RESUMO
In line with the embodied cognition perspective stating that cognitive processing results from the activation of the sensorimotor systems involved in perception and action (e.g., Glenberg, 1997), recent studies provided evidence that motor affordances played a role in serial memory for objects (e.g., see Downing-Doucet & Guérard, 2014). In the present study, we extended this line of research by investigating whether objects' motor affordances played a role in item memory, in immediate and long-term retention. Participants had to retain pairs of objects that were positioned in a way that was congruent for action or not. The results showed that motor suppression disrupted the retention of congruent pairs, but not that of incongruent pairs when short lists of six objects had to be retained over a short period of time (Experiment 1). However, when participants had to retain lists of 60 pairs, motor suppression had no effect on retention (Experiment 2). These results suggest that the motor system was recruited for the immediate retention of objects, but not for their long-term retention.
Assuntos
Cognição/fisiologia , Memória/fisiologia , Feminino , Humanos , Masculino , Memória de Longo Prazo/fisiologia , Movimento/fisiologia , Estimulação Luminosa , Desempenho Psicomotor/fisiologia , Adulto JovemRESUMO
Tumor necrosis factor (TNF) is a key cytokine in the effector phase of graft-versus-host disease (GVHD) after bone marrow transplantation, and TNF inhibitors have shown efficacy in clinical and experimental GVHD. TNF signals through the TNF receptors (TNFR), which also bind soluble lymphotoxin (LTalpha3), a TNF family member with a previously unexamined role in GVHD pathogenesis. We have used preclinical models to investigate the role of LT in GVHD. We confirm that grafts deficient in LTalpha have an attenuated capacity to induce GVHD equal to that seen when grafts lack TNF. This is not associated with other defects in cytokine production or T-cell function, suggesting that LTalpha3 exerts its pathogenic activity directly via TNFR signaling. We confirm that donor-derived LTalpha is required for graft-versus-leukemia (GVL) effects, with equal impairment in leukemic clearance seen in recipients of LTalpha- and TNF-deficient grafts. Further impairment in tumor clearance was seen using Tnf/Lta(-/-) donors, suggesting that these molecules play nonredundant roles in GVL. Importantly, donor TNF/LTalpha were only required for GVL where the recipient leukemia was susceptible to apoptosis via p55 TNFR signaling. These data suggest that antagonists neutralizing both TNF and LTalpha3 may be effective for treatment of GVHD, particularly if residual leukemia lacks the p55 TNFR.
Assuntos
Doença Enxerto-Hospedeiro/imunologia , Linfotoxina-alfa/imunologia , Animais , Apoptose , Transplante de Medula Óssea , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/imunologia , Linhagem Celular Tumoral , Doença Enxerto-Hospedeiro/patologia , Mediadores da Inflamação/metabolismo , Camundongos , Multimerização Proteica , Receptores de Antígenos de Linfócitos T/imunologia , Receptores Imunológicos/administração & dosagem , Receptores Imunológicos/imunologia , Receptores do Fator de Necrose Tumoral/administração & dosagem , Receptores do Fator de Necrose Tumoral/imunologia , Solubilidade , Fator de Necrose Tumoral alfa/deficiência , Fator de Necrose Tumoral alfa/imunologiaRESUMO
Invariant natural killer T cells (iNKT cells) have pivotal roles in graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) effects. iNKT cells are activated through their T-cell receptors by glycolipid moieties (typically the alpha-galactosylceramide [alpha-GalCer] derivative KRN7000) presented within CD1d. We investigated the ability of modified alpha-GalCer molecules to differentially modulate alloreactivity and GVL. KRN7000 and the N-acyl variant, C20:2, were administered in multiple well-established murine models of allogeneic stem cell transplantation. The highly potent and specific activation of all type I NKT cells with C20:2 failed to exacerbate and in most settings inhibited GVHD late after transplantation, whereas effects on GVL were variable. In contrast, the administration of KRN7000 induced hyperacute GVHD and early mortality in all models tested. Administration of KRN7000, but not C20:2, was found to result in downstream interleukin (IL)-12 and dendritic cell (DC)-dependent natural killer (NK)- and conventional T-cell activation. Specific depletion of host DCs, IL-12, or donor NK cells prevented this pathogenic response and the induction of hyperacute GVHD. These data demonstrate the ability of profound iNKT activation to modulate both the innate and adaptive immune response via the DC-NK-cell interaction and raise concern for the use of alpha-GalCer therapeutically to modulate GVHD and GVL effects.
