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1.
PLoS Biol ; 19(4): e3001199, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33901179

RESUMO

Programmed cell death protein 1 (PD-1) is expressed on T cells upon T cell receptor (TCR) stimulation. PD-1 ligand 1 (PD-L1) is expressed in most tumor environments, and its binding to PD-1 on T cells drives them to apoptosis or into a regulatory phenotype. The fact that PD-L1 itself is also expressed on T cells upon activation has been largely neglected. Here, we demonstrate that PD-L1 ligation on human CD25-depleted CD4+ T cells, combined with CD3/TCR stimulation, induces their conversion into highly suppressive T cells. Furthermore, this effect was most prominent in memory (CD45RA-CD45RO+) T cells. PD-L1 engagement on T cells resulted in reduced ERK phosphorylation and decreased AKT/mTOR/S6 signaling. Importantly, T cells from rheumatoid arthritis patients exhibited high basal levels of phosphorylated ERK and following PD-L1 cross-linking both ERK signaling and the AKT/mTOR/S6 pathway failed to be down modulated, making them refractory to the acquisition of a regulatory phenotype. Altogether, our results suggest that PD-L1 signaling on memory T cells could play an important role in resolving inflammatory responses; maintaining a tolerogenic environment and its failure could contribute to ongoing autoimmunity.


Assuntos
Antígeno B7-H1/metabolismo , Linfócitos T CD4-Positivos/fisiologia , Linfócitos T Reguladores/fisiologia , Antígeno B7-H1/fisiologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/fisiologia , Transdiferenciação Celular/genética , Transdiferenciação Celular/imunologia , Estudos de Coortes , Humanos , Tolerância Imunológica/genética , Tolerância Imunológica/imunologia , Memória Imunológica/fisiologia , Antígenos Comuns de Leucócito/metabolismo , Fenótipo , Receptor de Morte Celular Programada 1/metabolismo , Receptor de Morte Celular Programada 1/fisiologia , Transdução de Sinais/fisiologia , Linfócitos T Reguladores/metabolismo
2.
Molecules ; 28(3)2023 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-36771148

RESUMO

Regulatory T cells (Tregs) are a promising candidate cell therapy to treat autoimmune diseases and aid the longevity of transplanted solid organs. Despite increasing numbers of clinical trials using human Treg therapy, important questions pertaining to their in vivo fate, distribution, and function remain unanswered. Treg accumulation in relevant tissues was found to be crucial for Treg therapy efficacy, but existing blood-borne biomarkers are unlikely to accurately reflect the tissue state. Non-invasive Treg tracking by whole-body imaging is a promising alternative and can be achieved by direct radiolabelling of Tregs and following the radiolabelled cells with positron emission tomography (PET). Our goal was to evaluate the radiolabelling of polyclonal Tregs with 89Zr to permit their in vivo tracking by PET/CT for longer than one week with current preclinical PET instrumentation. We used [89Zr]Zr(oxinate)4 as the cell-labelling agent and achieved successful radiolabelling efficiency of human Tregs spanning 0.1-11.1 Bq 89Zr/Treg cell, which would be compatible with PET tracking beyond one week. We characterized the 89Zr-Tregs, assessing their phenotypes, and found that they were not tolerating these intracellular 89Zr amounts, as they failed to survive or expand in a 89Zr-dose-dependent manner. Even at 0.1 Bq 89Zr per Treg cell, while 89Zr-Tregs remained functional as determined by a five-day-long effector T cell suppression assay, they failed to expand beyond day 3 in vitro. Moreover, PET imaging revealed signs of 89Zr-Treg death after adoptive transfer in vivo. In summary, 89Zr labelling of Tregs at intracellular radioisotope amounts compatible with cell tracking over several weeks did not achieve the desired outcomes, as 89Zr-Tregs failed to expand and survive. Consequently, we conclude that indirect Treg labelling is likely to be the most effective alternative method to satisfy the requirements of this cell tracking scenario.


