RESUMO
The Production Assistance for Cellular Therapies (PACT) Program, is funded and supported by the US Department of Health and Human Services' National Institutes of Health (NIH) National Heart Lung and Blood Institute (NHLBI) to advance development of somatic cell and genetically modified cell therapeutics in the areas of heart, lung, and blood diseases. The program began in 2003, continued under two competitive renewals, and ended June 2021. PACT has supported cell therapy product manufacturing, investigational new drug enabling preclinical studies, and translational services, and has provided regulatory assistance for candidate cell therapy products that may aid in the repair and regeneration of damaged/diseased cells, tissues, and organs. PACT currently supports the development of novel cell therapies through five cell processing facilities. These facilities offer manufacturing processes, analytical development, technology transfer, process scale-up, and preclinical development expertise necessary to produce cell therapy products that are compliant with Good Laboratory Practices, current Good Manufacturing Practices, and current Good Tissue Practices regulations. The Emmes Company, LLC, serves as the Coordinating Center and assists with the management and coordination of PACT and its application submission and review process. This paper discusses the impact and accomplishments of the PACT program on the cell therapy field and its evolution over the duration of the program. It highlights the work that has been accomplished and provides a foundation to build future programs with similar goals to advance cellular therapeutics in a coordinated and centralized programmatic manner to support unmet medical needs within NHLBI purview.
Assuntos
Terapia Baseada em Transplante de Células e Tecidos/economia , Financiamento Governamental , National Heart, Lung, and Blood Institute (U.S.) , Academias e Institutos , Regulamentação Governamental , Estados UnidosRESUMO
The International Workshop on Clinical Transplant Tolerance is a biennial meeting that aims to provide an update on the progress of studies of immunosuppression minimization or withdrawal in solid organ transplantation. The Fourth International Workshop on Clinical Tolerance was held in Pittsburgh, Pennsylvania, September 5-6, 2019. This report is a summary of presentations on the status of clinical trials designed to minimize or withdraw immunosuppressive drugs in kidney, liver, and lung transplantation without subsequent evidence of rejection. All protocols had in common the use of donor or recipient cell therapy combined with organ transplantation. The workshop also included presentations of mechanistic studies designed to improve understanding of the cellular and molecular basis of tolerance and to identify potential predictors/biomarkers of tolerance. Strategies to enhance the safety of hematopoietic cell transplantation and to improve patient selection/risk stratification for clinical trials were also discussed.
Assuntos
Transplante de Órgãos , Tolerância ao Transplante , Rejeição de Enxerto/etiologia , Rejeição de Enxerto/prevenção & controle , Humanos , Tolerância Imunológica , Terapia de Imunossupressão , Imunossupressores , PennsylvaniaRESUMO
The National Heart, Lung, and Blood Institute (NHLBI), within the United States' National Institutes of Health (NIH), established the Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC) in 2008 to develop the infrastructure needed to link the contents of the NHLBI Biorepository and the NHLBI Data Repository, and to promote the utilization of these scientific resources by the broader research community. Program utilization metrics were developed to measure the impact of BioLINCC on Biorepository access by researchers, including visibility, program efficiency, user characteristics, scientific impact, and research types. Input data elements were defined and are continually populated as requests move through the process of initiation through fulfillment and publication. This paper reviews the elements of the tracking metrics which were developed for BioLINCC and reports the results for the first six on-line years of the program.