Assuntos
Galactosilceramidas/administração & dosagem , Células T Matadoras Naturais/efeitos dos fármacos , Transplante de Células-Tronco , Animais , Citocinas/biossíntese , Feminino , Galactosilceramidas/química , Galactosilceramidas/farmacologia , Efeito Enxerto vs Leucemia/efeitos dos fármacos , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Camundongos , Células T Matadoras Naturais/imunologia , Taxa de Sobrevida , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Transplante Homólogo , Resultado do TratamentoRESUMO
Granulocyte colony-stimulating factor (G-CSF) is often used to hasten neutrophil recovery after allogeneic bone marrow transplantation (BMT), but the clinical and immunological consequences evoked remain unclear. We examined the effect of G-CSF administration after transplantation in mouse models and found that exposure to either standard G-CSF or pegylated-G-CSF soon after BMT substantially increased graft-versus-host disease (GVHD). This effect was dependent on total body irradiation (TBI) rendering host dendritic cells (DCs) responsive to G-CSF by upregulating their expression of the G-CSF receptor. Stimulation of host DCs by G-CSF subsequently unleashed a cascade of events characterized by donor natural killer T cell (NKT cell) activation, interferon-gamma secretion and CD40-dependent amplification of donor cytotoxic T lymphocyte function during the effector phase of GVHD. Crucially, the detrimental effects of G-CSF were only present when it was administered after TBI conditioning and at a time when residual host antigen presenting cells were still present, perhaps explaining the conflicting and somewhat controversial clinical studies from the large European and North American BMT registries. These data have major implications for the use of G-CSF in disease states where NKT cell activation may have effects on outcome.
Assuntos
Transplante de Medula Óssea/imunologia , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Células Matadoras Naturais/imunologia , Neutrófilos/fisiologia , Animais , Linfócitos T CD8-Positivos/imunologia , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Doença Enxerto-Hospedeiro/imunologia , Humanos , Interferon gama/fisiologia , Ativação Linfocitária/efeitos dos fármacos , Transfusão de Linfócitos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos , Modelos Animais , Neutrófilos/efeitos dos fármacos , Linfócitos T/transplante , Transplante Homólogo/imunologia , Irradiação Corporal TotalRESUMO
Although proinflammatory cytokines are key mediators of tissue damage during graft-versus-host disease (GVHD), IFNgamma has previously been attributed with both protective and pathogenic effects. We have resolved this paradox by using wild-type (wt), IFNgamma(-/-), and IFNgammaR(-/-) mice as donors or recipients in well-described models of allogeneic stem cell transplantation (SCT). We show that donor-derived IFNgamma augments acute GVHD via direct effects on (1) the donor T cell to promote T helper 1 (Th1) differentiation and (2) the gastrointestinal (GI) tract to augment inflammatory cytokine generation. However, these detrimental effects are overwhelmed by a protective role of IFNgamma in preventing the development of idiopathic pneumonia syndrome (IPS). This is the result of direct effects on pulmonary parenchyma to prevent donor cell migration and expansion within the lung. Thus, IFNgamma is the key cytokine differentially controlling the development of IPS and gastrointestinal GVHD after allogeneic SCT.
