RESUMO
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive myeloid malignancy of the dendritic cell lineage that affects patients of all ages, though the incidence appears to be highest in patients over the age of 60 years. Diagnosis is based on the presence of plasmacytoid dendritic cell precursors expressing CD123, the interleukin-3 (IL-3) receptor alpha, and a distinct histologic appearance. Timely diagnosis remains a challenge, due to lack of disease awareness and overlapping biologic and clinical features with other hematologic malignancies. Prognosis is poor with a median overall survival of 8 to 14 months, irrespective of disease presentation pattern. Historically, the principal treatment was remission induction therapy followed by a stem cell transplant (SCT) in eligible patients. However, bridging to SCT is often not achieved with induction chemotherapy regimens. The discovery that CD123 is universally expressed in BPDCN and is considered to have a pathogenetic role in its development paved the way for the successful introduction of tagraxofusp, a recombinant human IL-3 fused to a truncated diphtheria toxin payload, as an initial treatment for BPDCN. Tagraxofusp was approved in 2018 by the United States Food and Drug Administration for the treatment of patients aged 2 years and older with newly diagnosed and relapsed/refractory BPDCN, and by the European Medicines Agency in 2021 for first-line treatment of adults. The advent of tagraxofusp has opened a new era of precision oncology in the treatment of BPDCN. Herein, we present an overview of BPDCN biology, its diagnosis, and treatment options, illustrated by clinical cases.
Assuntos
Neoplasias Hematológicas , Transtornos Mieloproliferativos , Neoplasias Cutâneas , Adulto , Humanos , Pessoa de Meia-Idade , Subunidade alfa de Receptor de Interleucina-3 , Interleucina-3/uso terapêutico , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/tratamento farmacológico , Medicina de Precisão , Doença Aguda , Transtornos Mieloproliferativos/patologia , Neoplasias Cutâneas/patologia , Células Dendríticas/patologia , BiologiaRESUMO
Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults. Due to the development of drug resistance to traditional chemotherapies and high relapse rate, AML still has a low survival rate and there is in an urgent need for better treatment strategies. CD123 is widely expressed by AML cells, also associated with the poor prognosis of AML. In this study, we fabricated nanomicelles loaded with a lab-designed CD123 antagonistic peptide, which were referred to as mPO-6. The antagonistic and therapeutic effects were investigated with CD123+ AML cell lines and a refractory AML mouse (AE and CKITD816V) model. Results show that mPO-6 can specifically bind to the CD123+ AML cells and inhibit the cell viability effectively. Intravenous administration of mPO-6 significantly reduces the percentage of AML cells' infiltration and prolongs the median survival of AML mice. Further, the efficiency of mPO-6 is demonstrated to interfere with the axis of CD123/IL-3 via regulating the activation of STAT5, PI3K/AKT, and NF-κB signaling pathways related to cell proliferation or apoptosis at the level of mRNA and protein in vivo and in vitro. In conclusion, the novel CD123 antagonistic peptide micelle formulation mPO-6 can significantly enhance apoptosis and prolong the survival of AML mice by effectively interfering with the axis of CD123/IL-3 and therefore is a promising therapeutic candidate for the treatment of refractory AML.
Assuntos
Subunidade alfa de Receptor de Interleucina-3 , Leucemia Mieloide Aguda , Animais , Proliferação de Células , Interleucina-3/farmacologia , Interleucina-3/uso terapêutico , Subunidade alfa de Receptor de Interleucina-3/metabolismo , Subunidade alfa de Receptor de Interleucina-3/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Camundongos , Fosfatidilinositol 3-QuinasesRESUMO
Tagraxofusp (tagraxofusp-erzs) [Elzonris™] is an intravenously administered CD123-directed cytotoxin (composed of human interleukin-3 and a truncated diphtheria toxin payload) that was developed by Stemline Therapeutics, Inc. for the treatment of blastic plasmacytoid dendritic cell neoplasm (BPDCN). In December 2018, tagraxofusp received its first global approval in the USA for the treatment of BPDCN in adults and in paediatric patients aged 2 years and older. A centralized registration application for the use of tagraxofusp in patients with BPDCN is under review in the EU. This article summarizes the milestones in the development of tagraxofusp leading to its first global approval for the treatment of BPDCN.