Assuntos
Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Linfócitos T Reguladores , Humanos , Oxiquinolina , Rastreamento de Células , Radioisótopos/metabolismo
3.
Immunol Rev ; 292(1): 164-179, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31559645

RESUMO

The interest in regulatory B cells (Bregs) began in the 1970s with the evidence that B cells could downregulate the immune system by the production of "inhibitory" antibodies. Subsequently, a series of results from different studies have emphasized that B cells have antibody-independent immunoregulatory functions. Since then, different subsets of B cells with regulatory functions and their development and mechanisms of action have been identified both in human and in animal models of inflammation, transplantation, and autoimmunity. The present review outlines the suggested pathways by which Bregs develop, describes the different subsets of Bregs with their phenotypes and function as well as their role in transplantation, highlighting the differences between human and animal studies throughout.


Assuntos
Autoimunidade/imunologia , Subpopulações de Linfócitos B/imunologia , Linfócitos B Reguladores/imunologia , Inflamação/imunologia , Transplante/métodos , Animais , Subpopulações de Linfócitos B/metabolismo , Humanos , Inflamação/metabolismo , Fenótipo , Transdução de Sinais/imunologia , Imunologia de Transplantes
4.
Eur J Immunol ; 51(8): 2086-2092, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33949684

RESUMO

Regulatory T-cells (Tregs) are a subset of T cells generated in the thymus with intrinsic immunosuppressive properties. Phase I clinical trials have shown safety and feasibility of Treg infusion to promote immune tolerance and new studies are ongoing to evaluate their efficacy. During heart transplantation, thymic tissue is routinely discarded providing an attractive source of Tregs. In this study, we developed a GMP-compatible protocol for expanding sorted thymus-derived CD3+ CD4+ CD25+ CD127- (Tregs) as well as CD3+ CD4+ CD25+ CD127- CD45RA+ (RA+ Tregs) cells. We aimed to understand whether thymic RA+ Tregs can be isolated and expanded offering an advantage in terms of stability as it has been previously shown for circulating adult CD45RA+ Tregs. We show that both Tregs and RA+ Tregs could be expanded in large numbers and the presence of rapamycin is essential to inhibit the growth of IFN-γ producing cells. High levels of FOXP3, CTLA4, and CD25 expression, demethylation of the FOXP3 promoter, and high suppressive ability were found with no differences between Tregs and RA+ Tregs. After freezing and thawing, all Treg preparations maintained their suppressive ability, stability, as well as CD25 and FOXP3 expression. The number of thymic Tregs that could be isolated with our protocol, their fold expansion, and functional characteristics allow the clinical application of this cell population to promote tolerance in pediatric heart transplant patients.


Assuntos
Citometria de Fluxo/métodos , Transplante de Coração , Linfócitos T Reguladores , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Timo/citologia
5.
Eur J Immunol ; 51(10): 2522-2530, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34320225

RESUMO

Clinical trials of Treg therapy in transplantation are currently entering phases IIa and IIb, with the majority of these employing polyclonal Treg populations that harbor a broad specificity. Enhancing Treg specificity is possible with the use of chimeric antigen receptors (CARs), which can be customized to respond to a specific human leukocyte antigen (HLA). In this study, we build on our previous work in the development of HLA-A2 CAR-Tregs by further equipping cells with the constitutive expression of interleukin 10 (IL-10) and an imaging reporter as additional payloads. Cells were engineered to express combinations of these domains and assessed for phenotype and function. Cells expressing the full construct maintained a stable phenotype after transduction, were specifically activated by HLA-A2, and suppressed alloresponses potently. The addition of IL-10 provided an additional advantage to suppressive capacity. This study therefore provides an important proof-of-principle for this cell engineering approach for next-generation Treg therapy in transplantation.


Assuntos
Expressão Gênica , Imunomodulação , Interleucina-10/genética , Fenótipo , Receptores de Antígenos Quiméricos/genética , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Ordem dos Genes , Engenharia Genética , Vetores Genéticos/genética , Humanos , Interleucina-10/metabolismo , Receptores de Antígenos Quiméricos/imunologia
6.
Am J Transplant ; 21(4): 1415-1426, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-32483894