Assuntos
Bancos de Espécimes Biológicos/organização & administração , Manejo de Espécimes/métodos , Humanos , Internet , National Heart, Lung, and Blood Institute (U.S.) , National Institutes of Health (U.S.) , Desenvolvimento de Programas , Estados UnidosRESUMO
On March 25 and 26, 2015, the National Heart, Lung, and Blood Institute sponsored a meeting on the State of the Science in Transfusion Medicine on the National Institutes of Health (NIH) campus in Bethesda, Maryland, which was attended by a diverse group of 330 registrants. The meeting's goal was to identify important research questions that could be answered in the next 5 to 10 years and which would have the potential to transform the clinical practice of transfusion medicine. These questions could be addressed by basic, translational, and/or clinical research studies and were focused on four areas: the three "classical" transfusion products (i.e., red blood cells, platelets, and plasma) and blood donor issues. Before the meeting, four working groups, one for each area, prepared five major questions for discussion along with a list of five to 10 additional questions for consideration. At the meeting itself, all of these questions, and others, were discussed in keynote lectures, small-group breakout sessions, and large-group sessions with open discourse involving all meeting attendees. In addition to the final lists of questions, provided herein, the meeting attendees identified multiple overarching, cross-cutting themes that addressed issues common to all four areas; the latter are also provided. It is anticipated that addressing these scientific priorities, with careful attention to the overarching themes, will inform funding priorities developed by the NIH and provide a solid research platform for transforming the future practice of transfusion medicine.
Assuntos
Transfusão de Sangue , Animais , Congressos como Assunto , Humanos , National Heart, Lung, and Blood Institute (U.S.) , Estados UnidosAssuntos
Terapia Baseada em Transplante de Células e Tecidos , Pesquisa Translacional Biomédica/organização & administração , Terapia Baseada em Transplante de Células e Tecidos/efeitos adversos , Terapia Baseada em Transplante de Células e Tecidos/estatística & dados numéricos , Coleta de Dados , Bases de Dados Factuais , Controle de Formulários e Registros , Humanos , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/estatística & dados numéricos , Internet , National Heart, Lung, and Blood Institute (U.S.) , Vigilância de Produtos Comercializados/métodos , Pesquisa Translacional Biomédica/estatística & dados numéricos , Resultado do Tratamento , Estados UnidosRESUMO
Clinical trials for pediatric diseases face many challenges, including trial design, accrual, ethical considerations for children as research subjects, and the cost of long-term follow-up studies. In September 2011, the Production Assistance for Cellular Therapies Program, funded by the National Heart, Lung, and Blood Institute of the National Institutes of Health, sponsored a workshop, "Cell Therapy for Pediatric Diseases: A Growing Frontier," with the overarching goal of optimizing the path of discovery in research involving novel cellular therapeutic interventions for debilitating pediatric conditions with few or no available treatment options. Academic and industry investigators in the fields of cellular therapy and regenerative medicine described the obstacles encountered in conducting a clinical trial from concept to conclusion. Patient and parent advocates, bioethicists, biostatisticians, regulatory representatives from the US Food and Drug Administration, and translational scientists actively participated in this workshop, seeking to identify the unmet needs specific to cellular therapies and treatment of pediatric diseases and propose strategies to facilitate the development of novel therapies. In this article we summarize the obstacles and potential corrective strategies identified by workshop participants to maximize the speed of cell therapy translational research for childhood diseases.
Assuntos
Terapia Baseada em Transplante de Células e Tecidos , Pesquisa Translacional Biomédica , Criança , Ensaios Clínicos como Assunto , Comportamento Cooperativo , Difusão de Inovações , Educação , Acessibilidade aos Serviços de Saúde , Humanos , Comunicação Interdisciplinar , Avaliação das Necessidades , Estados UnidosRESUMO
The primary tumor represents a potential source of antigens for priming immune responses for disseminated disease. Current means of debulking tumors involves the use of cytoreductive conditioning that impairs immune cells or removal by surgery. We hypothesized that activation of the immune system could occur through the localized release of tumor antigens and induction of tumor death due to physical disruption of tumor architecture and destruction of the primary tumor in situ. This was accomplished by intratumor injection of magneto-rheological fluid (MRF) consisting of iron microparticles, in Balb/c mice bearing orthotopic 4T1 breast cancer, followed by local application of a magnetic field resulting in immediate coalescence of the particles, tumor cell death, slower growth of primary tumors as well as decreased tumor progression in distant sites and metastatic spread. This treatment was associated with increased activation of DCs in the draining lymph nodes and recruitment of both DCs and CD8(+)T cells to the tumor. The particles remained within the tumor and no toxicities were observed. The immune induction observed was significantly greater compared to cryoablation. Further anti-tumor effects were observed when MRF/magnet therapy was combined with systemic low dose immunotherapy. Thus, mechanical disruption of the primary tumor with MRF/magnetic field application represents a novel means to induce systemic immune activation in cancer.