Assuntos
Gastroenteropatias/imunologia , Doença Enxerto-Hospedeiro/imunologia , Interferon gama/imunologia , Pneumonia/imunologia , Transplante de Células-Tronco , Doença Aguda , Animais , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Movimento Celular/genética , Movimento Celular/imunologia , Feminino , Gastroenteropatias/complicações , Gastroenteropatias/genética , Gastroenteropatias/patologia , Trato Gastrointestinal/imunologia , Trato Gastrointestinal/patologia , Doença Enxerto-Hospedeiro/complicações , Doença Enxerto-Hospedeiro/genética , Doença Enxerto-Hospedeiro/patologia , Inflamação/genética , Inflamação/imunologia , Inflamação/patologia , Interferon gama/deficiência , Pulmão/imunologia , Pulmão/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Pneumonia/etiologia , Pneumonia/genética , Pneumonia/patologia , Síndrome , Células Th1/imunologia , Células Th1/patologia , Transplante HomólogoRESUMO
Antigen-presenting cells (APCs) are critical for the initiation of graft-versus-host disease (GVHD), although the responsible APC subset and molecular mechanisms remain unclear. Because dendritic cells (DCs) are the most potent APCs and the NF-kB/Rel family member RelB is associated with DC maturation and potent APC function, we examined their role in GVHD. Within 4 hours of total body irradiation, RelB nuclear translocation was increased and restricted to CD11c(hi) DCs within the host APC compartment. Furthermore, the transient depletion of CD11c(hi) donor DCs that reconstitute in the second week after transplantation resulted in a transient decrease in GVHD severity. By using RelB(-/-) bone marrow chimeras as transplant recipients or RelB(-/-) donor bone marrow, we demonstrate that the induction and maintenance of GVHD is critically dependent on this transcription factor within both host and donor APCs. Critically, RelB within APCs was required for the expansion of donor helper T cell type 1 (Th1) effectors and subsequent alloreactivity, but not the peripheral expansion or function of donor FoxP3(+) regulatory T cells. These data suggest that the targeted inhibition of nuclear RelB translocation within APCs represents an attractive therapeutic strategy to dissociate effector and regulatory T-cell function in settings of Th1-mediated tissue injury.
Assuntos
Núcleo Celular/metabolismo , Regulação da Expressão Gênica , Doença Enxerto-Hospedeiro/imunologia , Linfócitos T Reguladores/imunologia , Fator de Transcrição RelB/biossíntese , Transporte Ativo do Núcleo Celular , Animais , Anticorpos Monoclonais/química , Antígeno CD11c/biossíntese , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Linfócitos T Reguladores/metabolismo , Células Th1 , Transcrição GênicaRESUMO
Host antigen-presenting cells (APCs) are known to be critical for the induction of graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation (BMT), but the relative contribution of specific APC subsets remains unclear. We have studied the role of host B cells in GVHD by using B-cell-deficient microMT mice as BMT recipients in a model of CD4-dependent GVHD to major histocompatibility complex antigens. We demonstrate that acute GVHD is initially augmented in microMT recipients relative to wild-type recipients (mortality: 85% vs 44%, P < .01), and this is the result of an increase in donor T-cell proliferation, expansion, and inflammatory cytokine production early after BMT. Recipient B cells were depleted 28-fold at the time of BMT by total body irradiation (TBI) administered 24 hours earlier, and we demonstrate that TBI rapidly induces sustained interleukin-10 (IL-10) generation from B cells but not dendritic cells (DCs) or other cellular populations within the spleen. Finally, recipient mice in which B cells are unable to produce IL-10 due to homologous gene deletion develop more severe acute GVHD than recipient mice in which B cells are wild type. Thus, the induction of IL-10 in host B cells during conditioning attenuates experimental acute GVHD.
Assuntos
Linfócitos B/metabolismo , Transplante de Medula Óssea/métodos , Doença Enxerto-Hospedeiro/metabolismo , Interleucina-10/fisiologia , Transplante Homólogo/métodos , Animais , Células Apresentadoras de Antígenos/química , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Deleção de Genes , Interleucina-10/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Irradiação Corporal TotalRESUMO
NKT cells have pivotal roles in immune regulation and tumor immunosurveillance. We report that the G-CSF and FMS-like tyrosine kinase 3 ligand (Flt-3L) chimeric cytokine, progenipoietin-1, markedly expands the splenic and hepatic NKT cell population and enhances functional responses to alpha-galactosylceramide. In a murine model of allogeneic stem cell transplantation, donor NKT cells promoted host DC activation and enhanced perforin-restricted CD8+ T cell cytotoxicity against host-type antigens. Following leukemic challenge, donor treatment with progenipoietin-1 significantly improved overall survival when compared with G-CSF or control, attributable to reduced graft-versus-host disease mortality and paradoxical augmentation of graft-versus-leukemia (GVL) effects. Enhanced cellular cytotoxicity was dependent on donor NKT cells, and leukemia clearance was profoundly impaired in recipients of NKT cell-deficient grafts. Enhanced cytotoxicity and GVL effects were not associated with Flt-3L signaling or effects on DCs but were reproduced by prolonged G-CSF receptor engagement with pegylated G-CSF. Thus, modified G-CSF signaling during stem cell mobilization augments NKT cell-dependent CD8+ cytotoxicity, effectively separating graft-versus-host disease and GVL and greatly expanding the potential applicability of allogeneic stem cell transplantation for the therapy of malignant disease.
