD were determined by a combination of MHC allele type and recipient strain, with BALB recipients being the most susceptible. The C57BL/6 into BALB.B combination most closely modeled the human syndrome. In this strain combination moderate aGVHD was observed and BALB.B survivors developed overt cGVHD at 6 to 12 months affecting eyes, skin, and liver. Naïve CD4+ cells caused this syndrome as no significant pathology was induced by grafts composed of purified hematopoietic stem cells (HSCs) or HSC plus effector memory CD4+ or CD8+ cells. Furthermore, co-transferred naïve and effector memory CD4+ T cells demonstrated differential homing patterns and locations of persistence. No clear association with donor Th17 cells and the phenotype of aGVHD or cGVHD was observed in this model. Donor CD4+ cells caused injury to medullary thymic epithelial cells, a key population responsible for negative T cell selection, suggesting that impaired thymic selection was an underlying cause of the cGVHD syndrome. In conclusion, we report for the first time that the C57BL/6 into BALB.B combination is a representative model of cGVHD that evolves from immunologic events during the early post-transplant period.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Doença Enxerto-Hospedeiro/imunologia , Transplante de Células-Tronco Hematopoéticas , Antígenos de Histocompatibilidade/imunologia , Células Th17/imunologia , Animais , Linfócitos T CD8-Positivos/patologia , Doença Crônica , Modelos Animais de Doenças , Doença Enxerto-Hospedeiro/patologia , Camundongos , Camundongos Endogâmicos AKR , Camundongos Endogâmicos BALB C , Células Th17/patologiaRESUMO
Recently, an immunodeficiency syndrome caused by guanine-adenine-thymine-adenine 2 (GATA2) deficiency has been described. The syndrome is characterized by (i) typical onset in early adulthood, (ii) profound peripheral blood cytopenias of monocytes, B lymphocytes, and NK cells, (iii) distinct susceptibility to disseminated non-tuberculous mycobacterial (NTM) and other opportunistic infections (particularly human papillomavirus), and (iv) a high risk of developing hematologic malignancies (myelodysplastic syndromes (MDS); acute myeloid leukemias (AML)). Considerable clinical heterogeneity exists among patients with GATA2 deficiency, but once infectious symptoms occur or MDS/AML arises, survival declines significantly. Allogeneic hematopoietic cell transplantation (HCT) currently provides the only curative treatment option for both MDS/AML and dysfunctional immunity with life-threatening opportunistic infections. Strategies regarding timing of allogeneic HCT, antimicrobial prophylaxis and treatment, intensity of the preparative regimen, and optimal donor and graft source have not been clearly defined due to the rarity of the disease. Here, we provide a comprehensive analysis of the available literature and published case reports on the use of allogeneic HCT in patients with GATA2 deficiency. In addition, a case of a young woman with GATA2 deficiency, who developed an immune reconstitution inflammatory syndrome in her mycobacterial skin lesions post allogeneic HCT is presented and illustrates distinct problems encountered in this disease context.
Assuntos
Fator de Transcrição GATA2/deficiência , Transplante de Células-Tronco Hematopoéticas , Síndrome Inflamatória da Reconstituição Imune/etiologia , Síndromes de Imunodeficiência/terapia , Infecções por Mycobacterium não Tuberculosas/etiologia , Adolescente , Adulto , Aloenxertos , Criança , Pré-Escolar , Suscetibilidade a Doenças , Feminino , Humanos , Síndromes de Imunodeficiência/genética , Masculino , Pessoa de Meia-Idade , Infecções por Mycobacterium não Tuberculosas/imunologia , Infecções por Mycobacterium não Tuberculosas/patologia , Mycobacterium abscessus/isolamento & purificação , Síndromes Mielodisplásicas/etiologia , Transplante de Células-Tronco de Sangue Periférico , Embolia Pulmonar/etiologia , Úlcera Cutânea/etiologia , Verrugas/etiologia , Adulto JovemRESUMO
T cells are widely used to promote engraftment of hematopoietic stem cells (HSCs) during an allogeneic hematopoietic cell transplantation. Their role in overcoming barriers to HSC engraftment is thought to be particularly critical when patients receive reduced doses of preparative chemotherapy and/or radiation compared with standard transplantations. In this study, we sought to delineate the effects CD4+ cells on engraftment and blood formation in a model that simulates clinical hematopoietic cell transplantation by transplanting MHC-matched, minor histocompatibility-mismatched grafts composed of purified HSCs, HSCs plus bulk T cells, or HSCs plus T cell subsets into mice conditioned with low-dose irradiation. Grafts containing conventional CD4+ T cells caused marrow inflammation and inhibited HSC engraftment and blood formation. Posttransplantation, the marrows of HSCs plus CD4+ cell recipients contained IL-12-secreting CD11c+ cells and IFN-γ-expressing donor Th1 cells. In this setting, host HSCs arrested at the short-term stem cell stage and remained in the marrow in a quiescent cell cycling state (G0). As a consequence, donor HSCs failed to engraft and hematopoiesis was suppressed. Our data show that Th1 cells included in a hematopoietic allograft can negatively impact HSC activity, blood reconstitution, and engraftment of donor HSCs. This potential negative effect of donor T cells is not considered in clinical transplantation in which bulk T cells are transplanted. Our findings shed new light on the effects of CD4+ T cells on HSC biology and are applicable to other pathogenic states in which immune activation in the bone marrow occurs such as aplastic anemia and certain infectious conditions.
