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1.
J Immunother Cancer ; 10(4)2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35387779

RESUMO

BACKGROUND: Targeting immune checkpoints that inhibit antitumor immune responses has emerged as a powerful new approach to treat cancer. We recently showed that blocking the tumor necrosis factor receptor-type 2 (TNFR2) pathway induces the complete loss of the protective function of regulatory T cells (Tregs) in a model of graft-versus-host disease (GVHD) prevention that relies on Treg-based cell therapy. Here, we tested the possibility of amplifying the antitumor response by targeting TNFR2 in a model of tumor relapse following hematopoietic stem-cell transplantation, a clinical situation for which the need for efficient therapeutic options is still unmet. METHOD: We developed appropriate experimental conditions that mimic patients that relapsed from their initial hematological malignancy after hematopoietic stem-cell transplantation. This consisted of defining in allogeneic bone marrow transplantation models developed in mice, the maximum number of required tumor cells and T cells to infuse into recipient mice to develop a model of tumor relapse without inducing GVHD. We next evaluated whether anti-TNFR2 treatment could trigger alloreactivity and consequently antitumor immune response. In parallel, we also studied the differential expression of TNFR2 on T cells including Treg from patients in post-transplant leukemia relapse and in patients developing GVHD. RESULTS: Using experimental conditions in which neither donor T cells nor TNFR2-blocking antibody per se have any effect on tumor relapse, we observed that the coadministration of a suboptimal number of T cells and an anti-TNFR2 treatment can trigger alloreactivity and subsequently induce a significant antitumor effect. This was associated with a reduced percentage of activated CD4+ and CD8+ Tregs. Importantly, human Tregs over-expressed TNFR2 relative to conventional T cells in healthy donors and in patients experiencing leukemia relapse or cortico-resistant GVHD after hematopoietic stem cell transplantation. CONCLUSIONS: These results highlight TNFR2 as a new target molecule for the development of immunotherapies to treat blood malignancy relapse, used either directly in grafted patients or to enhance donor lymphocyte infusion strategies. More widely, they open the door for new perspectives to amplify antitumor responses against solid cancers by directly targeting Tregs through their TNFR2 expression.


Assuntos
Doença Enxerto-Hospedeiro , Neoplasias Hematológicas , Transplante de Células-Tronco Hematopoéticas , Leucemia , Animais , Doença Enxerto-Hospedeiro/etiologia , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Imunidade , Leucemia/terapia , Camundongos , Receptores Tipo II do Fator de Necrose Tumoral , Recidiva , Linfócitos T Reguladores , Transplante Homólogo
2.
World J Gastroenterol ; 23(38): 6962-6972, 2017 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-29097869

RESUMO

AIM: To test whether a delayed and short course of rapamycin would induce immunosuppressive effects following allogeneic orthotopic liver transplantation (OLT) in rats. METHODS: Allogeneic OLTs were performed using Dark Agouti livers transplanted into Lewis recipients, and syngeneic OLTs were performed using the Lewis rat strain. Rapamycin (1 mg/kg per day) was administered by gavage from day 4 to day 11 post-transplantation. Lymphocyte cellular compartments were analyzed by flow cytometry in draining lymph nodes, non-draining lymph nodes and the spleen at days 11 and 42 in rapamycin-treated rats, untreated control rats and syngeneic grafted rats. Skin grafts from Dark agouti or from F344 RT were performed at day 30 on liver grafted rats treated with rapamycin. RESULTS: An 8-d course of rapamycin treatment initiated 4 d following transplantation resulted in the survival of grafted rats for more than 100 d. In contrast, untreated rats died of liver failure within 13 to 21 d. The analysis of the cellular compartment revealed an increase in two cellular subpopulations, specifically myeloid-derived suppressor cells (MDSCs) and CD8+CD45RClow T cells, without major modifications in the regulatory T cell (Treg) compartment in treated rats in the early stages after grafting. We evaluated the ability of treated rats to reject third-party allogeneic skin grafts to confirm their immune competence. In contrast, when skin was collected from rats syngeneic to the grafted liver, it was not rejected. CONCLUSION: Our results demonstrate that short and delayed rapamycin treatment allows for tolerance in allogeneic OLT. The results also allowed for the identification of the mechanisms of tolerance induced by rapamycin by identifying MDSCs and CD8+CD45RClow T cells as associated with the state of tolerance.