Assuntos
Antineoplásicos/farmacologia , Ferro/farmacologia , Neoplasias Mamárias Animais/radioterapia , Animais , Linfócitos T CD8-Positivos/citologia , Células Dendríticas/citologia , Progressão da Doença , Feminino , Citometria de Fluxo/métodos , Sistema Imunitário , Imunoterapia/métodos , Campos Magnéticos , Magnetismo , Neoplasias Mamárias Animais/metabolismo , Neoplasias Mamárias Animais/terapia , Camundongos , Camundongos Endogâmicos BALB C , Necrose , Metástase Neoplásica , Neoplasias/imunologia , Células-TroncoRESUMO
Graft-versus-host disease (GVHD) is a major complication of allogeneic bone marrow transplantation. It has been previously reported that lung GVHD severity directly correlates with the expansion of donor Th17 cells in the absence of IFN-γ. However, the consequence of Th17-associated lung GVHD in the presence of IFN-γ has not been well characterized. In the current study, T cells from IFN-γ receptor knockout (IFN-γR(-/-)) mice, capable of producing IFN-γ but unable to signal in response to IFN-γ, have been used to elucidate further the role of IFN-γ in GVHD. We found the transfer of donor T cells from either IFN-γR(-/-) or IFN-γ knockout (IFN-γ(-/-)) mice resulted in significant increases in donor Th17 cells in the lung. Marked increases in IL-4-producing Th2 cells infiltrating the lungs were also observed in the mice of donor IFN-γR(-/-) T cells. Notably, despite the presence of these cells, these mice did not show the severe immune-mediated histopathological lung injury observed in mice receiving donor IFN-γ(-/-) T cells. Increases in lung GVHD did occur in mice with donor IFN-γR(-/-) T cells when treated in vivo with anti-IFN-γ demonstrating that the cytokine has a protective role on host tissues in GVHD. A survival benefit from acute GVHD was also observed using donor cells from IFN-γR(-/-) T cells compared with control donors. Importantly, tumor-bearing mice receiving IFN-γR(-/-) T cells versus wild-type donor T cells displayed similar graft-versus-tumor (GVT) effects. These results demonstrate the critical role of IFN-γ on host tissues and cell effector functions in GVHD/GVT.
Assuntos
Transplante de Medula Óssea/imunologia , Doença Enxerto-Hospedeiro/imunologia , Efeito Enxerto vs Tumor/imunologia , Interferon gama/imunologia , Linfócitos T/transplante , Animais , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Interferon/deficiência , Subpopulações de Linfócitos T/imunologia , Linfócitos T/imunologia , Doadores de Tecidos , Transplante Homólogo , Receptor de Interferon gamaRESUMO
The synthetic triterpenoid CDDO-Me has been shown to directly inhibit the growth of myeloid leukemias and lends itself to a wide array of therapeutic indications, including inflammatory conditions, because of its inhibition of NF-κB. We have previously demonstrated protection from acute graft-versus-host disease after CDDO-Me administration in an allogeneic bone marrow transplantation model. In the current study, we observed that CDDO-Me promoted myelopoiesis in both naive and transplanted mice. This effect was dose dependent, as high doses of CDDO-Me inhibited myeloid growth in vitro. All lineages (granulocyte macrophage colony-forming unit, BFU-E) were promoted by CDDO-Me. We then compared the effects with granulocyte colony-stimulating factor, a known inducer of myeloid expansion and mobilization from the bone marrow. Whereas both drugs induced terminal myeloid expansion in the spleen, peripheral blood, and bone marrow, granulocyte colony-stimulating factor only induced granulocyte macrophage colony-forming unit precursors in the spleen, while CDDO-Me increased these precursors in the spleen and bone marrow. After sublethal total-body irradiation, mice pretreated with CDDO-Me further displayed an accelerated recovery of myeloid progenitors and total nucleated cells in the spleen. A similar expansion of myeloid and myeloid progenitors was noted with CDDO-Me treatment after syngeneic bone marrow transplantation. Combined, these data suggest that CDDO-Me may be of use posttransplantation to accelerate myeloid recovery in addition to the prevention of graft-versus-host disease.
