RESUMO
Hematopoietic stem cell transplantation (HSCT) is curative for many non-malignant disorders. As HSCT and supportive care technologies improve, this life-saving treatment may be offered to more and more patients. With the development of new preparative regimens, expanded alternative donor availability, and graft manipulation techniques, there are many options when choosing the best regimen for patients. Herein the authors review transplant considerations, transplant goals, conditioning regimens, donor choice, and graft manipulation strategies for patients with non-malignant disorders undergoing HSCT.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Humanos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Doadores de Tecidos , Transplante Homólogo , Condicionamento Pré-Transplante , Doença Enxerto-Hospedeiro/etiologiaRESUMO
BACKGROUND AIMS: Allogeneic hematopoietic stem cell transplant is a curative approach for many malignant and non-malignant hematologic conditions. Despite advances in its prevention and treatment, the morbidity and mortality related to graft-versus-host disease (GVHD) remains. The mechanisms by which currently used pharmacologic agents impair the activation and proliferation of potentially alloreactive T cells reveal pathways essential for the detrimental activities of these cell populations. Importantly, these same pathways can be important in mediating the graft-versus-leukemia effect in recipients transplanted for malignant disease. This knowledge informs potential roles for cellular therapies such as mesenchymal stromal cells and regulatory T cells in preventing or treating GVHD. This article reviews the current state of adoptive cellular therapies focused on GVHD treatment. METHODS: We conducted a search for scientific literature in PubMed® and ongoing clinical trials in clinicaltrial.gov with the keywords "Graft-versus-Host Disease (GVHD)," "Cellular Therapies," "Regulatory T cells (Tregs)," "Mesenchymal Stromal (Stem) Cells (MSCs)," "Natural Killer (NK) Cells," "Myeloid-derived suppressor cells (MDSCs)," and "Regulatory B-Cells (B-regs)." All the published and available clinical studies were included. RESULTS: Although most of the existing clinical data focus on cellular therapies for GVHD prevention, there are observational and interventional clinical studies that explore the potential for cellular therapies to be safe modalities for GVHD treatment while maintaining the graft-versus-leukemia effect in the context of malignant diseases. However, there are multiple challenges that limit the broader use of these approaches in the clinical scenario. CONCLUSIONS: There are many ongoing clinical trials to date with the promise to expand our actual knowledge on the role of cellular therapies for GVHD treatment in an attempt to improve GVHD-related outcomes in the near future.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Leucemia , Neoplasias , Humanos , Doença Enxerto-Hospedeiro/terapia , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante Homólogo , Leucemia/terapia , Engenharia CelularRESUMO
Thalassemia and sickle cell disease (SCD) are the most common monogenic diseases in the world and represent a growing global health burden. Management is limited by a paucity of disease-modifying therapies; however, allogeneic hematopoietic stem cell transplantation (HSCT) and autologous HSCT after genetic modification offer patients a curative option. Allogeneic HSCT is limited by donor selection, morbidity and mortality from transplant conditioning, graft-versus-host disease and graft rejection, whereas significant concerns regarding long-term safety, efficacy and cost limit the broad applicability of gene therapy. Here the authors review current outcomes in allogeneic and autologous HSCT for transfusion-dependent thalassemia and SCD and provide our perspective on issues surrounding accessibility and costs as barriers to offering curative therapy to patients with hereditary hemoglobinopathies.