Assuntos
Rejeição de Enxerto/prevenção & controle , Tolerância Imunológica/efeitos dos fármacos , Imunossupressores/administração & dosagem , Transplante de Fígado , Sirolimo/administração & dosagem , Animais , Avaliação Pré-Clínica de Medicamentos , Tolerância Imunológica/imunologia , Masculino , Ratos Endogâmicos Lew , Transplante Homólogo
3.
Transplantation ; 101(7): e205-e213, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28403128

RESUMO

BACKGROUND: Control of warm ischemia (WI) lesions that occur with donation after circulatory death (DCD) would significantly increase the donor pool for liver transplantation. We aimed to determine whether a novel, oxygenated and hypothermic machine perfusion device (HMP Airdrive system) improves the quality of livers derived from DCDs using a large animal model. METHODS: Cardiac arrest was induced in female large white pigs by intravenous injection of potassium chloride. After 60 minutes of WI, livers were flushed in situ with histidine-tryptophan-ketoglutarate and subsequently preserved either by simple cold storage (WI-SCS group) or HMP (WI-HMP group) using Belzer-MPS solution. Liver grafts procured from heart-beating donors and preserved by SCS served as controls. After 4 hours of preservation, all livers were transplanted. RESULTS: All recipients in WI-SCS group died within 6 hours after transplantation. In contrast, the HMP device fully protected the liver against lethal ischemia/reperfusion injury, allowing 100% survival rate. A postreperfusion syndrome was observed in all animals of the WI-SCS group but none of the control or WI-HMP groups. After reperfusion, HMP-preserved livers functioned better and showed less hepatocellular and endothelial cell injury, in agreement with better-preserved liver histology relative to WI-SCS group. In addition to improved energy metabolism, this protective effect was associated with an attenuation of inflammatory response, oxidative load, endoplasmic reticulum stress, mitochondrial damage, and apoptosis. CONCLUSIONS: This study demonstrates for the first time the efficacy of the HMP Airdrive system to protect liver grafts from lethal ischemic damage before transplantation in a clinically relevant DCD model.


Assuntos
Hepatectomia , Transplante de Fígado/instrumentação , Fígado/cirurgia , Perfusão/instrumentação , Traumatismo por Reperfusão/prevenção & controle , Isquemia Quente/instrumentação , Aloenxertos , Animais , Biomarcadores/metabolismo , Modelos Animais de Doenças , Metabolismo Energético , Desenho de Equipamento , Feminino , Glucose/farmacologia , Sobrevivência de Enxerto , Parada Cardíaca/induzido quimicamente , Hepatectomia/efeitos adversos , Fígado/metabolismo , Fígado/patologia , Testes de Função Hepática , Transplante de Fígado/efeitos adversos , Transplante de Fígado/métodos , Manitol/farmacologia , Teste de Materiais , Soluções para Preservação de Órgãos/farmacologia , Perfusão/efeitos adversos , Perfusão/métodos , Cloreto de Potássio/farmacologia , Procaína/farmacologia , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Sus scrofa , Fatores de Tempo , Sobrevivência de Tecidos , Isquemia Quente/efeitos adversos , Isquemia Quente/métodos
4.
Nat Commun ; 7: 13027, 2016 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-27708334

RESUMO

Type 1 diabetes (T1D) is characterized by a chronic, progressive autoimmune attack against pancreas-specific antigens, effecting the destruction of insulin-producing ß-cells. Here we show interleukin-2 (IL-2) is a non-pancreatic autoimmune target in T1D. Anti-IL-2 autoantibodies, as well as T cells specific for a single orthologous epitope of IL-2, are present in the peripheral blood of non-obese diabetic (NOD) mice and patients with T1D. In NOD mice, the generation of anti-IL-2 autoantibodies is genetically determined and their titre increases with age and disease onset. In T1D patients, circulating IgG memory B cells specific for IL-2 or insulin are present at similar frequencies. Anti-IL-2 autoantibodies cloned from T1D patients demonstrate clonality, a high degree of somatic hypermutation and nanomolar affinities, indicating a germinal centre origin and underscoring the synergy between cognate autoreactive T and B cells leading to defective immune tolerance.