Assuntos
Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/efeitos dos fármacos , Mielopoese/efeitos dos fármacos , Ácido Oleanólico/análogos & derivados , Animais , Feminino , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Ácido Oleanólico/farmacologiaRESUMO
The occurrence of acute graft-versus-host disease (aGVHD) and tumor relapse represent the two major obstacles impeding the efficacy of allogeneic bone marrow transplantation (BMT) in cancer. We have previously shown that the synthetic triterpenoid 2-cyano-3, 12-dioxooleana-1, 9-dien-28-oic acid (CDDO) can inhibit murine early aGVHD, but antitumor effects were not assessed. In the current study, we found that a new derivative of CDDO, CDDO-Me, had an increased ability to inhibit allogeneic T cell responses and induce cell death of alloreactive T cells in vitro. Administration of CDDO-Me to mice following allogeneic BMT resulted in significant and increased protection from lethal aGVHD compared to CDDO. This correlated with reduced TNF-alpha production, reduced donor T cell proliferation, and decreased adhesion molecule (alpha(4)beta(7) integrin) expression on the donor T cells. CDDO-Me was also superior to CDDO in inhibiting leukemia growth in vitro. When CDDO-Me was administered following an allogeneic BMT to leukemia-bearing mice, significant increases in survival were observed. These findings suggest that CDDO-Me is superior to CDDO in delaying aGVHD, while preserving or possibly even augmenting GVT effects.
Assuntos
Transplante de Medula Óssea/métodos , Doença Enxerto-Hospedeiro/prevenção & controle , Efeito Enxerto vs Tumor/imunologia , Ácido Oleanólico/análogos & derivados , Animais , Apoptose/efeitos dos fármacos , Apoptose/imunologia , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Colo/patologia , Feminino , Doença Enxerto-Hospedeiro/sangue , Doença Enxerto-Hospedeiro/patologia , Efeito Enxerto vs Tumor/efeitos dos fármacos , Imunossupressores/administração & dosagem , Imunossupressores/farmacologia , Imunossupressores/uso terapêutico , Integrinas/metabolismo , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/terapia , Fígado/patologia , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Teste de Cultura Mista de Linfócitos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Ácido Oleanólico/administração & dosagem , Ácido Oleanólico/farmacologia , Ácido Oleanólico/uso terapêutico , Baço/citologia , Baço/imunologia , Análise de Sobrevida , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Linfócitos T/transplante , Transplante Homólogo , Fator de Necrose Tumoral alfa/sangueRESUMO
Donor NK cells have been shown to be able to promote engraftment during allogeneic bone marrow transplantation. They could specifically suppress or delete host reactive cells, thereby facilitating engraftment of donor marrow. To further elucidate the mechanism, we showed that activated H2(d) ALAK cells (adherent lymphokine activated killer, IL-2 activated T cell-depleted bone marrow and spleen cells) from BALB/c mice significantly suppressed the proliferation of H2(b) splenocytes from C57BL/6 mice in mixed lymphocyte responses (MLR) stimulated with irradiated H2(d) splenocytes from BALB/c mice (P < .01). The ability for H2(b) splenocytes to kill H2(d) tumor targets was also significantly inhibited by activated H2(d) ALAK cells (P < .01). The same number of H2(b) ALAK cells or H2(d) splenocytes did not show the same suppressive effect. These results suggested that activated H2(d) ALAK cells could specifically suppress the anti-H2(d) activity of the H2(b) splenocytes. Anti-tumor growth factor (TGF)beta antibody blockade did not diminish this suppressive effect of ALAK cells, suggesting that this activity is not dependent on TGF-beta secretion. ALAKs from gld (FasL mutant) mice suppressed the allo-responses as well as the wild-type ALAK cells. The ALAKs from pfp (perforin knockout) mice did not completely block the inhibitory effect, which suggested that the suppressive effect of the allogeneic ALAK cells could be partially caused by perforin-mediated killing. We further demonstrated that donor ALAK cells could promote engraftment by suppressing host alloreactive responses in a nonmyeloablative allogeneic BMT model. These studies suggest that activated donor NK cells specifically suppress the alloreactive cells and provide a promising way to promote donor engraftment without involving systemic and nonspecific suppression of the immune system.