Assuntos
Antineoplásicos/farmacocinética , Toxina Diftérica/farmacocinética , Interleucina-3/farmacocinética , Neoplasias Cutâneas/tratamento farmacológico , Administração Intravenosa , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Criança , Pré-Escolar , Toxina Diftérica/administração & dosagem , Toxina Diftérica/efeitos adversos , Toxina Diftérica/uso terapêutico , Aprovação de Drogas , Feminino , Humanos , Interleucina-3/administração & dosagem , Interleucina-3/efeitos adversos , Interleucina-3/uso terapêutico , Subunidade alfa de Receptor de Interleucina-3/metabolismo , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular/métodos , Resultado do Tratamento , Estados Unidos , United States Food and Drug Administration , Adulto JovemRESUMO
Osteoarthritis (OA) is a chronic disease of articular joints that leads to degeneration of both cartilage and subchondral bone. These degenerative changes are further aggravated by proinflammatory cytokines including IL-1ß and TNF-α. Previously, we have reported that IL-3, a cytokine secreted by activated T cells, protects cartilage and bone damage in murine models of inflammatory and rheumatoid arthritis. However, how IL-3 protects cartilage degeneration is not yet known. In this study, we investigated the role of IL-3 on cartilage degeneration under both in vitro and in vivo conditions. We found that both mouse and human chondrocytes show strong expression of IL-3R at gene and protein levels. IL-3 increases the expression of mouse chondrocyte-specific genes, Sox9 and collagen type IIa, which were downregulated by IL-1ß. Moreover, IL-3 downregulated IL-1ß- and TNF-α-induced expression of matrix metalloproteinases in both mouse and human chondrocytes. Interestingly, IL-3 reduces the degeneration of articular cartilage and subchondral bone microarchitecture in a mouse model of human OA. Moreover, IL-3 showed the preventive and therapeutic effects on cartilage degeneration induced by IL-1ß in micromass pellet cultures of human mesenchymal stem cells. Thus, to our knowledge, we provide the first evidence that IL-3 has therapeutic potential in amelioration of degeneration of articular cartilage and subchondral bone microarchitecture associated with OA.
Assuntos
Cartilagem Articular/patologia , Regulação para Baixo , Interleucina-3/uso terapêutico , Metaloproteinases da Matriz/genética , Osteoartrite/tratamento farmacológico , Animais , Cartilagem Articular/efeitos dos fármacos , Cartilagem Articular/imunologia , Células Cultivadas , Condrócitos/efeitos dos fármacos , Condrócitos/imunologia , Colágeno Tipo II/genética , Colágeno Tipo II/metabolismo , Modelos Animais de Doenças , Humanos , Interleucina-1beta/farmacologia , Interleucina-3/administração & dosagem , Interleucina-3/farmacologia , Subunidade alfa de Receptor de Interleucina-3/genética , Subunidade alfa de Receptor de Interleucina-3/metabolismo , Metaloproteinases da Matriz/metabolismo , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/imunologia , Camundongos , Osteoartrite/imunologia , Osteoartrite/fisiopatologia , Fatores de Transcrição SOX9/genética , Fatores de Transcrição SOX9/metabolismo , Fator de Necrose Tumoral alfa/farmacologiaRESUMO
This is the first prospective study of treatment of patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN), an aggressive hematologic malignancy derived from plasmacytoid dendritic cells that typically involves the skin and rapidly progresses to a leukemia phase. Despite being initially responsive to intensive combination chemotherapy, most patients relapse and succumb to their disease. Because BPDCN blasts overexpress the interleukin-3 receptor (IL3R), the activity of SL-401, diptheria toxin (DT)388IL3 composed of the catalytic and translocation domains of DT fused to IL3, was evaluated in BPDCN patients in a phase 1-2 study. Eleven patients were treated with a single course of SL-401 at 12.5 µg/kg intravenously over 15 minutes daily for up to 5 doses; 3 patients who had initial responses to SL-401 received a second course in relapse. The most common adverse events including fever, chills, hypotension, edema, hypoalbuminemia, thrombocytopenia, and transaminasemia were transient. Seven of 9 evaluable (78%) BPDCN patients had major responses including 5 complete responses and 2 partial responses after a single course of SL-401. The median duration of responses was 5 months (range, 1-20+ months). Further studies of SL-401 in BPDCN including those involving multiple sequential courses, alternate schedules, and combinations with other therapeutics are warranted. This trial is registered at clinicaltrials.gov as #NCT00397579.