RESUMO

B cells have been implicated in transplant rejection via antibody-mediated mechanisms and more recently by presenting donor antigens to T cells. We have shown in patients with chronic antibody-mediated rejection that B cells control the indirect T cell alloresponses. To understand more about the role of B cells as antigen-presenting cells for CD4+ T cell with indirect allospecificity, B cells were depleted in C57BL/6 mice, using an anti-CD20 antibody, prior to receiving MHC class I-mismatched (Kd ) skin. The absence of B cells at the time of transplantation prolonged skin graft survival. To study the mechanisms behind this observation, T cells with indirect allospecificity were transferred in mice receiving a Kd skin transplant. T cell proliferation was markedly inhibited in the absence of recipient B cells, suggesting that B cells contribute to indirect pathway sensitization. Furthermore, we have shown that a possible way in which B cells present alloantigens is via acquisition of MHC-peptide complexes. Finally, we demonstrate that the addition of B cell depletion to the transfer of regulatory T cells (Tregs) with indirect alloresponse further prolonged skin graft survival. This study supports an important role for B cells in indirect T cell priming and further emphasizes the advantage of combination therapies in prolonging transplant survival.


Assuntos
Linfócitos B , Vesículas Extracelulares , Animais , Rejeição de Enxerto/etiologia , Humanos , Isoantígenos , Camundongos , Camundongos Endogâmicos C57BL , Transplante Homólogo
7.
Am J Transplant ; 21(4): 1603-1611, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33171020

RESUMO

Short-term outcomes in kidney transplantation are marred by progressive transplant failure and mortality secondary to immunosuppression toxicity. Immune modulation with autologous polyclonal regulatory T cell (Treg) therapy may facilitate immunosuppression reduction promoting better long-term clinical outcomes. In a Phase I clinical trial, 12 kidney transplant recipients received 1-10 × 106 Treg per kg at Day +5 posttransplantation in lieu of induction immunosuppression (Treg Therapy cohort). Nineteen patients received standard immunosuppression (Reference cohort). Primary outcomes were rejection-free and patient survival. Patient and transplant survival was 100%; acute rejection-free survival was 100% in the Treg Therapy versus 78.9% in the reference cohort at 48 months posttransplant. Treg therapy revealed no excess safety concerns. Four patients in the Treg Therapy cohort had mycophenolate mofetil withdrawn successfully and remain on tacrolimus monotherapy. Treg infusion resulted in a long-lasting dose-dependent increase in peripheral blood Tregs together with an increase in marginal zone B cell numbers. We identified a pretransplantation immune phenotype suggesting a high risk of unsuccessful ex-vivo Treg expansion. Autologous Treg therapy is feasible, safe, and is potentially associated with a lower rejection rate than standard immunosuppression. Treg therapy may provide an exciting opportunity to minimize immunosuppression therapy and improve long-term outcomes.


Assuntos
Transplante de Rim , Estudos de Viabilidade , Rejeição de Enxerto/etiologia , Rejeição de Enxerto/prevenção & controle , Humanos , Imunossupressores/uso terapêutico , Doadores Vivos , Monitorização Imunológica , Linfócitos T Reguladores
8.
Lancet ; 395(10237): 1627-1639, 2020 05 23.
Artigo em Inglês | MEDLINE | ID: mdl-32446407

RESUMO

BACKGROUND: Use of cell-based medicinal products (CBMPs) represents a state-of-the-art approach for reducing general immunosuppression in organ transplantation. We tested multiple regulatory CBMPs in kidney transplant trials to establish the safety of regulatory CBMPs when combined with reduced immunosuppressive treatment. METHODS: The ONE Study consisted of seven investigator-led, single-arm trials done internationally at eight hospitals in France, Germany, Italy, the UK, and the USA (60 week follow-up). Included patients were living-donor kidney transplant recipients aged 18 years and older. The reference group trial (RGT) was a standard-of-care group given basiliximab, tapered steroids, mycophenolate mofetil, and tacrolimus. Six non-randomised phase 1/2A cell therapy group (CTG) trials were pooled and analysed, in which patients received one of six CBMPs containing regulatory T cells, dendritic cells, or macrophages; patient selection and immunosuppression mirrored the RGT, except basiliximab induction was substituted with CBMPs and mycophenolate mofetil tapering was allowed. None of the trials were randomised and none of the individuals involved were masked. The primary endpoint was biopsy-confirmed acute rejection (BCAR) within 60 weeks after transplantation; adverse event coding was centralised. The RTG and CTG trials are registered with ClinicalTrials.gov, NCT01656135, NCT02252055, NCT02085629, NCT02244801, NCT02371434, NCT02129881, and NCT02091232. FINDINGS: The seven trials took place between Dec 11, 2012, and Nov 14, 2018. Of 782 patients assessed for eligibility, 130 (17%) patients were enrolled and 104 were treated and included in the analysis. The 66 patients who were treated in the RGT were 73% male and had a median age of 47 years. The 38 patients who were treated across six CTG trials were 71% male and had a median age of 45 years. Standard-of-care immunosuppression in the recipients in the RGT resulted in a 12% BCAR rate (expected range 3·2-18·0). The overall BCAR rate for the six parallel CTG trials was 16%. 15 (40%) patients given CBMPs were successfully weaned from mycophenolate mofetil and maintained on tacrolimus monotherapy. Combined adverse event data and BCAR episodes from all six CTG trials revealed no safety concerns when compared with the RGT. Fewer episodes of infections were registered in CTG trials versus the RGT. INTERPRETATION: Regulatory cell therapy is achievable and safe in living-donor kidney transplant recipients, and is associated with fewer infectious complications, but similar rejection rates in the first year. Therefore, immune cell therapy is a potentially useful therapeutic approach in recipients of kidney transplant to minimise the burden of general immunosuppression. FUNDING: The 7th EU Framework Programme.