Assuntos
Diabetes Mellitus Tipo 1/imunologia , Tolerância Imunológica , Interleucina-2/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Autoanticorpos/imunologia , Epitopos/imunologia , Feminino , Humanos , Imunoglobulina G/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Pessoa de Meia-Idade , Pâncreas/imunologia , Peptídeos/imunologia , Linfócitos T/citologia , Adulto Jovem
5.
Brain Behav Immun ; 45: 219-32, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25483139

RESUMO

We previously showed that Trypanosomacruzi infection in C57BL/6 mice results in a lethal infection linked to unbalanced pro- and anti-inflammatory mediators production. Here, we examined the dynamics of CD4(+)Foxp3(+) regulatory T (Treg) cells within this inflammatory and highly Th1-polarized environment. Treg cells showed a reduced proliferation rate and their frequency is progressively reduced along infection compared to effector T (Teff) cells. Also, a higher fraction of Treg cells showed a naïve phenotype, meanwhile Teff cells were mostly of the effector memory type. T. cruzi infection was associated with the production of pro- and anti-inflammatory cytokines, notably IL-27p28, and with the induction of T-bet and IFN-γ expression in Treg cells. Furthermore, endogenous glucocorticoids released in response to T. cruzi-driven immune activation were crucial to sustain the Treg/Teff cell balance. Notably, IL-2 plus dexamethasone combined treatment before infection was associated with increased Treg cell proliferation and expression of GATA-3, IL-4 and IL-10, and increased mice survival time. Overall, our results indicate that therapies aimed at specifically boosting Treg cells, which during T. cruzi infection are overwhelmed by the effector immune response, represent new opportunities for the treatment of Chagas disease, which is actually only based on parasite-targeted chemotherapy.


Assuntos
Doença de Chagas/imunologia , Linfócitos T Reguladores/imunologia , Células Th1/imunologia , Trypanosoma cruzi/imunologia , Adrenalectomia , Animais , Cardiomiopatia Chagásica/imunologia , Cardiomiopatia Chagásica/patologia , Doença de Chagas/patologia , Corticosterona/sangue , Dexametasona/farmacologia , Modelos Animais de Doenças , Fator de Transcrição GATA3/efeitos dos fármacos , Fator de Transcrição GATA3/imunologia , Glucocorticoides/farmacologia , Interferon gama/efeitos dos fármacos , Interferon gama/imunologia , Interleucina-10/imunologia , Interleucina-2/farmacologia , Interleucina-4/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Músculo Esquelético/patologia , Miocárdio/patologia , Fenótipo , Linfócitos T Reguladores/efeitos dos fármacos , Células Th1/efeitos dos fármacos
6.
Am J Hematol ; 89(3): 261-6, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24779034

RESUMO

Sickle cell disease (SCD) is a chronic inflammatory disease associated with multiple organ damage, chronic anemia, and infections. SCD patients have a high rate of alloimmunization against red blood cells (RBCs) following transfusion and may develop autoimmune diseases. Studies in mouse models have suggested that regulatory T cells (Treg) play a role in alloimmunization against RBC antigens. We characterized the phenotype and function of the Treg cell population in a homogeneous cohort of transfused SCD patients. We found that the distribution of Treg subpopulations differed significantly between SCD patients and healthy blood donors. SCD patients have a particular Treg phenotype, with strong CTLA-4 and CD39 expression and weak HLA-DR and CCR7 expression. Finally, we show that this particular phenotype is related to SCD rather than alloimmunization status. Indeed, we observed no difference in Treg phenotype or function in vitro using autologous feeder cells between strong and weak responders to alloimmunization.