Assuntos
Células Dendríticas/patologia , Neoplasias Hematológicas/patologia , Neoplasias Hematológicas/terapia , Receptores de Interleucina-3/antagonistas & inibidores , Proteínas Recombinantes de Fusão/uso terapêutico , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/terapia , Adulto , Idoso , Células Dendríticas/imunologia , Toxina Diftérica/administração & dosagem , Toxina Diftérica/efeitos adversos , Toxina Diftérica/uso terapêutico , Neoplasias Hematológicas/imunologia , Humanos , Interleucina-3/administração & dosagem , Interleucina-3/efeitos adversos , Interleucina-3/uso terapêutico , Masculino , Terapia de Alvo Molecular , Estudos Prospectivos , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/efeitos adversos , Neoplasias Cutâneas/imunologia , Resultado do TratamentoRESUMO
This article concisely summarizes data on the action of one of the principal and best known growth factors, the granulocyte colony-stimulating factor (G-CSF), in a mammalian organism exposed to radiation doses inducing acute radiation syndrome. Highlighted are the topics of its real or anticipated use in radiation accident victims, the timing of its administration, the possibilities of combining G-CSF with other drugs, the ability of other agents to stimulate endogenous G-CSF production, as well as of the capability of this growth factor to ameliorate not only the bone marrow radiation syndrome but also the gastrointestinal radiation syndrome. G-CSF is one of the pivotal drugs in the treatment of radiation accident victims and its employment in this indication can be expected to remain or even grow in the future.
Assuntos
Síndrome Aguda da Radiação/tratamento farmacológico , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Síndrome Aguda da Radiação/patologia , Animais , Medula Óssea/patologia , Medula Óssea/efeitos da radiação , Esquema de Medicação , Quimioterapia Combinada , Fator Estimulador de Colônias de Granulócitos/biossíntese , Humanos , Interleucina-3/uso terapêutico , Proteínas de Membrana/uso terapêutico , Liberação Nociva de Radioativos , Proteínas Recombinantes/uso terapêutico , Fator de Células-Tronco/uso terapêutico , Trombopoetina/uso terapêutico , Fatores de TempoRESUMO
We have re-evaluated the benefit of using erythropoietin (Epo) as a pleiotropic cytokine to counteract hematological and extra-hematological toxicity following lethal irradiation. B6D2F1 mice were exposed to a dose of 9 Gy gamma radiation resulting in 90% mortality at 30 days, and then injected with stem cell factor, FLT-3 ligand, thrombopoietin and interleukin-3 [i.e. SFT3] at two and 24 hours with or without Epo (1,000 IU/kg) at 2 hours and day 8. As controls, two groups of irradiated mice were given only Epo or Phosphate-buffered saline. Epo synergized with SFT3 to rescue lethally-irradiated mice from radiation-induced death (survival: 60%, 95% and 5% respectively for SFT3, SFT3+Epo and controls at 30 days, p<0.05), whereas Epo alone exhibited no protective effect. Hematopoietic parameters did not differ significantly between SFT3 and SFT3+Epo groups during the animal death period. Some beneficial effects on gastro-intestinal toxicity were noticed following administration of Epo, although lung, liver and kidney were not protected. Further studies are necessary to understand fully the mechanisms involved in these effects of Epo in order to optimize treatment with cytokines following high-dose irradiation.