Assuntos
Fator Estimulador de Colônias de Granulócitos/farmacologia , Mobilização de Células-Tronco Hematopoéticas/métodos , Células Matadoras Naturais/efeitos dos fármacos , Leucemia Experimental/tratamento farmacológico , Linfócitos T/efeitos dos fármacos , Animais , Linfócitos T CD4-Positivos/fisiologia , Linfócitos T CD8-Positivos/imunologia , Fatores Estimuladores de Colônias/farmacologia , Células Dendríticas/imunologia , Feminino , Galactosilceramidas/fisiologia , Efeito Enxerto vs Leucemia/efeitos dos fármacos , Efeito Enxerto vs Leucemia/imunologia , Células Matadoras Naturais/metabolismo , Leucemia Experimental/imunologia , Proteínas de Membrana/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Recombinantes/farmacologia , Transdução de Sinais/imunologia , Transplante de Células-Tronco , Linfócitos T/metabolismoRESUMO
The lineage of dendritic cells (DC), and in particular their relationship to monocytes and macrophages, remains obscure. Furthermore, the requirement for the macrophage growth factor CSF-1 during DC homeostasis is unclear. Using a transgenic mouse in which the promoter for the CSF-1R (c-fms) directs the expression of enhanced GFP in cells of the myeloid lineage, we determined that although the c-fms promoter is inactive in DC precursors, it is up-regulated in all DC subsets during differentiation. Furthermore, plasmacytoid DC and all CD11c(high) DC subsets are reduced by 50-70% in CSF-1-deficient osteopetrotic mice, confirming that CSF-1 signaling is required for the optimal differentiation of DC in vivo. These data provide additional evidence that the majority of tissue DC is of myeloid origin during steady state and supports a close relationship between DC and macrophage biology in vivo.
Assuntos
Diferenciação Celular/imunologia , Proliferação de Células , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Fator Estimulador de Colônias de Macrófagos/metabolismo , Receptor de Fator Estimulador de Colônias de Macrófagos/biossíntese , Animais , Contagem de Células Sanguíneas , Antígeno CD11c/biossíntese , Antígeno CD11c/sangue , Diferenciação Celular/genética , Células Cultivadas , Células Dendríticas/citologia , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/imunologia , Células-Tronco Hematopoéticas/metabolismo , Antígenos Comuns de Leucócito/biossíntese , Fator Estimulador de Colônias de Macrófagos/deficiência , Fator Estimulador de Colônias de Macrófagos/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Camundongos Knockout , Camundongos Transgênicos , Receptor de Fator Estimulador de Colônias de Macrófagos/fisiologia , Transdução de Sinais/genética , Transdução de Sinais/imunologiaRESUMO
Donor treatment with granulocyte-colony-stimulating factor (G-CSF) attenuates the ability of donor T cells to induce acute graft-versus-host disease (aGVHD) but increases the severity of chronic GVHD (cGVHD). We investigated the role of the regulatory cytokine transforming growth factor beta (TGF-beta) in this paradox in well-established murine models of aGVHD and cGVHD wherein recipients undergo transplantation with splenocytes from donors treated with G-CSF. Neutralization of TGF-beta after stem-cell transplantation (SCT) significantly increased the severity of aGVHD, and the concurrent prevention of interleukin-10 (IL-10) production further exaggerated this effect. Early after SCT, donor T cells were the predominant source of TGF-beta and were able to attenuate aGVHD in a TGF-beta-dependent fashion. Although the neutralization of TGF-beta augmented the proliferation and expansion of donor T cells after SCT, it paradoxically impaired cellular cytotoxicity to host antigens and associated graft-versus-leukemia (GVL) effects. In cGVHD, neutralization of TGF-beta from day 14 after SCT attenuated histologic abnormalities, and CD11b+ mononuclear cells infiltrating sclerodermatous skin produced 50-fold more TGF-beta than corresponding T cells. Thus, though the production of TGF-beta by donor T cells early after transplantation attenuates aGVHD and is required for optimal GVL, the production of TGF-beta late after SCT is preferentially from mononuclear cells and mediates cGVHD. These data have important implications for the timing of therapeutic TGF-beta neutralization to prevent cGVHD after allogeneic SCT.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Fator de Crescimento Transformador beta/farmacologia , Doença Aguda , Animais , Doença Crônica , Modelos Animais de Doenças , Efeito Enxerto vs Leucemia/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos , Neoplasias Experimentais/complicações , Neoplasias Experimentais/terapia , Linfócitos T/metabolismo , Fatores de Tempo , Fator de Crescimento Transformador beta/metabolismo , Transplante HomólogoRESUMO