Assuntos
Células-Tronco Hematopoéticas/imunologia , Células-Tronco de Sangue Periférico/fisiologia , Células Th1/imunologia , Condicionamento Pré-Transplante , Animais , Transplante de Medula Óssea , Linfócitos T CD4-Positivos/imunologia , Ciclo Celular , Sobrevivência de Enxerto , Hematopoese , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Células-Tronco Hematopoéticas/fisiologia , Interferon gama/imunologia , Interleucina-12/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Células-Tronco de Sangue Periférico/imunologia , Doadores de Tecidos , Quimeras de TransplanteAssuntos
Injúria Renal Aguda/diagnóstico , Injúria Renal Aguda/etiologia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Creatinina/sangue , Leucemia Mieloide Aguda/complicações , Cuidados Pré-Operatórios , Adolescente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores , Feminino , Taxa de Filtração Glomerular , Transplante de Células-Tronco Hematopoéticas , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Cuidados Pré-Operatórios/efeitos adversos , Cuidados Pré-Operatórios/métodos , Prognóstico , Estudos Retrospectivos , Adulto JovemRESUMO
This brief communication reports on a patient with an exceedingly rare "8p11 (eight-p-eleven) myeloproliferative syndrome" (EMS) with CEP110-FGFR1 rearrangement who responded to treatment with the multi-tyrosine kinase inhibitor (TKI) dasatinib. Dasatinib improved quality of life substantially by increasing blood counts and reducing the need for transfusions. This report demonstrates that the second-generation TKI may provide a therapeutic option for elderly and frail EMS patients who cannot be offered aggressive therapy, including allogeneic hematopoietic cell transplantation. The Oncologist 2017;22:480-483.
Assuntos
Proteínas de Ciclo Celular/genética , Síndrome de Down/tratamento farmacológico , Reação Leucemoide/tratamento farmacológico , Neoplasias/tratamento farmacológico , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Cromossomos Humanos Par 8/genética , Dasatinibe/administração & dosagem , Síndrome de Down/genética , Síndrome de Down/patologia , Feminino , Humanos , Reação Leucemoide/genética , Reação Leucemoide/patologia , Pessoa de Meia-Idade , Neoplasias/genética , Neoplasias/patologia , Proteínas de Fusão Oncogênica/genética , Inibidores de Proteínas Quinases/administração & dosagem , Qualidade de Vida , Translocação Genética/genéticaRESUMO
Acute graft-versus-host disease (GVHD) is induced by alloreactivity of donor T cells toward host antigens presented on antigen-presenting cells (APCs). Apoptotic cells are capable of inducing tolerance by altering APC maturation. Apoptosis can be induced by extracorporeal photopheresis (ECP). We demonstrate that the use of ECP as a prophylaxis prior to conditioning significantly improves survival (P < .0001) after bone marrow transplantation (BMT) by inhibiting the initiation phase of acute GVHD in a murine BMT model. ECP-treated autologous splenocytes resulted in immune tolerance in the host, including reduced dendritic cell activation with decreased nuclear factor-κB engagement, increased regulatory T-cell (Treg) numbers with enhanced expression of cytolytic T lymphocyte-associated antigen 4, potentiating their suppressive function. The protective effect required host production of interleukin-10 and host Tregs. Conventional T cells that entered this tolerant environment experienced reduced proliferation, as well as a reduction of tissue homing and expression of activation markers. The induction of this tolerant state by ECP was obviated by cotreatment with lipopolysaccharide, suggesting that the inflammatory state of the recipient prior to treatment would play a role in potential clinical translation. The use of prophylactic ECP may provide an alternative and safe method for immunosuppression in the bone marrow transplant setting.