Assuntos
Citocinas/uso terapêutico , Eritropoetina/uso terapêutico , Lesões por Radiação/tratamento farmacológico , Protetores contra Radiação/uso terapêutico , Fator de Células-Tronco/uso terapêutico , Animais , Citocinas/administração & dosagem , Sinergismo Farmacológico , Eritropoetina/administração & dosagem , Raios gama , Trato Gastrointestinal/efeitos dos fármacos , Trato Gastrointestinal/efeitos da radiação , Interleucina-3/administração & dosagem , Interleucina-3/uso terapêutico , Rim/efeitos dos fármacos , Rim/efeitos da radiação , Fígado/efeitos dos fármacos , Fígado/efeitos da radiação , Pulmão/efeitos dos fármacos , Pulmão/efeitos da radiação , Proteínas de Membrana/administração & dosagem , Proteínas de Membrana/uso terapêutico , Camundongos , Protetores contra Radiação/administração & dosagem , Distribuição Aleatória , Fator de Células-Tronco/administração & dosagem , Trombopoetina/administração & dosagem , Trombopoetina/uso terapêutico , Irradiação Corporal TotalRESUMO
Macrophage-like cells densely accumulate in stab wound-induced brain lesions in rats. Many of these cells express the macrophage marker Iba1 and the oligodendrocyte progenitor cell marker NG2 chondroitin sulfate proteoglycan (NG2), and have been termed BINCs (brain Iba1(+)/NG2(+) cells). Results from our previous study showed that BINCs elicit neuroprotective action, and agents inducing BINC activation or proliferation are expected to ameliorate traumatic brain injuries (TBIs). In the present study, TBI was established by inserting a needle into the cerebrum and moving the needle in a longitudinal, fan-like movement. Isolated BINCs from these stab lesions expressed mRNAs encoding receptors for interleukin-3 (IL-3) and granulocyte/macrophage colony-stimulating factor (GM-CSF). When this mixture of cytokines was added to the cultured BINCs, expression of mRNAs encoding insulin-like growth factor-1, hepatocyte growth factor, and proliferating cell nuclear antigen increased. The cytokine mixture induced enhanced wound healing in BINCs-brain cell co-cultures in vitro. Stab wounds in the rats resulted in significant brain tissue loss at 2 months post-lesion. However, tissue loss was reduced by 40% when the combination of IL-3 and GM-CSF was subcutaneously injected 7 times (once per day) beginning at 2 or 3 days post-lesion (dpl). BINCs are highly proliferative and an intraperitoneal injection of 5-fluorouracil (5FU) at 2 dpl eliminated the BINCs, resulting in death of the rats. The cytokine mixture injection significantly reduced mortality of the 5FU-treated rats. These results suggest that the combination of IL-3 and GM-CSF serves as a promising agent to ameliorate TBI via action on BINCs.
Assuntos
Lesões Encefálicas/terapia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/uso terapêutico , Interleucina-3/uso terapêutico , Cicatrização/fisiologia , Animais , Lesões Encefálicas/metabolismo , Lesões Encefálicas/patologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Fator de Crescimento de Hepatócito/genética , Fator de Crescimento de Hepatócito/metabolismo , Fator de Crescimento Insulin-Like I/genética , Fator de Crescimento Insulin-Like I/metabolismo , Interleucina-3/metabolismo , Macrófagos/metabolismo , Macrófagos/patologia , Antígeno Nuclear de Célula em Proliferação/genética , Antígeno Nuclear de Célula em Proliferação/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Resultado do TratamentoRESUMO
IL-3, a cytokine secreted by Th cells, functions as a link between the immune and the hematopoietic system. We previously demonstrated the potent inhibitory role of IL-3 on osteoclastogenesis, pathological bone resorption, and inflammatory arthritis. In this study, we investigated the novel role of IL-3 in development of regulatory T (Treg) cells. We found that IL-3 in a dose-dependent manner increases the percentage of Foxp3(+) Treg cells indirectly through secretion of IL-2 by non-Treg cells. These IL-3-expanded Treg cells are competent in suppressing effector T cell proliferation. Interestingly, IL-3 treatment significantly reduces the severity of arthritis and restores the loss of Foxp3(+) Treg cells in thymus, lymph nodes, and spleen in collagen-induced arthritis mice. Most significantly, we show that IL-3 decreases the production of proinflammatory cytokines IL-6, IL-17A, TNF-α, and IL-1 and increases the production of anti-inflammatory cytokines IFN-γ and IL-10 in collagen-induced arthritis mice. Thus, to our knowledge, we provide the first evidence that IL-3 play an important role in modulation of Treg cell development in both in vitro and in vivo conditions, and we suggest its therapeutic potential in the treatment of rheumatoid arthritis and other autoimmune diseases.