Assuntos
Terapia Baseada em Transplante de Células e Tecidos/métodos , Rejeição de Enxerto/prevenção & controle , Terapia de Imunossupressão/métodos , Imunossupressores/uso terapêutico , Transplante de Rim , Terapia Baseada em Transplante de Células e Tecidos/efeitos adversos , Células Dendríticas/imunologia , Rejeição de Enxerto/imunologia , Humanos , Terapia de Imunossupressão/efeitos adversos , Macrófagos/imunologia , Linfócitos T Reguladores/imunologia
9.
Kidney Int ; 91(2): 477-492, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27988211

RESUMO

Chronic antibody-mediated rejection, a common cause of renal transplant failure, has a variable clinical phenotype. Understanding why some with chronic antibody-mediated rejection progress slowly may help develop more effective therapies. B lymphocytes act as antigen-presenting cells for in vitro indirect antidonor interferon-γ production in chronic antibody-mediated rejection, but many patients retain the ability to regulate these responses. Here we test whether particular patterns of T and B cell antidonor response associate with the variability of graft dysfunction in chronic antibody-mediated rejection. Our results confirm that dynamic changes in indirect antidonor CD4+ T-cell responses correlate with changes in estimated glomerular filtration rates, independent of other factors. Graft dysfunction progressed rapidly in patients who developed unregulated B-cell-driven interferon-γ production. However, conversion to a regulated or nonreactive pattern, which could be achieved by optimization of immunosuppression, associated with stabilization of graft function. Functional regulation by B cells appeared to activate an interleukin-10 autocrine pathway in CD4+ T cells that, in turn, impacted on antigen-specific responses. Thus, our data significantly enhance the understanding of graft dysfunction associated with chronic antibody-mediated rejection and provide the foundation for strategies to prolong renal allograft survival, based on regulation of interferon-γ production.


Assuntos
Comunicação Autócrina , Linfócitos B/imunologia , Rejeição de Enxerto/imunologia , Antígenos HLA/imunologia , Interferon gama/imunologia , Isoanticorpos/sangue , Transplante de Rim/efeitos adversos , Rim/imunologia , Células Th1/imunologia , Adulto , Área Sob a Curva , Comunicação Autócrina/efeitos dos fármacos , Linfócitos B/efeitos dos fármacos , Linfócitos B/metabolismo , Biópsia , Distribuição de Qui-Quadrado , Doença Crônica , Progressão da Doença , ELISPOT , Feminino , Taxa de Filtração Glomerular , Rejeição de Enxerto/sangue , Rejeição de Enxerto/tratamento farmacológico , Rejeição de Enxerto/fisiopatologia , Sobrevivência de Enxerto , Histocompatibilidade , Humanos , Imunossupressores/uso terapêutico , Interferon gama/metabolismo , Testes de Liberação de Interferon-gama , Interleucina-10/imunologia , Interleucina-10/metabolismo , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/fisiopatologia , Modelos Lineares , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Valor Preditivo dos Testes , Curva ROC , Fatores de Risco , Transdução de Sinais , Células Th1/efeitos dos fármacos , Células Th1/metabolismo , Fatores de Tempo , Resultado do Tratamento
11.
Eur J Immunol ; 45(3): 843-53, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25408265