Assuntos
Anemia Falciforme , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Hemoglobinopatias , Talassemia beta , Anemia Falciforme/genética , Anemia Falciforme/terapia , Engenharia Celular , Terapia Genética , Doença Enxerto-Hospedeiro/terapia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Hemoglobinopatias/genética , Hemoglobinopatias/terapia , Humanos , Condicionamento Pré-Transplante , Talassemia beta/genética , Talassemia beta/terapiaRESUMO
Allogeneic stem cell transplantation is a potentially curative therapy for some malignant and non-malignant disease. There have been substantial advances since the approaches first introduced in the 1970s, and the development of approaches to transplant with HLA incompatible or alternative donors has improved access to transplant for those without a fully matched donor. However, success is still limited by morbidity and mortality from toxicity and imperfect disease control. Here we review our emerging understanding of how reconstitution of effective immunity after allogeneic transplant can protect from these events and improve outcomes. We provide perspective on milestones of immune reconstitution that are easily measured and modifiable.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Reconstituição Imune , Engenharia Celular , Humanos , Transplante HomólogoRESUMO
Despite recent advances in the field of HSCT, viral infections remain a frequent causeof morbidity and mortality among HSCT recipients. Adoptive transfer of viral specific T cells has been successfully used both as prophylaxis and treatment of viral infections in immunocompromised HSCT recipients. Increasingly, precise risk stratification of HSCT recipients with infectious complications should incorporate not only pretransplant clinical criteria, but milestones of immune reconstitution as well. These factors can better identify those at highest risk of morbidity and mortality and identify a population of HSCT recipients in whom adoptive therapy with viral specific T cells should be considered for either prophylaxis or second line treatment early after inadequate response to first line antiviral therapy. Broadening these approaches to improve outcomes for transplant recipients in countries with limited resources is a major challenge. While the principles of risk stratification can be applied, early detection of viral reactivation as well as treatment is challenging in regions where commercial PCR assays and antiviral agents are not readily available.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Viroses , Transferência Adotiva , Antivirais/uso terapêutico , Engenharia Celular , Terapia Genética , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Viroses/etiologia , Viroses/prevenção & controleRESUMO
There has been much effort to prioritize genomic variants with respect to their impact on "function". However, function is often not precisely defined: sometimes it is the disease association of a variant; on other occasions, it reflects a molecular effect on transcription or epigenetics. Here, we coupled multiple genomic predictors to build GRAM, a GeneRAlized Model, to predict a well-defined experimental target: the expression-modulating effect of a non-coding variant on its associated gene, in a transferable, cell-specific manner. Firstly, we performed feature engineering: using LASSO, a regularized linear model, we found transcription factor (TF) binding most predictive, especially for TFs that are hubs in the regulatory network; in contrast, evolutionary conservation, a popular feature in many other variant-impact predictors, has almost no contribution. Moreover, TF binding inferred from in vitro SELEX is as effective as that from in vivo ChIP-Seq. Second, we implemented GRAM integrating only SELEX features and expression profiles; thus, the program combines a universal regulatory score with an easily obtainable modifier reflecting the particular cell type. We benchmarked GRAM on large-scale MPRA datasets, achieving AUROC scores of 0.72 in GM12878 and 0.66 in a multi-cell line dataset. We then evaluated the performance of GRAM on targeted regions using luciferase assays in the MCF7 and K562 cell lines. We noted that changing the insertion position of the construct relative to the reporter gene gave very different results, highlighting the importance of carefully defining the exact prediction target of the model. Finally, we illustrated the utility of GRAM in fine-mapping causal variants and developed a practical software pipeline to carry this out. In particular, we demonstrated in specific examples how the pipeline could pinpoint variants that directly modulate gene expression within a larger linkage-disequilibrium block associated with a phenotype of interest (e.g., for an eQTL).
Assuntos
Regulação da Expressão Gênica/genética , Variação Genética/genética , Análise de Sequência de DNA/métodos , Algoritmos , Sítios de Ligação , Simulação por Computador , Previsões/métodos , Genômica/métodos , Humanos , Desequilíbrio de Ligação/genética , Modelos Genéticos , Ligação Proteica/genética , Locos de Características Quantitativas/genética , Software , Fatores de Transcrição/genéticaRESUMO