Assuntos
Artrite Experimental/imunologia , Artrite Experimental/terapia , Diferenciação Celular/imunologia , Colágeno/administração & dosagem , Fatores de Transcrição Forkhead/biossíntese , Interleucina-3/uso terapêutico , Linfócitos T Reguladores/imunologia , Animais , Artrite Experimental/patologia , Artrite Reumatoide/imunologia , Artrite Reumatoide/patologia , Artrite Reumatoide/terapia , Interleucina-3/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos DBA , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/uso terapêutico , Linfócitos T Reguladores/patologiaRESUMO
Interleukin-3 (IL-3) regulates the proliferation, survival and differentiation of haematopoietic cells via interaction with specific cell-surface receptors. IL-3 is expressed in several non-hematopoietic cell types. Studies have demonstrated the presence of IL-3 in the central nervous system, however, its physiological role in these cells is poorly understood. Previously we have been demonstrated that IL-3 prevents neuronal death induced by fibrillary ß amyloid in these cells, by PI 3-kinase and Jak/STAT pathway activation. In this study, we demonstrated that IL-3 significantly reduced Aß-promoted neurite degeneration and toxicity. Thus, this cytokine provides cellular protection against Aß neurotoxicity in primary cortical neuronal cells, by modulating microtubular dynamics and prevention of tau cleavage and hyperphosphorylation. We also demonstrates that IL-3 is expressed in the "in vivo" mouse model of AD, Tg2576, which also expresses human AßPP with the Swedish mutation. In summary, these results suggest that IL-3 could play a neuroprotective role in AD.
Assuntos
Doença de Alzheimer/metabolismo , Citoproteção/fisiologia , Interleucina-3/fisiologia , Degeneração Neural/metabolismo , Degeneração Neural/prevenção & controle , Proteínas tau/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/toxicidade , Animais , Células Cultivadas , Citoproteção/efeitos dos fármacos , Humanos , Interleucina-3/uso terapêutico , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Degeneração Neural/patologia , Proteínas tau/fisiologiaRESUMO
A 48-year-old woman was admitted to our hospital in 2003, complaining of weight loss. Complete blood cell count revealed thrombocytopenia. Abdominal CT demonstrated marked splenomegaly. FDG-PET revealed a hot spot in the whole spleen. A splenectomy was performed. Histological examination was typical for angiosarcoma. Adjuvant chemotherapy was given, and high-dose chemotherapy with autologous peripheral blood stem cell transplantation was performed. Thrombocytopenia developed again in 2008. CT scan showed a hepatic tumor. A fine-needle biopsy of the liver revealed the first relapse. Despite hepatic lobectomy, radiofrequency ablations and administration of recombinant interleukin-2, she died from respiratory failure in 2009.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Hemangiossarcoma/terapia , Transplante de Células-Tronco de Sangue Periférico , Esplenectomia , Neoplasias Esplênicas/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Ablação por Cateter , Quimioterapia Adjuvante , Terapia Combinada , Ciclofosfamida/administração & dosagem , Doxorrubicina/administração & dosagem , Evolução Fatal , Feminino , Hemangiossarcoma/tratamento farmacológico , Hemangiossarcoma/cirurgia , Hepatectomia , Humanos , Interleucina-3/uso terapêutico , Pessoa de Meia-Idade , Prednisona/administração & dosagem , Proteínas Recombinantes/uso terapêutico , Neoplasias Esplênicas/tratamento farmacológico , Neoplasias Esplênicas/cirurgia , Trombocitopenia/etiologia , Vincristina/administração & dosagemAssuntos
Fatores de Crescimento de Células Hematopoéticas/uso terapêutico , Interleucina-3/uso terapêutico , Neutropenia/tratamento farmacológico , Europa (Continente)/epidemiologia , Filgrastim , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Humanos , Incidência , Neutropenia/complicações , Neutropenia/prevenção & controle , Polietilenoglicóis , Proteínas RecombinantesRESUMO
The effects of inhibition of the Raf/MEK/ERK and PI3K/Akt/mTOR signaling pathways and chemotherapeutic drugs on cell cycle progression and drug sensitivity were examined in cytokine-dependent FL5.12 hematopoietic cells. We examined their effects, as these cells resemble normal hematopoietic precursor cells as they do not exhibit "oncogene-addicted" growth, while they do display "cytokine-addicted" proliferation as cytokine removal resulted in apoptosis in greater than 80% of the cells within 48 hrs. When cytokine-dependent FL5.12 cells were cultured in the presence of IL-3, which stimulated multiple proliferation and anti-apoptotic cascades, MEK, PI3K and mTOR inhibitors transiently suppressed but did not totally inhibit cell cycle progression or induce apoptosis while chemotherapeutic drugs such as doxorubicin and paclitaxel were more effective in inducing cell cycle arrest and apoptosis. Doxorubicin induced a G(1) block, while paclitaxel triggered a G(2)/M block. Doxorubicin was more effective in inducing cell death than paclitaxel. Furthermore the effects of doxorubicin could be enhanced by addition of MEK, PI3K or mTOR inhibitors. Cytokine-dependent cells which proliferate in vitro and are not "oncogene-addicted" may represent a pre-malignant stage, more refractory to treatment with targeted therapy. However, these cells are sensitive to chemotherapeutic drugs. It is important to develop methods to inhibit the growth of such cytokine-dependent cells as they may resemble the leukemia stem cell and other cancer initiating cells. These results demonstrate the enhanced effectiveness of targeting early hematopoietic progenitor cells with combinations of chemotherapeutic drugs and signal transduction inhibitors.