Assuntos
Anemia Falciforme/imunologia , Incompatibilidade de Grupos Sanguíneos/imunologia , Eritrócitos/imunologia , Linfócitos T Reguladores/imunologia , Adulto , Antígenos CD/imunologia , Antígenos de Grupos Sanguíneos/imunologia , Antígeno CTLA-4/imunologia , Feminino , Antígenos HLA-DR/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Receptores CCR7/imunologia , Adulto Jovem
7.
Blood ; 117(10): 2975-83, 2011 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-21193693

RESUMO

Recipient-specific regulatory T cells (rsTreg) can prevent graft-versus-host disease (GVHD) by inhibiting donor T-cell expansion after hematopoietic stem cell transplantation (HSCT) in mice. Importantly, in adult humans, because of thymus involution, immune reconstitution during the first months after HSCT relies on the peripheral expansion of donor T cells initially present in the graft. Therefore, we developed a mouse model of HSCT that excludes thymic output to study the effect of rsTreg on immune reconstitution derived from postthymic mature T cells present within the graft. We showed that GVHD prevention with rsTreg was associated with improvement of the limited immune reconstitution compared with GVHD mice in terms of cell numbers, activation phenotype, and cytokine production. We further demonstrated a preserved in vivo immune function using vaccinia infection and third-party skin-graft rejection models, suggesting that rsTreg immunosuppression was relatively specific of GVHD. Finally, we showed that rsTreg extensively proliferated during the first 2 weeks and then declined. In turn, donor Treg proliferated from day 15 on. Taken together, these results suggest that rsTreg GVHD prevention is associated with improved early immune reconstitution in a model that more closely approximates the biology of allogeneic HSCT in human adults.


Assuntos
Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/transplante , Animais , Modelos Animais de Doenças , Doença Enxerto-Hospedeiro/imunologia , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL
8.
Nephrol Dial Transplant ; 26(3): 1087-93, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20667993

RESUMO

BACKGROUND: Belatacept is thought to disrupt the interaction between CD80/86 and CD28, thus preventing T-cell activation by blocking the co-stimulatory second signal. However, the consequences on the T-cell profile in human renal transplant cases have not been determined. METHODS: In this study, we analysed intra-graft levels of the mRNAs for Treg (FOXP3), cytotoxic CD8 T cells (Granzyme B), Th1 (INFγ, Tbet), Th2 (GATA3) and Th17 (RORγt and IL-17) in protocol biopsies obtained 12 months after renal transplantation in recipients treated with Belatacept or calcineurin inhibitor (CNI). RESULTS: Only the intra-graft abundance of FOXP3 mRNA was significantly lower (P < 0.001) in the Belatacept group than the CNI group. Conclusions. These results are in agreement with in vitro data suggesting that CD28 is a major co-stimulatory signal of both Tregs development and peripheral homeostasis but contrast with clinical trials showing a better 1-year graft function and a lower incidence of chronic allograft nephropathy in patients receiving Belatacept than patients treated with CNI. They suggest that immune benefits induced by Belatacept are not mediated by Treg expansion and that FOXP3 is not by itself a prognostic marker of long-term graft function in a non-inflammatory context. These results have to be, however, considered as preliminary since the size of our study population is limited.


Assuntos
Fatores de Transcrição Forkhead/antagonistas & inibidores , Rejeição de Enxerto/prevenção & controle , Imunoconjugados/uso terapêutico , Transplante de Rim/imunologia , Linfócitos T Reguladores/efeitos dos fármacos , Tolerância ao Transplante/efeitos dos fármacos , Abatacepte , Antígeno B7-1/imunologia , Antígeno B7-2/imunologia , Biópsia , Antígenos CD28/imunologia , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Feminino , Citometria de Fluxo , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Rejeição de Enxerto/imunologia , Humanos , Técnicas Imunoenzimáticas , Imunossupressores/uso terapêutico , Interleucina-17/metabolismo , Nefropatias/imunologia , Nefropatias/cirurgia , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , Fenótipo , Prognóstico , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Risco , Taxa de Sobrevida , Linfócitos T Reguladores/imunologia , Células Th1/imunologia , Células Th2/imunologia , Tolerância ao Transplante/imunologia
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