High-dose chemotherapy (HDT) followed by autologous hematopoietic stem cell transplantation (AHSCT) improves survival in patients with chemosensitive non-Hodgkin lymphoma (NHL). Determination of the Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) has contributed to improve patient selection while allowing for prediction of nonrelapse mortality. We previously demonstrated the efficacy and safety of AHSCT in a cohort of older patients with chemosensitive NHL. Quality of life following AHSCT still has not been widely evaluated. The goal of this study was to assess the long-term quality of life of elderly patients surviving AHSCT. This single-center, Research and Ethics Committee-approved study investigated QoL in survivors of AHSCT for the treatment of NHL in a cohort of older patients. Inclusion criteria were defined as patients age ≥60 years who underwent AHSCT for NHL between January 1, 2008, and January 1, 2015, at our center. Fifty-nine patients from the original cohort of 90 survived at a median of 50 months post-AHSCT. Forty-seven (79.7%) of those patients agreed to complete the QoL assessment questionnaires after the transplantation and are included in this report. All patients provided signed informed consent. We used the EQ-5D instrument to assess mobility, self-care, usual activities, pain/discomfort, and anxiety/depression and the Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) questionnaire to assess physical, social/family, emotional, and functional well-being and BMT-specific concerns. With both tools, a higher score indicates better QoL. Fifteen percent of patients were in relapse at the time of the QoL assessment. In the EQ-5D, few patients (9%) reported severe impairment, which requires significant negative effects in 4 or 5 domains. Lower Karnofsky Performance Status (KPS) score at the time of transplantation was negatively correlated with mobility (P= .001), self-care (P= .001), and usual activities (P= .007) dysfunction. Anxiety was significant for patients in relapsed after transplantation (P= .002). FACT-BMT questionnaire results demonstrated that physical, social, and emotional well-being were all well preserved after the transplantation, whereas functional well-being was more variable among patients. Relapse was associated with impaired functional well-being (P= .007) and lower total FACT-BMT score (P= .014). Other comparators, including the conditioning regimen, sex, age subgroups (<65 or ≥65 years), HCT-CI score, and disease status at transplantation, did not impact any of these outcomes. This study demonstrates that physical, social, and functional well-being are preserved in older patients following AHSCT. Low KPS score before AHSCT is a predictor of disability at distance from AHSCT. Relapse following AHSCT remains the most significant impediment to maintaining a good QoL. Innovative interventions to improve performance status before transplantation and measures to prevent relapse thereafter should be investigated to improve survival and QoL.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Linfoma não Hodgkin/mortalidade , Linfoma não Hodgkin/terapia , Qualidade de Vida , Idoso , Autoenxertos , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
Optimal cord blood (CB) unit selection is critical to maximize the likelihood of successful engraftment and survival after CB transplantation (CBT). However, unit selection can be complex because multiple characteristics must be considered including unit cell dose, donor-recipient human leukocyte antigen (HLA) match, and unit quality. This review provides evidence-based and experience-based comprehensive guidelines for CB unit selection. Topics addressed include the use of both the TNC and the CD34+ cell dose, as well as the CD34+ cell to TNC content ratio to evaluate unit progenitor cell content and engraftment potential, the acceptable TNC and CD34+ cell dose criteria that define an adequate single-unit graft, and the indication and acceptable cell dose criteria for double-unit grafts. The acceptable criteria for 6-loci (HLA-A, -B antigen, -DRB1 allele) and 8-allele (HLA-A, -B, -C, -DRB1) donor-recipient HLA match, the evaluation of patients with donor-specific HLA antibodies, and the multiple determinants of unit quality are also reviewed in detail. Finally, a practical step-by-step guide to CB searches and the principles that guide ultimate graft selection are outlined.
Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical , Transplante de Células-Tronco Hematopoéticas , Sangue Fetal , Antígenos HLA , Teste de Histocompatibilidade , Humanos , Doadores de TecidosRESUMO
Haplo-identical donors have been increasingly used as an alternative source of stem cells in patients with severe aplastic anemia in need of an allogeneic transplantation but lack a matched donor. Single cord blood (CB) transplant also offers a curative option for this disease, but few adult patients have been reported due to low number of progenitor cells leading to prolonged cytopenias and a high risk of infections. CB stem cell expansion may theoretically solve these pitfalls but has not been used previously in non-malignant diseases, likely due to fear of graft rejection and lack of availability of expanded CBs outside clinical trials. We report the first case of an adult patient with severe aplastic anemia who was successfully transplanted with a UM171-expanded CB graft. After a conditioning of rabbit antithymocyte globulin, fludarabine, cyclophosphamide, and total body irradiation, a UM171 expanded graft of 3.29 × 106 CD34 + cells/kg (a 51-fold increase) was infused. Full donor chimerism was observed on day + 14, with neutrophil and platelet engraftment on days + 23 and + 27. There was no severe infection or graft-vs-host disease. UM171-expanded grafts offer a valuable option for patients with aplastic anemia in need of transplantation but have no suitable donor.