Assuntos
Antineoplásicos/uso terapêutico , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Inibidores de Fosfoinositídeo-3 Quinase , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Animais , Antibióticos Antineoplásicos/uso terapêutico , Apoptose , Butadienos/uso terapêutico , Linhagem Celular Tumoral , Cromonas/uso terapêutico , Doxorrubicina/uso terapêutico , Fase G1 , Interleucina-3/uso terapêutico , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Leucemia Prolinfocítica/tratamento farmacológico , Camundongos , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Morfolinas/uso terapêutico , Nitrilas/uso terapêutico , Paclitaxel/uso terapêutico , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Sirolimo/uso terapêutico , Serina-Treonina Quinases TORRESUMO
The endothelium was the first non-hematopoietic tissue to be identified as a physiological target for erythropoietin (EPO). EPO is involved in recruitment and mobilization of endothelial progenitors and stimulates the production of erythroid cell regulatory factors in endothelial cells. Production of these EPO-dependent factors is inhibited by IL-3 in vitro. Furthermore, EPO-dependent red cell formation in anemic mice is equally repressed by IL-3. The number of IL-3 receptors on endothelial cells increases in chronic inflammation and IL-3 may be one of the inflammatory cytokines, together with TNF-alpha, IFN-gamma or IL-6, which prevents optimal red cell formation in many patients with kidney failure receiving high doses of EPO. These patients could benefit from the administration of some of the EPO-stimulated endothelial factors, such as C21 (the C-terminal segment thrombospondin-4), thrombospondin-1 and chaperonin 10, because these proteins bypass EPO receptors and signaling pathways that are usually compromised in EPO resistance. C21 stimulates red cell formation in anemic mice, increases human hematopoietic cell proliferation in vitro and could eventually fight inflammation, because it is an osteopontin antagonist. Thrombospondin-1 prevents inflammation, stimulates erythroblast proliferation and counteracts IGFBP-3-mediated erythroid inhibition. Finally, chaperonin 10 stimulates hemoglobin synthesis and has anti-inflammatory properties through the inhibition of Toll-like receptor signaling pathways.
Assuntos
Endotélio/metabolismo , Eritropoetina/biossíntese , Interleucina-3/uso terapêutico , Animais , Anti-Inflamatórios/uso terapêutico , Chaperonina 10/uso terapêutico , Resistência a Medicamentos/efeitos dos fármacos , Células Endoteliais/metabolismo , Eritropoetina/antagonistas & inibidores , Humanos , Receptores da Eritropoetina/metabolismo , Trombospondina 1/uso terapêutico , TrombospondinasRESUMO
Despite initial remissions, most patients with Ph chromosome positive (Ph(+)) acute leukemia (AL) become refractory to tyrosine kinase inhibitors (TKIs) such as imatinib and dasatinib. This study was designed to determine if targeting the interleukin-3 receptor (IL-3R) with a diphtheria toxin fusion protein (DT(388)IL3) would improve the effectiveness of TKIs against Ph(+) AL cells. IL-3R subunits were detected on most Ph(+) cells and the IC50 for killing of colony forming cell (CFC) with DT(388)IL3 correlated with the level of IL-3Ralpha subunit by FACS. DT(388)IL3 synergized with both imatinib and dasatinib for killing of malignant CFCs. Long-term suspension culture-initiating cells (SC-ICs) and quiescent leukemic cells (G(0) in cell cycle) also were studied and synergistic interactions were again demonstrated. Thus, cotreatment with TKIs and DT(388)IL3 is much more effective in eliminating Ph(+) leukemic progenitors that express IL-3R than either agent alone.