Assuntos
Células Apresentadoras de Antígenos/transplante , Apoptose , Doença Enxerto-Hospedeiro/prevenção & controle , Tolerância Imunológica , Animais , Células Apresentadoras de Antígenos/imunologia , Células Apresentadoras de Antígenos/patologia , Autoenxertos , Transplante de Medula Óssea , Modelos Animais de Doenças , Doença Enxerto-Hospedeiro/genética , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/patologia , Interleucina-10/genética , Interleucina-10/imunologia , Camundongos , Camundongos Endogâmicos AKR , Camundongos Endogâmicos BALB C , Camundongos Knockout , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/patologiaRESUMO
Total lymphoid irradiation (TLI) with antithymocyte globulin (ATG) is a unique regimen that prepares recipients for allogeneic hematopoietic cell transplantation by targeting lymph nodes, while sparing large areas of the bone marrow. TLI is reported to increase the frequency of CD4(+)CD25(+)FoxP3(+) T-regulatory cells (Treg) relative to conventional T cells. In this study, barriers to hematopoietic stem cell (HSC) engraftment following this nonmyeloablative conditioning were evaluated. TLI/ATG resulted in profound lymphoablation but endogenous host HSC remained. Initial donor HSC engraftment occurred only in radiation exposed marrow sites, but gradually distributed to bone marrow outside the radiation field. Sustained donor engraftment required host lymphoid cells insofar as lymphocyte deficient Rag2γc(-/-) recipients had unstable engraftment compared with wild-type. TLI/ATG treated wild-type recipients had increased proportions of Treg that were associated with increased HSC frequency and proliferation. In contrast, Rag2γc(-/-) recipients who lacked Treg did not. Adoptive transfer of Treg into Rag2γc(-/-) recipients resulted in increased cell cycling of endogenous HSC. Thus, we hypothesize that Treg influence donor engraftment post-TLI/ATG by increasing HSC cell cycling, thereby promoting the exit of host HSC from the marrow niche. Our study highlights the unique dynamics of donor hematopoiesis following TLI/ATG, and the effect of Treg on HSC activity.
Assuntos
Sobrevivência de Enxerto/imunologia , Hematopoese/imunologia , Linfócitos T Reguladores/imunologia , Condicionamento Pré-Transplante/métodos , Animais , Medula Óssea/imunologia , Medula Óssea/metabolismo , Medula Óssea/efeitos da radiação , Sobrevivência de Enxerto/genética , Hematopoese/genética , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/metabolismo , Tecido Linfoide/imunologia , Tecido Linfoide/efeitos da radiação , Camundongos , Camundongos Knockout , Linfócitos T Reguladores/metabolismo , Doadores de Tecidos , Quimeras de Transplante , Transplante HomólogoRESUMO
RATIONALE: Fibrosis is mediated partly by extracellular matrix-depositing fibroblasts in the heart. Although these mesenchymal cells are reported to have multiple embryonic origins, the functional consequence of this heterogeneity is unknown. OBJECTIVE: We sought to validate a panel of surface markers to prospectively identify cardiac fibroblasts. We elucidated the developmental origins of cardiac fibroblasts and characterized their corresponding phenotypes. We also determined proliferation rates of each developmental subset of fibroblasts after pressure overload injury. METHODS AND RESULTS: We showed that Thy1(+)CD45(-)CD31(-)CD11b(-)Ter119(-) cells constitute the majority of cardiac fibroblasts. We characterized these cells using flow cytometry, epifluorescence and confocal microscopy, and transcriptional profiling (using reverse transcription polymerase chain reaction and RNA-seq). We used lineage tracing, transplantation studies, and parabiosis to show that most adult cardiac fibroblasts derive from the epicardium, a minority arises from endothelial cells, and a small fraction from Pax3-expressing cells. We did not detect generation of cardiac fibroblasts by bone marrow or circulating cells. Interestingly, proliferation rates of fibroblast subsets on injury were identical, and the relative abundance of each lineage remained the same after injury. The anatomic distribution of fibroblast lineages also remained unchanged after pressure overload. Furthermore, RNA-seq analysis demonstrated that Tie2-derived and Tbx18-derived fibroblasts within each operation group exhibit similar gene expression profiles. CONCLUSIONS: The cellular expansion of cardiac fibroblasts after transaortic constriction surgery was not restricted to any single developmental subset. The parallel proliferation and activation of a heterogeneous population of fibroblasts on pressure overload could suggest that common signaling mechanisms stimulate their pathological response.