Assuntos
Anemia Aplástica/terapia , Transplante de Células-Tronco de Sangue do Cordão Umbilical , Células-Tronco Hematopoéticas/efeitos dos fármacos , Indóis/farmacologia , Pirimidinas/farmacologia , Anemia Aplástica/diagnóstico , Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Rejeição de Enxerto , Sobrevivência de Enxerto , Humanos , Índice de Gravidade de Doença , Doadores de Tecidos , Condicionamento Pré-Transplante/métodos , Transplante Homólogo , Resultado do TratamentoRESUMO
BACKGROUND: Long-term survival in patients progressing after tandem autologous-allogeneic stem cell transplant (SCT) has been reported, suggesting a persistent graft-vs-myeloma (GvM) effect even after post-transplant progression. METHODS: In order to confirm this observation, we updated the results of our previously published cohort of 92 newly diagnosed myeloma patients who received tandem transplant and compared them with 81 contemporary patients who received autologous transplant only. RESULTS: With a median follow-up of 13.1 and 10.2 years, respectively, median overall survival (OS) in the tandem group has not been reached, compared with 6.1 years after auto-SCT (P ≤ .001). Disease progression occurred less frequently after tandem transplant, with an estimated 10-year cumulative incidence of 49% vs 76% (P ≤ .001). Cumulative incidence of extensive chronic graft-vs-host disease (cGVHD) was high at 83%, with modest benefits on OS (60% vs 49%, P = .550) but sharp improvement of progression-free survival (PFS; 55% vs 10%, P = .002) at 10 years associated with development of cGVHD. After first progression, median OS was 5.8 years in tandem and 5.2 years in the auto-group (P = .062); median PFS was also similar. CONCLUSION: Despite confirmation of better outcomes after upfront tandem transplant, our data do not support persistence of a strong, clinically significant graft-vs-myeloma effect after first progression, emphasizing the need to better characterize the GvM effect.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Mieloma Múltiplo , Autoenxertos , Intervalo Livre de Doença , Humanos , Mieloma Múltiplo/terapia , Recidiva Local de Neoplasia , Transplante de Células-Tronco , Transplante Autólogo , Transplante Homólogo , Resultado do TratamentoRESUMO
Graft-versus-host disease (GVHD) is a major cause of transplant-related mortality (TRM) after allogeneic haematopoietic stem cell transplantation (HSCT) and presents a challenge in haploidentical HSCT. GVHD may be prevented by ex vivo graft T-cell depletion or in vivo depletion of proliferating lymphocytes. However, both approaches pose significant risks, particularly infections and relapse, compromising survival. A photodepletion strategy to eliminate alloreactive T cells from mismatched donor lymphocyte infusions (enabling administration without immunosuppression), was used to develop ATIR101, an adjunctive therapy for use after haploidentical HSCT. In this phase I dose-finding study, 19 adults (median age: 54 years) with high-risk haematological malignancies were treated with T-cell-depleted human leucocyte antigen-haploidentical myeloablative HSCT followed by ATIR101 at doses of 1 × 104 -5 × 106 CD3+ cells/kg (median 31 days post-transplant). No patient received post-transplant immunosuppression or developed grade III/IV acute GVHD, demonstrating the feasibility of ATIR101 infusion for evaluation in two subsequent phase 2 studies. Additionally, we report long-term follow -up of patients treated with ATIR101 in this study. At 1 year, all 9 patients receiving doses of 0·3-2 × 106 CD3+ cells/kg ATIR101 remained free of serious infections and after more than 8 years, TRM was 0%, relapse-related mortality was 33% and overall survival was 67% in these patients.