RESUMO

In humans, tolerance to renal transplants has been associated with alterations in B-cell gene transcription and maintenance of the numbers of circulating transitional B cells. Here, we use a mouse model of transplantation tolerance to investigate the contribution of B cells to allograft survival. We demonstrate that transfer of B cells from mice rendered tolerant to MHC class I mismatched skin grafts can prolong graft survival in a dose-dependent and antigen-specific manner to a degree similar to that afforded by graft-specific regulatory T (Treg) cells. Tolerance in this model was associated with an increase in transitional-2 (T2) B cells. Only T2 B cells from tolerized mice, not naïve T2 nor alloantigen experienced T2, were capable of prolonging skin allograft survival, and suppressing T-cell activation. Tolerized T2 B cells expressed lower levels of CD86, increased TIM-1, and demonstrated a preferential survival in vivo. Furthermore, we demonstrate a synergistic effect between tolerized B cells and graft-specific Treg cells. IL-10 production by T2 B cells did not contribute to tolerance, as shown by transfer of B cells from IL-10(-/-) mice. These results suggest that T2 B cells in tolerant patients may include a population of regulatory B cells that directly inhibit graft rejection.


Assuntos
Sobrevivência de Enxerto/imunologia , Ativação Linfocitária , Células Precursoras de Linfócitos B/imunologia , Transplante de Pele , Linfócitos T Reguladores/imunologia , Tolerância ao Transplante , Aloenxertos , Animais , Sobrevivência de Enxerto/genética , Interleucina-10/genética , Interleucina-10/imunologia , Camundongos , Camundongos Knockout
12.
Haematologica ; 101(1): 91-100, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26471483

RESUMO

Immunosuppressive drugs in clinical transplantation are necessary to inhibit the immune response to donor antigens. Although they are effective in controlling acute rejection, they do not prevent long-term transplant loss from chronic rejection. In addition, immunosuppressive drugs have adverse side effects, including increased rate of infections and malignancies. Adoptive cell therapy with human Tregs represents a promising strategy for the induction of transplantation tolerance. Phase I/II clinical trials in transplanted patients are already underway, involving the infusion of Tregs alongside concurrent immunosuppressive drugs. However, it remains to be determined whether the presence of immunosuppressive drugs negatively impacts Treg function and stability. We tested in vitro and in vivo the effects of tacrolimus, mycophenolate and methylprednisolone (major ISDs used in transplantation) on ex vivo expanded, rapamycin-treated human Tregs. The in vitro results showed that these drugs had no effect on phenotype, function and stability of Tregs, although tacrolimus affected the expression of chemokine receptors and IL-10 production. However, viability and proliferative capacity were reduced in a dose-dependent manner by all the three drugs. The in vivo experiments using a humanized mouse model confirmed the in vitro results. However, treatment of mice with only rapamycin maintained the viability, function and proliferative ability of adoptively transferred Tregs. Taken together, our results suggest that the key functions of ex vivo expanded Tregs are not affected by a concurrent immunosuppressive therapy. However, the choice of the drug combination and their timing and dosing should be considered as an essential component to induce and maintain tolerance by Treg.


Assuntos
Transferência Adotiva , Regulação da Expressão Gênica/efeitos dos fármacos , Imunossupressores/farmacologia , Interleucina-10/imunologia , Receptores de Quimiocinas/imunologia , Linfócitos T Reguladores/imunologia , Animais , Células Cultivadas , Feminino , Regulação da Expressão Gênica/imunologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout
13.
Kidney Int ; 88(3): 560-8, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25830760

RESUMO

We explored how B-lymphocytes influence in vitro T-cell alloresponses in patients with antibody-mediated rejection (AMR), testing whether B-cells would be preferentially involved in this group of patients. Peripheral blood mononuclear cells were collected from 65 patients having biopsy: 14 patients with AMR and 5 with no pathology on protocol; 38 with AMR and 8 with nonimmunologic damage on 'for cause'. Using enzyme-linked immunosorbent spot assays, we found interferon-γ production by indirect allorecognition in 45 of 119 total samples from the 65 patients. B-cells preferentially processed and presented donor alloantigens in samples from AMR patients. In a further 25 samples, B-cell-dependent allo-specific reactivity was shown by depletion of CD25(+) cells and these individuals had higher percentages of CD4CD25hi cells. In 21 samples, reactivity was shown by depletion of CD19(+) cells, associated with polarized cytokine production toward IL-10 after polyclonal activation by IgG/IgM. Overall, this shows a significant contribution by B-cells to indirect donor-specific T-cell reactivity in vitro in patients with AMR. Active suppression by distinct phenotypes of T- or B-cells in approximately half of the patients indicates that chronic AMR is not characterized by a universal loss of immune regulation. Thus, stratified approaches that accommodate the heterogeneity of cell-mediated immunity might be beneficial to treat graft dysfunction.


