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1.
Eur J Immunol ; 51(1): 39-55, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33275279

RESUMO

CD4+ CD25high CD127low/- FOXP3+ T regulatory cells are responsible for maintaining immune tolerance and controlling excessive immune responses. Treg cell use in pre-clinical animal models showed the huge therapeutic potential of these cells in immune-mediated diseases and laid the foundations for their applications in therapy in humans. Currently, there are several clinical trials utilizing the adoptive transfer of Treg cells to reduce the morbidity in autoimmune disorders, allogeneic HSC transplantation, and solid organ transplantation. However, a large part of them utilizes total Treg cells without distinction of their biological variability. Many studies on the heterogeneity of Treg cell population revealed distinct subsets with different functions in the control of the immune response and induction of peripheral tolerance. Some of these subsets also showed a role in controlling the general homeostasis of non-lymphoid tissues. All these Treg cell subsets and their peculiar properties can be therefore exploited to develop novel therapeutic approaches. This review describes these functionally distinct subsets, their phenotype, homing properties and functions in lymphoid and non-lymphoid tissues. In addition, we also discuss the limitations in using Treg cells as a cellular therapy and the strategies to enhance their efficacy.


Assuntos
Imunoterapia Adotiva/métodos , Linfócitos T Reguladores/classificação , Linfócitos T Reguladores/imunologia , Tecido Adiposo/citologia , Tecido Adiposo/imunologia , Aloenxertos , Animais , Doenças Autoimunes/imunologia , Doenças Autoimunes/terapia , Fatores de Transcrição Forkhead/imunologia , Transplante de Células-Tronco Hematopoéticas , Humanos , Tolerância Imunológica , Camundongos , Modelos Imunológicos , Tolerância Periférica , Imunologia de Transplantes , Cicatrização/imunologia
2.
Am J Transplant ; 20(4): 1125-1136, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31715056

RESUMO

Regulatory T cells (Tregs) are a lymphocyte subset with intrinsic immunosuppressive properties that can be expanded in large numbers ex vivo and have been shown to prevent allograft rejection and promote tolerance in animal models. To investigate the safety, applicability, and biological activity of autologous Treg adoptive transfer in humans, we conducted an open-label, dose-escalation, Phase I clinical trial in liver transplantation. Patients were enrolled while awaiting liver transplantation or 6-12 months posttransplant. Circulating Tregs were isolated from blood or leukapheresis, expanded under good manufacturing practices (GMP) conditions, and administered intravenously at either 0.5-1 million Tregs/kg or 3-4.5 million Tregs/kg. The primary endpoint was the rate of dose- limiting toxicities occurring within 4 weeks of infusion. The applicability of the clinical protocol was poor unless patient recruitment was deferred until 6-12 months posttransplant. Thus, only 3 of the 17 patients who consented while awaiting liver transplantation were dosed. In contrast, all six patients who consented 6-12 months posttransplant received the cell infusion. Treg transfer was safe, transiently increased the pool of circulating Tregs and reduced anti-donor T cell responses. Our study opens the door to employing Treg immunotherapy to facilitate the reduction or complete discontinuation of immunosuppression following liver transplantation.


Assuntos
Transplante de Fígado , Linfócitos T Reguladores , Transferência Adotiva , Animais , Humanos , Terapia de Imunossupressão , Doadores de Tecidos
3.
Front Immunol ; 9: 354, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29535728

RESUMO

Solid organ transplantation is the treatment of choice for patients with end-stage organ dysfunction. Despite improvements in short-term outcome, long-term outcome is suboptimal due to the increased morbidity and mortality associated with the toxicity of immunosuppressive regimens and chronic rejection (1-5). As such, the attention of the transplant community has focused on the development of novel therapeutic strategies to achieve allograft tolerance, a state whereby the immune system of the recipient can be re-educated to accept the allograft, averting the need for long-term immunosuppression. Indeed, reports of "operational" tolerance, whereby the recipient is off all immunosuppressive drugs and maintaining good graft function, is well documented in the literature for both liver and kidney transplantations (6-8). However, this phenomenon is rare and in the setting of liver transplantation has been shown to occur late after transplantation, with the majority of patients maintained on life-long immunosupression to prevent allograft rejection (9). As such, significant research has focused on immune regulation in the context of organ transplantation with regulatory T cells (Tregs) identified as cells holding considerable promise in this endeavor. This review will provide a brief introduction to human Tregs, their phenotypic and functional characterization and focuses on our experience to date at the clinical translation of Treg immunotherapy in the setting of solid organ transplantation.