The initiation of graft-vs-host disease (GVHD) after stem cell transplantation is dependent on direct Ag presentation by host APCs, whereas the effect of donor APC populations is unclear. We studied the role of indirect Ag presentation in allogenic T cell responses by adding populations of cytokine-expanded donor APC to hemopoietic grafts that would otherwise induce lethal GVHD. Progenipoietin-1 (a synthetic G-CSF/Flt-3 ligand molecule) and G-CSF expanded myeloid dendritic cells (DC), plasmacytoid DC, and a novel granulocyte-monocyte precursor population (GM) that differentiate into class II+,CD80/CD86+,CD40- APC during GVHD. Whereas addition of plasmacytoid and myeloid donor DC augmented GVHD, GM cells promoted transplant tolerance by MHC class II-restricted generation of IL-10-secreting, Ag-specific regulatory T cells. Importantly, although GM cells abrogated GVHD, graft-vs-leukemia effects were preserved. Thus, a population of cytokine-expanded GM precursors function as regulatory APCs, suggesting that G-CSF derivatives may have application in disorders characterized by a loss of self-tolerance.
Assuntos
Células Apresentadoras de Antígenos/imunologia , Fatores Estimuladores de Colônias/administração & dosagem , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Interleucina-10/biossíntese , Células Progenitoras Mieloides/imunologia , Linfócitos T Reguladores/imunologia , Tolerância ao Transplante , Animais , Células Apresentadoras de Antígenos/metabolismo , Células Apresentadoras de Antígenos/transplante , Diferenciação Celular/imunologia , Células Cultivadas , Centrifugação com Gradiente de Concentração , Técnicas de Cocultura , Epitopos de Linfócito T/imunologia , Feminino , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/prevenção & controle , Efeito Enxerto vs Leucemia/imunologia , Granulócitos/citologia , Granulócitos/transplante , Antígenos H-2/imunologia , Antígeno de Histocompatibilidade H-2D , Humanos , Interleucina-10/deficiência , Interleucina-10/genética , Interleucina-10/fisiologia , Depleção Linfocítica , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Camundongos Knockout , Monócitos/citologia , Monócitos/transplante , Células Progenitoras Mieloides/metabolismo , Células Progenitoras Mieloides/transplante , Proteínas Recombinantes , Baço/citologia , Baço/transplante , Linfócitos T Reguladores/metabolismoRESUMO
The use of granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood as a source of stem cells has resulted in a high incidence of severe chronic graft-versus-host disease (cGVHD), which compromises the outcome of clinical allogeneic stem cell transplantation. We have studied the effect of G-CSF on both immune complex and fibrotic cGVHD directed to major (DBA/2 --> B6D2F1) or minor (B10.D2 --> BALB/c) histocompatibility antigens. In both models, donor pretreatment with G-CSF reduced cGVHD mortality in association with type 2 differentiation. However, after escalation of the donor T-cell dose, scleroderma occurred in 90% of the recipients of grafts from G-CSF-treated donors. In contrast, only 11% of the recipients of control grafts developed scleroderma, and the severity of hepatic cGVHD was also reduced. Mixing studies confirmed that in the presence of high donor T-cell doses, the severity of scleroderma was determined by the non-T-cell fraction of grafts from G-CSF-treated donors. These data confirm that the induction of cGVHD after donor treatment with G-CSF is dependent on the transfer of large numbers of donor T cells in conjunction with a putatively expanded myeloid lineage, providing a further rationale for the limitation of cell dose in allogeneic stem cell transplantation.