Assuntos
Linfócitos B/imunologia , Comunicação Celular , Rejeição de Enxerto/imunologia , Imunidade Humoral , Transplante de Rim/efeitos adversos , Rim/imunologia , Linfócitos T/imunologia , Linfócitos B/metabolismo , Biópsia , Células Cultivadas , Doença Crônica , ELISPOT , Rejeição de Enxerto/diagnóstico , Rejeição de Enxerto/metabolismo , Humanos , Imunofenotipagem , Interferon gama/imunologia , Interferon gama/metabolismo , Testes de Liberação de Interferon-gama , Isoanticorpos/imunologia , Isoanticorpos/metabolismo , Isoantígenos/imunologia , Ativação Linfocitária , Fenótipo , Linfócitos T/metabolismo , Resultado do Tratamento
14.
Eur J Immunol ; 44(7): 2188-91, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24643793

RESUMO

DC vaccines have been used to induce tumour-specific cytotoxic T cells . However, this approach to cancer immunotherapy has had limited success. To be successful, injected DCs need to migrate to the LNs where they can stimulate effector T cells . We and others have previously demonstrated by MRI that tumour antigen-pulsed-DCs labelled ex vivo with superparamagnetic iron oxide nanoparticles migrated to the draining LNs and are capable of activating antigen-specific T cells . The results from our study demonstrated that ex vivo superparamagnetic iron oxide nanoparticles-labelled and OVA-pulsed DCs prime cytotoxic CD8(+) T-cell responses to protect against a B16-OVA tumour challenge. In the clinic, a possible noninvasive surrogate marker for efficacy of DC vaccination is to image the specific migration and accumulation of T cells following DC vaccination.


Assuntos
Células Dendríticas/imunologia , Linfócitos T Citotóxicos/imunologia , Tecnécio Tc 99m Exametazima , Vacinação , Animais , Camundongos , Camundongos Endogâmicos BALB C , Tomografia Computadorizada de Emissão de Fóton Único , Tomografia Computadorizada por Raios X
15.
Nat Rev Immunol ; 3(2): 147-58, 2003 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-12563298

RESUMO

Neonatal tolerance of alloantigens was described in mice nearly half a century ago, but unfortunately, the translation of these early findings into the clinical arena proved to be much more challenging than was first anticipated. However, the past decade has seen considerable progress in our understanding of the mechanisms that contribute to transplantation tolerance in experimental models. This review outlines our current understanding of the mechanisms of allograft tolerance, emphasizing the complementary roles of deletion and regulation of alloreactive T cells.


Assuntos
Tolerância Imunológica , Imunologia de Transplantes , Animais , Rejeição de Enxerto/etiologia , Rejeição de Enxerto/imunologia , Humanos , Terapia de Imunossupressão , Isoantígenos , Camundongos , Antígenos de Histocompatibilidade Menor , Modelos Imunológicos , Linfócitos T/imunologia
16.
Eur J Immunol ; 43(8): 2043-54, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23677517

RESUMO

Treg cells are critical for the prevention of autoimmune diseases and are thus prime candidates for cell-based clinical therapy. However, human Treg cells are "plastic", and are able to produce IL-17 under inflammatory conditions. Here, we identify and characterize the human Treg subpopulation that can be induced to produce IL-17 and identify its mechanisms. We confirm that a subpopulation of human Treg cells produces IL-17 in vitro when activated in the presence of IL-1ß, but not IL-6. "IL-17 potential" is restricted to population III (CD4(+) CD25(hi) CD127(lo) CD45RA(-) ) Treg cells expressing the natural killer cell marker CD161. We show that these cells are functionally as suppressive and have similar phenotypic/molecular characteristics to other subpopulations of Treg cells and retain their suppressive function following IL-17 induction. Importantly, we find that IL-17 production is STAT3 dependent, with Treg cells from patients with STAT3 mutations unable to make IL-17. Finally, we show that CD161(+) population III Treg cells accumulate in inflamed joints of patients with inflammatory arthritis and are the predominant IL-17-producing Treg-cell population at these sites. As IL-17 production from this Treg-cell subpopulation is not accompanied by a loss of regulatory function, in the context of cell therapy, exclusion of these cells from the cell product may not be necessary.