Assuntos
Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Imunoterapia/métodos , Linfócitos T/metabolismo , Condicionamento Pré-Transplante/efeitos adversos , Adulto , Feminino , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Condicionamento Pré-Transplante/métodosRESUMO
UNLABELLED: Antibodies (Abs) specific for the V3 loop of the HIV-1 gp120 envelope neutralize most tier 1 and many tier 2 viruses and are present in essentially all HIV-infected individuals as well as immunized humans and animals. Vaccine-induced V3 Abs are associated with reduced HIV infection rates in humans and affect the nature of transmitted viruses in infected vaccinees, despite the fact that V3 is often occluded in the envelope trimer. Here, we link structural and experimental data showing how conformational alterations of the envelope trimer render viruses exceptionally sensitive to V3 Abs. The experiments interrogated the neutralization sensitivity of pseudoviruses with single amino acid mutations in various regions of gp120 that were predicted to alter packing of the V3 loop in the Env trimer. The results indicate that the V3 loop is metastable in the envelope trimer on the virion surface, flickering between states in which V3 is either occluded or available for binding to chemokine receptors (leading to infection) and to V3 Abs (leading to virus neutralization). The spring-loaded V3 in the envelope trimer is easily released by disruption of the stability of the V3 pocket in the unliganded trimer or disruption of favorable V3/pocket interactions. Formation of the V3 pocket requires appropriate positioning of the V1V2 domain, which is, in turn, dependent on the conformation of the bridging sheet and on the stability of the V1V2 B-C strand-connecting loop. IMPORTANCE: The levels of antibodies to the third variable region (V3) of the HIV envelope protein correlate with reduced HIV infection rates. Previous studies showed that V3 is often occluded, as it sits in a pocket of the envelope trimer on the surface of virions; however, the trimer is flexible, allowing occluded portions of the envelope (like V3) to flicker into an exposed position that binds antibodies. Here we provide a systematic interrogation of mechanisms by which single amino acid changes in various regions of gp120 (i) render viruses sensitive to neutralization by V3 antibodies, (ii) result in altered packing of the V3 loop, and (iii) activate an open conformation that exposes V3 to the effects of V3 Abs. Taken together, these and previous studies explain how V3 antibodies can protect against HIV-1 infection and why they should be one of the targets of vaccine-induced antibodies.
Assuntos
Anticorpos Neutralizantes/imunologia , Anticorpos Anti-HIV/imunologia , Proteína gp120 do Envelope de HIV/imunologia , HIV-1/imunologia , Substituição de Aminoácidos , Proteína gp120 do Envelope de HIV/química , Proteína gp120 do Envelope de HIV/genética , HIV-1/química , HIV-1/genética , Modelos Moleculares , Proteínas Mutantes/química , Proteínas Mutantes/genética , Proteínas Mutantes/imunologia , Conformação ProteicaRESUMO
BACKGROUND: Clostridium difficile infection (CDI) is a significant complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Our primary objective was to determine risk factors for the development of CDI during the first year following allo-HSCT. METHODS: A matched case-control study nested in a cohort of allo-HSCT at a single hospital in Montréal, Québec, Canada, was conducted from 2002 through 2011. RESULTS: Sixty-five of 760 patients who underwent allo-HSCT between 2002 and 2011 developed CDI, representing an incidence of 8.6%. We selected 123 controls matched for year of transplant for risk factor analyses. In the multivariable analysis, receipt of trimethoprim-sulfamethoxazole (TMP-SMX) prior to transplantation (adjusted odds ratio [aOR] 0.07, 95% confidence interval [CI] 0.02-0.27), mucositis (aOR 5.90, 95% CI 2.08-16.72), and reactivation of cytomegalovirus (CMV) (aOR 6.17, 95% CI 2.17-17.57) and of other Herpesviridae viruses (aOR 3.04, 95% CI 1.13-8.16) were the variables that remained statistically associated with CDI. High-risk antibiotic use in the late post-transplant period (aOR 7.63, 95% CI 2.14-27.22) was associated with development of late CDI. CONCLUSION: This study revealed reactivation of CMV and other Herpesviridae viruses as novel risk factors for CDI. Administration of TMP-SMX prior to transplantation was independently associated with a decreased risk of CDI. Early and late CDI after HSCT may have distinct risk factors.