Assuntos
Transplante de Medula Óssea , Isoantígenos/imunologia , Células Matadoras Naturais/imunologia , Imunologia de Transplantes/imunologia , Animais , Anticorpos/imunologia , Anticorpos/farmacologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Contagem de Células , Proliferação de Células/efeitos dos fármacos , Citotoxicidade Imunológica/efeitos dos fármacos , Citotoxicidade Imunológica/imunologia , Feminino , Sobrevivência de Enxerto/imunologia , Antígenos H-2/imunologia , Interleucina-2/metabolismo , Células Matadoras Naturais/metabolismo , Células Matadoras Naturais/transplante , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Teste de Cultura Mista de Linfócitos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Citotóxicas Formadoras de Poros/genética , Proteínas Citotóxicas Formadoras de Poros/metabolismo , Baço/citologia , Baço/imunologia , Linfócitos T/citologia , Linfócitos T/imunologia , Linfócitos T Citotóxicos/citologia , Linfócitos T Citotóxicos/imunologia , Fator de Crescimento Transformador beta/imunologia , Fator de Crescimento Transformador beta/metabolismo , Transplante HomólogoRESUMO
The proteasome and its associated ubiquitin protein modification system have proved to be an important therapeutic target in the treatment of multiple myeloma and other cancers. In addition to direct antitumor effects, proteasome inhibition also exerts strong effects on nonneoplastic immune cells. This indicates that proteasome inhibition, through the use of agents like bortezomib, could be used therapeutically to modulate immune responses. In this review we explore the emerging data, both preclinical and clinical, highlighting the importance of proteasome targeting of immunologic responses, primarily in the context of allogeneic hematopoietic stem cell transplantation (HSCT), both for the control of transplant-related toxicities like acute and chronic graft-versus-host disease (aGVHD, cGHVHD), and for improved malignant disease control after allogeneic HSCT.
Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Inibidores de Proteases/farmacologia , Animais , Doença Enxerto-Hospedeiro/terapia , Humanos , Inibidores de Proteases/química , Condicionamento Pré-Transplante/métodosRESUMO
BACKGROUND: Allogeneic hematopoietic stem cell transplantation offers great promise for the treatment of a variety of diseases including malignancies and other diseases of hematopoietic origin. However, morbidity and mortality due to graft-versus-host disease (GVHD) remain a major barrier to its application. OBJECTIVE: This review will provide an overview of the pathophysiology of GVHD and discuss the recent advances in GVHD management in both preclinical and clinical studies. METHODS: An extensive literature search on PubMed from 1995 to 2008 was performed. RESULTS/CONCLUSION: There has been much progress in our understanding of GVHD and finding new means to control acute GVHD. While these approaches hold promise, as yet none has been able to replace the standard methods we may use routinely to decrease the incidence of the condition.