Assuntos
Toxina Diftérica/uso terapêutico , Proteínas de Fusão bcr-abl/genética , Interleucina-3/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Células-Tronco Neoplásicas/efeitos dos fármacos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Recombinantes de Fusão/uso terapêutico , Adulto , Idoso , Benzamidas , Western Blotting , Ciclo Celular , Proliferação de Células , Células Cultivadas , Dasatinibe , Sinergismo Farmacológico , Feminino , Citometria de Fluxo , Proteínas de Fusão bcr-abl/metabolismo , Humanos , Mesilato de Imatinib , Subunidade alfa de Receptor de Interleucina-3/genética , Subunidade alfa de Receptor de Interleucina-3/metabolismo , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Células-Tronco Neoplásicas/patologia , Piperazinas/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Pirimidinas/uso terapêutico , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Tiazóis/uso terapêuticoRESUMO
Clinical composite tissue allotransplantation can adequately reconstruct defects that are not possible by other means. However, immunosuppressant toxicity limits the use of these techniques. Clinical attempts to reduce the amount of immunosuppression required by induction of an immunologically permissive state have so far been unsuccessful. The aim of this study was to induce tolerance in a preclinical large animal model. Donor hematopoietic stem cell (HSC) engraftment was induced by T-cell depletion, irradiation, and a short course of cyclosporine administered to the recipient, along with a hematopoietic cell infusion from a single haplotype major histocompatibility complex (MHC) mismatched donor. Skin was then allotransplanted from the donor. Both primarily vascularized skin flaps and secondarily vascularized conventional skin grafts were allotransplanted to investigate if the mode of transplantation affected outcome. Control animals received the skin allotransplants without conditioning. Tolerance was defined as no evidence of rejection at 90 days following transplantation. Conventional skin grafts only achieved prolonged survival (<65 days) in HSC-engrafted animals (P < .01). In contrast, there was indefinite skin flap survival with the achievement of tolerance in HSC-engrafted animals; this was confirmed on histology with donor-specific unresponsiveness on MLR and CML. Furthermore, a conventional skin donor graft subsequently applied to an animal tolerant to a skin flap was not rejected and did not trigger skin flap rejection. To our knowledge, this is the first time skin tolerance has been achieved across a MHC barrier in a large animal model. This is a significant step toward the goal of clinical skin tolerance induction.
Assuntos
Transplante de Pele/imunologia , Transplante Homólogo/imunologia , Animais , Ciclosporina/uso terapêutico , Sobrevivência de Enxerto/imunologia , Tolerância Imunológica/imunologia , Tolerância Imunológica/fisiologia , Imunossupressores/uso terapêutico , Interleucina-3/uso terapêutico , Depleção Linfocítica , Modelos Animais , Pele/irrigação sanguínea , Fator de Células-Tronco/uso terapêutico , Retalhos Cirúrgicos , Suínos , Linfócitos T/imunologiaRESUMO
Haematopoietic growth factors constitute an important group of proteins that predominantly regulate the process of haematopoiesis. While some of these proteins have a very broad array of action on very early haematopoietic progenitors leading to multi-lineage increases in haematopoietic cell production and differentiation, others act in a restricted manner on specific committed terminally differentiated cell types. On the basis of their unique spectrum of activities, several factors are approved for clinical use in various indications while others are under investigation in the clinic either alone or as combination therapy. In this review, we have described factors which directly and in some cases indirectly influence haematopoiesis with particular focus on those factors which are either approved or show potential for clinical use. A brief description of the products that are currently available for clinical use is also provided. At present, several new products which include fusion proteins, peptide mimetics are either at the pre-clinical stage or in clinical development for various indications and these are also briefly described.
Assuntos
Produtos Biológicos/uso terapêutico , Doenças Hematológicas/tratamento farmacológico , Hematopoese/efeitos dos fármacos , Fatores de Crescimento de Células Hematopoéticas/uso terapêutico , Células-Tronco Hematopoéticas/efeitos dos fármacos , Animais , Produtos Biológicos/efeitos adversos , Eritropoetina/uso terapêutico , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Fator Estimulador de Colônias de Granulócitos e Macrófagos/uso terapêutico , Doenças Hematológicas/fisiopatologia , Fatores de Crescimento de Células Hematopoéticas/efeitos adversos , Humanos , Interleucina-11/uso terapêutico , Interleucina-3/uso terapêutico , Fator Estimulador de Colônias de Macrófagos/uso terapêutico , Proteínas Recombinantes/uso terapêutico , Fator de Células-Tronco/uso terapêutico , Trombopoetina/uso terapêuticoRESUMO
Multicytokine therapy may be useful to counteract radiation-induced myelosuppression. We assessed the stem cell factor + glycosylated erythropoietin + pegylated granulocyte colony-stimulating factor combination (SEG) as an emergency treatment. SEG in highly irradiated monkeys efficacy appeared to be restricted to granulopoiesis. Early administration of Erythropoietin did not prevent radiation-induced anemia.