Assuntos
Doença Enxerto-Hospedeiro/mortalidade , Fator Estimulador de Colônias de Granulócitos/farmacologia , Mobilização de Células-Tronco Hematopoéticas , Transplante de Células-Tronco Hematopoéticas/métodos , Linfócitos T/transplante , Animais , Contagem de Células , Diferenciação Celular , Doença Crônica , Feminino , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/imunologia , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Mobilização de Células-Tronco Hematopoéticas/métodos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/mortalidade , Antígenos de Histocompatibilidade , Hepatopatias/etiologia , Transfusão de Linfócitos/métodos , Camundongos , Camundongos Endogâmicos , Esclerodermia Localizada/etiologia , Subpopulações de Linfócitos T , Transplante HomólogoRESUMO
We investigated whether the protection from graft-versus-host disease (GVHD) afforded by donor treatment with granulocyte colony-stimulating factor (G-CSF) could be enhanced by dose escalation. Donor treatment with human G-CSF prevented GVHD in the B6 --> B6D2F1 murine model in a dose-dependent fashion, and murine G-CSF provided equivalent protection from GVHD at 10-fold lower doses. Donor pretreatment with a single dose of pegylated G-CSF (peg-G-CSF) prevented GVHD to a significantly greater extent than standard G-CSF (survival, 75% versus 11%, P <.001). Donor T cells from peg-G-CSF-treated donors failed to proliferate to alloantigen and inhibited the responses of control T cells in an interleukin 10 (IL-10)-dependent fashion in vitro. T cells from peg-G-CSF-treated IL-10(-/-) donors induced lethal GVHD; T cells from peg-G-CSF-treated wild-type (wt) donors promoted long-term survival. Whereas T cells from peg-G-CSF wt donors were able to regulate GVHD induced by T cells from control-treated donors, T cells from G-CSF-treated wt donors and peg-G-CSF-treated IL-10(-/-) donors did not prevent mortality. Thus, peg-G-CSF is markedly superior to standard G-CSF for the prevention of GVHD following allogeneic stem cell transplantation (SCT), due to the generation of IL-10-producing regulatory T cells. These data support prospective clinical trials of peg-G-CSF-mobilized allogeneic blood SCT.
Assuntos
Fator Estimulador de Colônias de Granulócitos/farmacologia , Transplante de Células-Tronco Hematopoéticas/métodos , Tolerância Imunológica , Interleucina-10/biossíntese , Polietilenoglicóis/farmacologia , Linfócitos T/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Feminino , Doença Enxerto-Hospedeiro/prevenção & controle , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Camundongos , Camundongos Endogâmicos , Polietilenoglicóis/administração & dosagem , Taxa de Sobrevida , Linfócitos T/transplante , Doadores de Tecidos , Transplante HomólogoRESUMO
The granulocyte colony-stimulating factor (G-CSF) and Flt-3 receptor agonist progenipoietin-1 (ProGP-1) has potent effects on dendritic cell (DC) expansion and may be an alternative to G-CSF for the mobilization of stem cells for allogeneic stem cell transplantation (SCT). We studied the ability of stem cell grafts mobilized with this agent to induce graft-versus-host disease (GVHD) to minor and major histocompatibility antigens in the well-described B6 --> B6D2F1 SCT model. ProGP-1, G-CSF, or control diluent was administered to donor B6 mice. ProGP-1 expanded all cell lineages in the spleen, and unseparated splenocytes from these animals produced large amounts of interleukin 10 (IL-10) and transforming growth factor beta (TGFbeta) whereas the expression of T-cell adhesion molecules was diminished. Transplantation survival was 0%, 50%, and 90% in recipients of control-, G-CSF-, and ProGP-1-treated allogeneic donor splenocytes, respectively (P <.0001). Donor pretreatment with ProGP-1 allowed a 4-fold escalation in T-cell dose over that possible with G-CSF. Donor CD4 T cells from allogeneic SCT recipients of ProGP-1 splenocytes demonstrated an anergic response to host antigen, and cytokine production (interferon gamma [IFNgamma], IL-4, and IL-10) was also reduced while CD8 T-cell cytotoxicity to host antigens remained intact. Neither CD11c(hi) DCs nor CD11c(dim)/B220(hi) DCs from ProGP-1-treated animals conferred protection from GVHD when added to control spleen. Conversely, when equal numbers of purified T cells from control-, G-CSF-, or ProGP-1-treated allogeneic donors were added to allogeneic T-cell-depleted control spleen, survival at day 60 was 0%, 15%, and 90%, respectively (P <.0001). The improved survival in recipients of ProGP-1 T cells was associated with reductions in systemic tumor necrosis factor alpha generation and GVHD of the gastrointestinal tract. We conclude that donor pretreatment with ProGP-1 is superior to G-CSF for the prevention of GVHD after allogeneic SCT, primarily due to incremental affects on T-cell phenotype and function.