Assuntos
Linhagem da Célula , Proliferação de Células , Fibroblastos/citologia , Pericárdio/citologia , Animais , Antígenos CD/genética , Antígenos CD/metabolismo , Células da Medula Óssea/citologia , Células da Medula Óssea/metabolismo , Diferenciação Celular , Circulação Cruzada , Fibroblastos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/citologia , Miócitos Cardíacos/metabolismo , Fator de Transcrição PAX3 , Fatores de Transcrição Box Pareados/genética , Fatores de Transcrição Box Pareados/metabolismo , Pericárdio/crescimento & desenvolvimento , Receptor TIE-2/genética , Receptor TIE-2/metabolismo , Proteínas com Domínio T/genética , Proteínas com Domínio T/metabolismoRESUMO
Impaired immunity is a fundamental obstacle to successful allogeneic hematopoietic cell transplantation. Mature graft T cells are thought to provide protection from infections early after transplantation, but can cause life-threatening graft-vs.-host disease. Human CMV is a major pathogen after transplantation. We studied reactivity against the mouse homologue, murine CMV (MCMV), in lethally irradiated mice given allogeneic purified hematopoietic stem cells (HSCs) or HSCs supplemented with T cells or T-cell subsets. Unexpectedly, recipients of purified HSCs mounted superior antiviral responses compared with recipients of HSC plus unselected bulk T cells. Furthermore, supplementation of purified HSC grafts with CD8(+) memory or MCMV-specific T cells resulted in enhanced antiviral reactivity. Posttransplantation lymphopenia promoted massive expansion of MCMV-specific T cells when no competing donor T cells were present. In recipients of pure HSCs, naive and memory T cells and innate lymphoid cell populations developed. In contrast, the lymphoid pool in recipients of bulk T cells was dominated by effector memory cells. These studies show that pure HSC transplantations allow superior protective immunity against a viral pathogen compared with unselected mature T cells. This reductionist transplant model reveals the impact of graft composition on regeneration of host, newly generated, and mature transferred T cells, and underscores the deleterious effects of bulk donor T cells. Our findings lead us to conclude that grafts composed of purified HSCs provide an optimal platform for in vivo expansion of selected antigen-specific cells while allowing the reconstitution of a naive T-cell pool.
Assuntos
Epitopos/imunologia , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/citologia , Imunidade/imunologia , Linfócitos T/transplante , Animais , Linfócitos T CD8-Positivos/imunologia , Diferenciação Celular , Proliferação de Células , Modelos Animais de Doenças , Células-Tronco Hematopoéticas/metabolismo , Infecções por Herpesviridae/imunologia , Humanos , Imunização , Subpopulações de Linfócitos/imunologia , Linfopenia/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Muromegalovirus , Linfócitos T/citologia , Ativação Viral/imunologiaAssuntos
Transplante de Células-Tronco Hematopoéticas , Mieloma Múltiplo/terapia , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/mortalidade , Condicionamento Pré-Transplante , Transplante Homólogo , Resultado do TratamentoRESUMO
The hypomethylating agent 5-Azacytidine epigenetically modulates various genes, including tumor suppressor genes. For many years, the "new agent", which was first discovered in the 1960s, remained fairly unobtrusive in the rank of salvage treatment options for myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). When the significance of epigenetics in tumorigenesis became clear, 5-Azacytidine attracted new attention. Finally, it was the first drug approved for the treatment of all categories of MDS, and its survival benefit over best conventional care was confirmed. Today, in many clinical situations, when aggressive therapies including allogeneic hematopoietic cell transplantation are not an option, 5-Azacytidine is the first treatment of choice. Preliminary data on combinations of the hypomethylating agent with other new drugs are promising, and innovative strategies involving immune modulation and regenerative tissue repair hold a broad potential for future developments.
Assuntos
Antineoplásicos/uso terapêutico , Azacitidina/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Síndromes Mielodisplásicas/tratamento farmacológico , Animais , HumanosRESUMO
Because of the perception that depleting hematopoietic grafts of T cells will result in poorer immune recovery and in increased risk of graft rejection, pure hematopoietic stem cells (HSC), which avoid the potentially lethal complication of graft-versus-host disease (GVHD), have not been used for allogeneic hematopoietic cell transplantation (HCT) in humans. Ideal grafts should contain HSC plus mature cells that confer only the benefits of protection from pathogens and suppression of malignancies. This goal requires better understanding of the effects of each blood cell type and its interactions during engraftment and immune regeneration. Here, we studied hematopoietic reconstitution post-HCT, comparing grafts of purified HSC with grafts supplemented with T cells in a minor histocompatibility antigen (mHA)-mismatched mouse model. Cell counts, composition, and chimerism of blood and lymphoid organs were evaluated and followed intensively through the first month, and then subsequently for up to 1 yr. Throughout this period, recipients of pure HSC demonstrated superior total cell recovery and lymphoid reconstitution compared with recipients of T cell-containing grafts. In the latter, rapid expansion of T cells occurred, and suppression of hematopoiesis derived from donor HSC was observed. Our findings demonstrate that even early post-HCT, T cells retard donor HSC engraftment and immune recovery. These observations contradict the postulation that mature donor T cells provide important transient immunity and facilitate HSC engraftment.