Assuntos
Citocinas/uso terapêutico , Pancitopenia/tratamento farmacológico , Lesões Experimentais por Radiação/tratamento farmacológico , Animais , Transfusão de Sangue , Citocinas/administração & dosagem , Avaliação Pré-Clínica de Medicamentos , Quimioterapia Combinada , Emergências , Eritropoetina/administração & dosagem , Eritropoetina/uso terapêutico , Filgrastim , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Interleucina-3/administração & dosagem , Interleucina-3/uso terapêutico , Macaca fascicularis , Proteínas de Membrana/administração & dosagem , Proteínas de Membrana/uso terapêutico , Pancitopenia/sangue , Pancitopenia/etiologia , Pancitopenia/terapia , Polietilenoglicóis , Lesões Experimentais por Radiação/sangue , Lesões Experimentais por Radiação/etiologia , Lesões Experimentais por Radiação/terapia , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/uso terapêutico , Fator de Células-Tronco/administração & dosagem , Fator de Células-Tronco/uso terapêutico , Trombopoetina/administração & dosagem , Trombopoetina/uso terapêuticoRESUMO
DT(388)IL3 fusion protein containing the catalytic and translocation domains of diphtheria toxin fused to human interleukin 3 was administered in an inter-patient dose escalation trial by 15 min i.v. infusions every other day for up to 6 doses to patients with chemo-refractory acute myeloid leukemia (AML) and myelodysplasia (MDS). The maximal tolerated dose was >12.5 microg/kg/dose. Transient grade 3 transaminasemia and grade 2 fevers, chills, hypoalbuminemia, and hypotension occurred. Peak DT(388)IL3 levels correlated with dose and day of administration but not antibody titer. Anti-DT(388)IL3 antibodies developed in most patients between day 15 and 30. Of 40 evaluable AML patients, 1 had a CR (8 months) and 1 had PR (3 months). Of 5 MDS patients, 1 had a PR (4 months). Because of the prolonged infusion schedule, many patients failed to receive six doses. DT(388)IL3 produces remissions in patients with relapsed/refractory AML and MDS with minimal toxicities, and alternate schedules of administration are needed to enhance the response rate.
Assuntos
Toxina Diftérica/administração & dosagem , Interleucina-3/administração & dosagem , Leucemia Mieloide Aguda/tratamento farmacológico , Síndromes Mielodisplásicas/tratamento farmacológico , Proteínas Recombinantes de Fusão/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Toxina Diftérica/uso terapêutico , Feminino , Humanos , Interleucina-3/uso terapêutico , Isoanticorpos/biossíntese , Isoanticorpos/sangue , Leucemia Mieloide Aguda/complicações , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/complicações , Proteínas Recombinantes de Fusão/imunologia , Proteínas Recombinantes de Fusão/toxicidade , Indução de Remissão/métodos , Terapia de Salvação/métodos , Resultado do TratamentoRESUMO
Thrombocytopenia is a serious clinical problem in several different clinical settings. In chronic bone marrow failure states, which include aplastic anemia, myelodysplastic syndrome, and graft failure, the prolonged nature of thrombocytopenia often leads to alloimunization after repeated platelet transfusions, the consequence of which is a platelet-refractory state and enhanced risk of bleeding. Despite the introduction of several thrombopoietic factors into clinical trials, an effective way to alleviate thrombocytopenia has been elusive, and the problem in chronic bone marrow failure states has remained poorly addressed by clinical investigations. Even so, several studies by our group and others suggest that a subset of patients suffering from chronic bone marrow failure can respond to appropriate growth factor therapy. The temporal pace of response appears, however, to be much slower than that observed after administering growth factors which act on neutrophils. On the other hand, durable responses can be secured in some patients given thrombopoietic factors for long periods of time. Herein, we provide an overview of the clinical research investigations of thrombopoietic factors in chronic bone marrow failure, and the emerging insights these studies provide for understanding the process of thrombopoiesis and its therapy in this setting.