Assuntos
Doença Enxerto-Hospedeiro/prevenção & controle , Doença Enxerto-Hospedeiro/terapia , Transplante de Células-Tronco Hematopoéticas , Imunossupressores/uso terapêutico , Doença Aguda , Transferência Adotiva , Animais , Anticorpos Monoclonais/uso terapêutico , Soro Antilinfocitário/uso terapêutico , Movimento Celular , Citocinas/antagonistas & inibidores , Doença Enxerto-Hospedeiro/imunologia , Humanos , Células Matadoras Naturais/transplante , Transplante de Células-Tronco Mesenquimais , Camundongos , Fotoquimioterapia , Fotoferese , Linfócitos T/imunologia , Linfócitos T Reguladores/transplanteRESUMO
Dissociating graft-versus-tumor (GVT) effect from acute graft-versus-host disease (GVHD) still remains a great challenge in allogeneic bone marrow transplantation (allo-BMT). Bortezomib, a proteasome inhibitor, has shown impressive efficacy as a single agent in patients with hematologic malignancies but can result in toxicity when administered late after allogeneic transplantation in murine models of GVHD. In the current study, the effects of T-cell subsets and their associated cytokines on the efficacy of bortezomib in murine allogeneic BMT were investigated. Increased levels of serum tumor necrosis factor-alpha (TNFalpha) and interferon-gamma (IFNgamma) were observed after allo-BMT and continuous bortezomib administration. Bortezomib-induced GVHD-dependent mortality was preventable by depletion of CD4(+) but not CD8(+) T cells from the donor graft. The improved survival correlated with markedly reduced serum TNFalpha but not IFNgamma levels. Transfer of Tnf(-/-) T cells also protected recipients from bortezomib-induced GVHD-dependent toxicity. Importantly, prolonged administration of bortezomib after transplantation of purified CD8(+) T cells resulted in enhanced GVT response, which was dependent on donor CD8(+) T cell-derived IFNgamma. These results indicate that decreased toxicity and increased efficacy of bortezomib in murine allo-BMT can be achieved by removal of CD4(+) T cells from the graft or by inhibiting TNFalpha.
Assuntos
Transplante de Medula Óssea/métodos , Ácidos Borônicos/administração & dosagem , Citocinas/metabolismo , Pirazinas/administração & dosagem , Subpopulações de Linfócitos T/imunologia , Linfócitos T/transplante , Animais , Transplante de Medula Óssea/efeitos adversos , Bortezomib , Feminino , Efeito Enxerto vs Leucemia , Efeito Enxerto vs Tumor , Interferon gama , Depleção Linfocítica , Camundongos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Transplante Homólogo , Resultado do Tratamento , Fator de Necrose Tumoral alfa/metabolismoRESUMO
CD40/CD40L signaling promotes both B cell and CTL responses in vivo, the latter being beneficial in tumor models. Because CTL may also limit autoreactive B cell expansion in lupus, we asked whether an agonist CD40 mAb would exacerbate lupus due to B cell stimulation or would improve lupus due to CTL promotion. These studies used an induced model of lupus, the parent-into-F1 model in which transfer of DBA/2 splenocytes into B6D2F1 mice induces chronic lupus-like graft-vs-host disease (GVHD). Although agonist CD40 mAb treatment of DBA-->F1 mice initially exacerbated B cell expansion, it also strongly promoted donor CD8 T cell engraftment and cytolytic activity such that by 10 days host B cells were eliminated consistent with an accelerated acute GVHD. CD40 stimulation bypassed the requirement for CD4 T cell help for CD8 CTL possibly by licensing dendritic cells (DC) as shown by the following: 1) greater initial activation of donor CD8 T cells, but not CD4 T cells; 2) earlier activation of host DC; 3) host DC expansion that was CD8 dependent and CD4 independent; and 4) induction of acute GVHD using CD4-depleted purified DBA CD8+ T cells. A single dose of CD40 mAb improved lupus-like renal disease at 12 wk, but may not suffice for longer periods consistent with a need for continuing CD8 CTL surveillance. These results demonstrate that in the setting of lupus-like CD4 T cell-driven B cell hyperactivity, CTL promotion is both feasible and beneficial and the CTL-promoting properties of CD40 stimulation outweigh the B cell-stimulatory properties.
Assuntos
Linfócitos B/imunologia , Antígenos CD40/imunologia , Modelos Animais de Doenças , Lúpus Eritematoso Sistêmico/imunologia , Linfócitos T Citotóxicos/imunologia , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/uso terapêutico , Linfócitos T CD4-Positivos/imunologia , Antígenos CD40/agonistas , Células Cultivadas , Citotoxicidade Imunológica/imunologia , Células Dendríticas/imunologia , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/imunologia , Ativação Linfocitária/imunologia , Masculino , Camundongos , Fenótipo , Fatores de TempoRESUMO
Neuroendocrine hormones such as growth hormone (GH) and prolactin (PRL) have been demonstrated to accelerate the recovery of the immune response after chemotherapy and bone marrow transplantation and to enhance the restoration of immunity in individuals infected with HIV and in normal individuals with compromised immune systems associated with aging. As the mechanism of action of these hormones has been elucidated, it has become clear that they are integral members of the immunological cytokine/chemokine network and share regulatory mechanisms with a wide variety of cytokines and chemokines. The members of this cytokine network induce and can be regulated by members of the suppressor of cytokine signaling (SOCS) family of intracellular proteins. In order to take advantage of the potential beneficial effects of hormones such as GH or PRL, it is essential to take into consideration the overall cytokine network and the regulatory effects of SOCS proteins.