Assuntos
Terapia Baseada em Transplante de Células e Tecidos , Rejeição de Enxerto/terapia , Imunoterapia Adotiva/métodos , Transplante de Órgãos , Linfócitos T Reguladores/imunologia , Aloenxertos/imunologia , Animais , Humanos , Linfócitos T Reguladores/transplante , Pesquisa Translacional Biomédica , Tolerância ao Transplante
4.
Cell Rep ; 20(3): 757-770, 2017 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-28723576

RESUMO

Regulatory T cells (Tregs) play a pivotal role in maintaining immunological tolerance, but they can also play a detrimental role by preventing antitumor responses. Here, we characterized T helper (Th)-like Treg subsets to further delineate their biological function and tissue distribution, focusing on their possible contribution to disease states. RNA sequencing and functional assays revealed that Th2-like Tregs displayed higher viability and autocrine interleukin-2 (IL-2)-mediated activation than other subsets. Th2-like Tregs were preferentially found in tissues rather than circulation and exhibited the highest migratory capacity toward chemokines enriched at tumor sites. These cellular responses led us to hypothesize that this subset could play a role in maintaining a tumorigenic environment. Concurrently, Th2-like Tregs were enriched specifically in malignant tissues from patients with melanoma and colorectal cancer compared to healthy tissue. Overall, our results suggest that Th2-like Tregs may contribute to a tumorigenic environment due to their increased cell survival, higher migratory capacity, and selective T-effector suppressive ability.


Assuntos
Comunicação Autócrina/imunologia , Interleucina-2/imunologia , Melanoma/imunologia , Linfócitos T Reguladores/imunologia , Células Th2/imunologia , Microambiente Tumoral/imunologia , Adulto , Feminino , Humanos , Masculino , Melanoma/patologia , Linfócitos T Reguladores/patologia , Células Th2/patologia
5.
J Immunol Methods ; 341(1-2): 76-85, 2009 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-19056394

RESUMO

Exploring the intricacies of CD8(+) T-cell epitope recognition using emerging technologies to combine assessment of affinity, phenotype and resulting polyfunctional efficacy advances our understanding of HIV-1 immunopathogenesis and disease progression. Complexities within T-cell antigen recognition, such as epitope:MHC binding, stability and affinity, appear to influence the distinction between protective and ineffective anti-HIV-1 immune responses, which are thought to govern rate of disease progression. This study utilises the novel ProImmune REVEAL and ProVE(R) technology of rapid peptide synthesis, binding and affinity assays, and pentamer synthesis in conjunction with flow cytometry and simultaneous assessment of multiple CD8(+) T-cell effector functions in response to HLA-B3501-restricted HIV-1 Gag peptides, to discover new T-cell epitopes. The predicted HLA-B3501-restricted peptides, HPVHAGPIA and YPLTSLRSL, and relevant pentamers were used in parallel to validate T-cell epitopes on clinical HIV-1(+) samples, confirming correlation between the expected superior immunogenicity of newly discovered epitopes and the ex vivo T-cell response. Such a platform should be employed in prophylactic and therapeutic vaccine settings.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Mapeamento de Epitopos/métodos , Epitopos de Linfócito T/imunologia , HIV-1/imunologia , Antígenos HLA-B/imunologia , Produtos do Gene gag do Vírus da Imunodeficiência Humana/imunologia , Vacinas contra a AIDS/imunologia , Feminino , Antígeno HLA-B35 , Humanos , Imunoensaio/métodos , Masculino , Peptídeos/síntese química , Peptídeos/química , Peptídeos/imunologia , Receptores de Antígenos de Linfócitos T/imunologia
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