Assuntos
Clostridioides difficile/isolamento & purificação , Infecções por Clostridium/epidemiologia , Infecções por Citomegalovirus/complicações , Citomegalovirus/fisiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Ativação Viral , Adulto , Antibacterianos/administração & dosagem , Antibacterianos/uso terapêutico , Estudos de Casos e Controles , Infecções por Clostridium/complicações , Infecções por Clostridium/prevenção & controle , Citomegalovirus/isolamento & purificação , Infecções por Citomegalovirus/virologia , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Mucosite/complicações , Quebeque/epidemiologia , Estudos Retrospectivos , Fatores de Risco , Condicionamento Pré-Transplante/métodos , Transplante Homólogo/efeitos adversos , Combinação Trimetoprima e Sulfametoxazol/administração & dosagem , Combinação Trimetoprima e Sulfametoxazol/uso terapêuticoRESUMO
UNLABELLED: The V3 region of HIV-1 gp120 is important for virus-coreceptor interaction and highly immunogenic. Although most anti-V3 antibodies neutralize only the sensitive tier 1 viruses, anti-V3 antibodies effective against the more resistant viruses exist, and a better understanding of these antibodies and their epitopes would be beneficial for the development of novel vaccine immunogens against HIV. The HIV-1 isolate JRFL with its cryptic V3 is resistant to most V3-specific monoclonal antibodies (MAbs). However, the V3 MAb 2424 achieves 100% neutralization against JRFL. 2424 is encoded by IGHV3-53 and IGLV2-28 genes, a pairing rarely used by the other V3 MAbs. 2424 also has distinct binding and neutralization profiles. Studies of 2424-mediated neutralization of JRFL produced with a mannosidase inhibitor further revealed that its neutralizing activity is unaffected by the glycan composition of the virus envelope. To understand the distinct activity of 2424, we determined the crystal structure of 2424 Fab in complex with a JRFL V3 peptide and showed that the 2424 epitope is located at the tip of the V3 crown ((307)IHIGPGRAFYT(319)), dominated by interactions with His(P308), Pro(P313), and Arg(P315). The binding mode of 2424 is similar to that of the well-characterized MAb 447-52D, although 2424 is more side chain dependent. The 2424 epitope is focused on the very apex of V3, away from nearby glycans, facilitating antibody access. This feature distinguishes the 2424 epitope from the other V3 crown epitopes and indicates that the tip of V3 is a potential site to target and incorporate into HIV vaccine immunogens. IMPORTANCE: HIV/AIDS vaccines are crucial for controlling the HIV epidemics that continue to afflict millions of people worldwide. However, HIV vaccine development has been hampered by significant scientific challenges, one of which is the inability of HIV vaccine candidates evaluated thus far to elicit production of potent and broadly neutralizing antibodies. The V3 loop is one of the few immunogenic targets on the virus envelope glycoprotein that can induce neutralizing antibodies, but in many viruses, parts of V3 are inaccessible for antibody recognition. This study examined a V3-specific monoclonal antibody that can completely neutralize HIV-1 JRFL, a virus isolate resistant to most V3 antibodies. Our data reveal that this antibody recognizes the most distal tip of V3, which is not as occluded as other parts of V3. Hence, the epitope of 2424 is in one of the vulnerable sites on the virus that may be exploited in designing HIV vaccine immunogens.
Assuntos
Anticorpos Monoclonais/imunologia , Anticorpos Neutralizantes/imunologia , Anticorpos Anti-HIV/imunologia , Proteína gp120 do Envelope de HIV/imunologia , HIV-1/imunologia , Vacinas contra a AIDS/imunologia , Anticorpos Monoclonais/ultraestrutura , Especificidade de Anticorpos/imunologia , Linhagem Celular , Cristalografia por Raios X , Epitopos/imunologia , Células HEK293 , Antígenos HIV/imunologia , Humanos , Fragmentos Fab das Imunoglobulinas/imunologia , Fragmentos Fab das Imunoglobulinas/ultraestrutura , Manosidases/antagonistas & inibidores , Dados de Sequência Molecular , Polissacarídeos/imunologia , Estrutura Terciária de ProteínaRESUMO
PURPOSE OF REVIEW: Hematopoietic stem and progenitor cell (HSPC) transplantation is frequently used in the treatment of hematological diseases. The outcome of the procedure is strongly influenced by the quantity of injected cells, especially if low cell numbers are infused as frequently encountered with cord blood transplants. Ex-vivo expansion of cord blood HSPCs would increase cell numbers, thus accelerating engraftment and reducing infectious complications and transplant-related mortality. In addition, expansion would maximize accessibility to better HLA-matched units, further improving patients' outcome. Similarly, in-vitro maintenance or expansion of leukemic stem cells (LSCs) would enable research into the much awaited targeted therapies that spare normal hematopoietic stem cells (HSCs). Here, we review recent findings on small molecules (excluding biologicals) regulating the activity of normal and leukemic stem cells and provide insights into basic science and clinical implications. RECENT FINDINGS: High-throughput screening of small molecules active on primary hematopoietic cells has led to the identification of two potent series of chemical compounds, best exemplified by StemRegenin1 and UM171, that both expand HSPCs. Current data suggest that the aryl hydrocarbon receptor antagonist StemRegenin1 is most active on primitive normal hematopoietic progenitors and LSCs and that UM171 expands long-term normal HSCs. SUMMARY: Small molecules are clinically useful and powerful tools for expanding HSPCs. They are also of potential value for dissecting the still elusive regulatory networks that govern self-renewal of human HSCs.