Assuntos
Citocinas/imunologia , Hormônio do Crescimento/imunologia , Prolactina/imunologia , Transdução de Sinais , Envelhecimento/imunologia , Animais , Citocinas/metabolismo , Hormônio do Crescimento/metabolismo , Humanos , Sistemas Neurossecretores , Prolactina/metabolismoRESUMO
Recently, our laboratory reported that secondary CD8+ T cell-mediated antitumor responses were impaired following successful initial antitumor responses using various immunotherapeutic approaches. Although immunotherapy stimulated significant increases in CD8+ T cell numbers, the number of CD4+ T cells remained unchanged. The current investigation revealed a marked differential expansion of CD4+ T cell subsets. Successful immunotherapy surprisingly resulted in an expansion of CD4+Foxp3+ regulatory T (Treg) cells concurrent with a reduction of conventional CD4+ T (Tconv) cells, despite the marked antitumor responses. Following immunotherapy, we observed differential up-regulation of PD-1 on the surface of CD4+Foxp3+ Treg cells and CD4+Foxp3- Tconv cells. Interestingly, it was the ligand for PD-1, B7-H1 (PDL-1), that correlated with Tconv cell loss after treatment. Furthermore, IFN-gamma knockout (IFN-gamma-/-) and IFN-gamma receptor knockout (IFN-gammaR-/-) animals lost up-regulation of surface B7-H1 even though PD-1 expression of Tconv cells was not changed, and this correlated with CD4+ Tconv cell increases. These results suggest that subset-specific expansion may contribute to marked shifts in the composition of the T cell compartment, potentially influencing the effectiveness of some immunotherapeutic approaches that rely on IFN-gamma.
Assuntos
Antígenos de Superfície/biossíntese , Proteínas Reguladoras de Apoptose/biossíntese , Antígeno B7-1/biossíntese , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Imunoterapia , Glicoproteínas de Membrana/biossíntese , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Animais , Anticorpos/uso terapêutico , Antineoplásicos/uso terapêutico , Antígeno B7-H1 , Antígenos CD40/imunologia , Feminino , Humanos , Imunoterapia/métodos , Interleucina-2/uso terapêutico , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Peptídeos , Receptor de Morte Celular Programada 1 , Ratos , Proteínas Recombinantes/uso terapêuticoRESUMO
Acute graft-versus-host disease (aGVHD) still remains one of the life-threatening complications following allogeneic hematopoietic stem cell transplantation (allo-HSCT). Immunomodulation of alloreactive donor T cell responses, as well as cytokine secretion is a potential therapeutic approach for the prevention of aGVHD. The synthetic triterpenoid, CDDO (2-cyano-3, 12-dioxooleana-1, 9-dien-28-oic acid), exhibits potent antitumor activity and has also been shown to mediate anti-inflammatory and immunomodulatory effects. We therefore wanted to assess the effects of CDDO on early lethal aGVHD. In this study, we found that CDDO significantly inhibited in vitro mixed lymphocyte responses and preferentially promoted the apoptosis of proliferating but not resting alloreactive T cells. Using a full major histocompatibility complex (MHC)-disparate murine aGVHD model, we found that the administration of CDDO immediately after transplantation significantly decreased liver pathology as determined by histologic assessment and prolonged survival in mice. Importantly, administration of CDDO did not adversely impair donor myeloid reconstitution as determined by peripheral blood cell count and the extent of donor chimerism. These findings indicate that CDDO has a significant immunomodulatory effects in vitro and on early lethal aGVHD development, particularly affecting the liver, in a murine allo-HSCT model.