Assuntos
Sangue Fetal/efeitos dos fármacos , Células-Tronco Hematopoéticas/efeitos dos fármacos , Indóis/farmacologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Purinas/farmacologia , Pirimidinas/farmacologia , Contagem de Células , Técnicas de Cultura de Células , Proliferação de Células/efeitos dos fármacos , Sangue Fetal/citologia , Sangue Fetal/metabolismo , Regulação da Expressão Gênica , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/metabolismo , Ensaios de Triagem em Larga Escala , Humanos , Leucemia/genética , Leucemia/metabolismo , Leucemia/patologia , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Receptores de Hidrocarboneto Arílico/antagonistas & inibidores , Receptores de Hidrocarboneto Arílico/genética , Receptores de Hidrocarboneto Arílico/metabolismo , Transdução de SinaisRESUMO
Robust ex vivo expansion of umbilical cord blood (UCB) derived hematopoietic stem and progenitor cells (HSPCs) should enable the widespread use of UCB as a source of cells to treat hematologic and immune diseases. Novel approaches for HSPC expansion have recently been developed, setting the stage for the production of blood stem cell derived products that fulfill our current best known criteria of clinical relevance. Translating these technologies into clinical use requires bioengineering strategies to overcome challenges of scale-up, reproducibility, and product quality assurance. Clinical-scale implementation should also define criteria and targets for cost-effective cell manufacturing. As production strategies become more effective, new opportunities in the therapeutic use of ex vivo expanded hematopoietic cell products will emerge. Herein we examine key technological milestones that need to be met in order to move ex vivo expanded HSPC therapies from the bench-top to the bedside in a robust and reliable manner.
Assuntos
Sangue Fetal/citologia , Células-Tronco Hematopoéticas/citologia , Pesquisa Translacional Biomédica , Proliferação de Células , Células-Tronco Hematopoéticas/metabolismo , Humanos , Controle de Qualidade , Padrões de ReferênciaRESUMO
The role of allogeneic (allo-) and autologous stem cell transplantation (auto-SCT) in the management of patients with transformed indolent nonfollicular non-Hodgkin lymphoma is unknown. This is a multicenter, retrospective cohort study of patients with biopsy-proven indolent B cell nonfollicular non-Hodgkin lymphoma and simultaneous or subsequent biopsy-proven aggressive histology transformation who were treated with allo-SCT or auto-SCT between 1996 and 2013. All patients received myeloablative conditioning regimens. Outcomes were compared with a cohort of 246 patients with transformed follicular lymphoma who also underwent allo-SCT (n = 47) or auto-SCT (n = 199) across the same institutions and time frame. Thirty-four patients were identified with the following underlying indolent histologies: 15 (44%) marginal zone lymphoma, 11 (32%) chronic lymphocytic leukemia, 6 (18%) small lymphocytic lymphoma, and 2 (6%) lymphoplasmacytic lymphoma. Patients received various anthracycline or platinum-containing chemotherapy regimens for transformation, incorporating rituximab in 25 (74%). Twelve (35%) subsequently underwent allo-SCT, whereas 33 (65%) underwent auto-SCT. The 3-year overall survival rate after transplantation was 67% (allo-SCT 54%, auto-SCT 74%), and 3-year progression-free survival rate was 49% (allo-SCT 40%, auto-SCT 54%). The 3-year nonrelapse mortality rate was 14% (allo-SCT 15%, auto-SCT 7%). Transplant-related mortality at 100 days was 17% for allo-SCT and 0% for auto-SCT. Adjusted for type of stem cell transplantation, 3-year overall survival, progression-free survival, and nonrelapse mortality rates were similar to those of patients with transformed follicular lymphoma receiving allo-SCT and auto-SCT (P = .38, P = .69, and P = .54, respectively). Allo-SCT and auto-SCT may be reasonable treatments for selected patients with transformed nonfollicular indolent lymphoma, although medium-term outcomes and toxicity appear to be more favorable with auto-SCT.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/métodos , Linfoma de Células B/terapia , Adulto , Idoso , Antraciclinas/administração & dosagem , Anticorpos Monoclonais Murinos/administração & dosagem , Estudos de Coortes , Terapia Combinada , Intervalo Livre de Doença , Feminino , Humanos , Linfoma de Células B/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Compostos Organoplatínicos/administração & dosagem , Estudos Retrospectivos , Rituximab , Taxa de Sobrevida , Condicionamento Pré-Transplante , Resultado do TratamentoRESUMO
Melanocytes may assume unique shapes and sizes but rarely have clear cytoplasm. We studied 28 melanocytic lesions that contained clear-cell melanocytes of the balloon-cell and sebocyte-like types. Clear-cell melanocytes were found more commonly in females (64%) than in males (36%), with predominance in females younger than 50 years (79%) and predominance in males older than 50 years (67%). They were distributed evenly throughout the body but were not found on acral sites. Clear-cell melanocytes were most prevalent in congenital nevi (18 or 72%) but were also found in 5 Clark nevi, 2 Meischer nevi, 1 Unna nevus, 1 atypical intra-epidermal proliferation, and 1 melanoma. The clear cells were distributed diffusely in 86% of the lesions and focally in 14%. The overall percentage of clear-cell melanocytes was 56%. The percentage of balloon cells was 57% and sebocyte-like melanocytes 32%. Clear cells with morphologic features of both balloon cells and sebocyte-like melanocytes, that is, intermediate cells, were present in all lesions with an overall percentage of 12%. The presence of melanocytes of both the balloon-cell and sebocyte-like types and the finding of clear-cell melanocytes with intermediate features in all lesions lends support to the theory that balloon-cell and sebocyte-like melanocytes may represent morphologic expressions of the same alteration in melanogenesis.
Assuntos
Melanócitos/patologia , Neoplasias Cutâneas/patologia , Adolescente , Adulto , Idoso , Feminino , Humanos , Masculino , Melanoma/patologia , Pessoa de Meia-Idade , Nevo/patologia , Lesões Pré-Cancerosas/patologia , Adulto JovemRESUMO
Graft-versus-host disease (GVHD) remains a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). Measures developed that have significantly reduced GVHD were also frequently associated with an increased risk of relapse. GVHD and graft-versus-tumor (GVT) effects are tightly linked, and balance between both reactions is difficult to achieve. To have an impact on the outcome and quality of life after HSCT, improvements in current strategies to prevent and treat GVHD while preserving the GVT effect are clearly needed. Sirolimus (rapamycin) is a lipophilic macrocytic lactone with immunosuppressive, antitumor, and antiviral properties. Because of its multiple modes of activities, it is being increasingly used in the management of GVHD. This review aims to summarize its mechanisms of action and potential advantages over other immunosuppressors and to analyze the most relevant studies investigating its role in both prevention and treatment of GVHD.
Assuntos
Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas , Imunossupressores/uso terapêutico , Sirolimo/uso terapêutico , Feminino , Doença Enxerto-Hospedeiro/mortalidade , Doença Enxerto-Hospedeiro/patologia , Efeito Enxerto vs Tumor/efeitos dos fármacos , Humanos , Masculino , Recidiva , Transplante HomólogoRESUMO
High-dose chemotherapy with autologous stem cell transplantation (ASCT) remains the standard of care for patients with multiple myeloma. Outpatient ASCT can be an attractive option given wait times and costs associated with inpatient procedures. We initiated an outpatient transplantation protocol in 2006. Patients were treated at a university hospital outpatient clinic that was open 5 days a week. The present study investigated safety and cost-effectiveness of the outpatient program. Ninety-one patients underwent ASCT between 2006 and 2010. The majority of patients (77%) had Durie-Salmon stage III disease; 38% had 1 or more comorbidities. Seventy-six patients (84%) were hospitalized during the first 100 days, mainly for febrile neutropenia (n = 71). Overall survival at day 100 was 100%. No patient was admitted to an intensive care unit. Risk factors for prolonged hospitalization (longer than 7 days) were disease stage IIB or higher and age >60 years. The cost savings was $19,522 (Canadian dollars) per patient compared with inpatient ASCT, for an annual savings of approximately $740,000. In summary, outpatient ASCT performed in a weekday clinic for patients with multiple myeloma appears to be safe and cost-effective, but is associated with a relatively high hospitalization rate.