Assuntos
Interleucina-17/biossíntese , Subfamília B de Receptores Semelhantes a Lectina de Células NK/metabolismo , Fator de Transcrição STAT3/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Adulto , Idoso , Antígenos CD4/biossíntese , Células Cultivadas , Feminino , Fatores de Transcrição Forkhead/biossíntese , Humanos , Interleucina-1beta/metabolismo , Subunidade alfa de Receptor de Interleucina-2/biossíntese , Interleucina-6/metabolismo , Subunidade alfa de Receptor de Interleucina-7/biossíntese , Antígenos Comuns de Leucócito/biossíntese , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , Subfamília B de Receptores Semelhantes a Lectina de Células NK/imunologia , Fator de Transcrição STAT3/genética
17.
J Immunol ; 189(5): 2274-82, 2012 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-22821960

RESUMO

There is an increasing body of evidence suggesting that the transfer of preformed MHC class I:peptide complexes between a virus-infected cell and an uninfected APC, termed cross-dressing, represents an important mechanism of Ag presentation to CD8+ T cells in host defense. However, although it has been shown that memory CD8+ T cells can be activated by uninfected dendritic cells (DCs) cross-dressed by Ag from virus-infected parenchymal cells, it is unknown whether conditions exist during virus infection in which naive CD8+ T cells are primed and differentiate to cytolytic effectors through cross-dressing, and indeed which DC subset would be responsible. In this study, we determine whether the transfer of MHC class I:peptide complexes between infected and uninfected murine DC plays a role in CD8+ T cell priming to viral Ags in vivo. We show that MHC class I:peptide complexes from peptide-pulsed or virus-infected DCs are indeed acquired by splenic CD8α⁻ DCs in vivo. Furthermore, the acquired MHC class I:peptide complexes are functional in that they induced Ag-specific CD8+ T cell effectors with cytolytic function. As CD8α⁻ DCs are poor cross-presenters, this may represent the main mechanism by which CD8α⁻ DCs present exogenously encountered Ag to CD8+ T cells. The sharing of Ag as preformed MHC class I:peptide complexes between infected and uninfected DCs without the restraints of Ag processing may have evolved to accurately amplify the response and also engage multiple DC subsets critical in the generation of strong antiviral immunity.


Assuntos
Antivirais/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/virologia , Células Dendríticas/metabolismo , Células Dendríticas/virologia , Imunidade Celular , Complexo Principal de Histocompatibilidade/imunologia , Fragmentos de Peptídeos/metabolismo , Adenoviridae/imunologia , Adenoviridae/metabolismo , Transferência Adotiva , Animais , Linfócitos T CD8-Positivos/imunologia , Células Cultivadas , Apresentação Cruzada/imunologia , Células Dendríticas/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Ovalbumina/administração & dosagem , Ovalbumina/metabolismo , Fragmentos de Peptídeos/administração & dosagem , Fragmentos de Peptídeos/biossíntese
18.
Pediatr Nephrol ; 29(12): 2263-72, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24213880

RESUMO

Although transplantation has been a standard medical practice for decades, marked morbidity from the use of immunosuppressive drugs and poor long-term graft survival remain important limitations in the field. Since the first solid organ transplant between the Herrick twins in 1954, transplantation immunology has sought to move away from harmful, broad-spectrum immunosuppressive regimens that carry with them the long-term risk of potentially life-threatening opportunistic infections, cardiovascular disease, and malignancy, as well as graft toxicity and loss, towards tolerogenic strategies that promote long-term graft survival. Reports of "transplant tolerance" in kidney and liver allograft recipients whose immunosuppressive drugs were discontinued for medical or non-compliant reasons, together with results from experimental models of transplantation, provide the proof-of-principle that achieving tolerance in organ transplantation is fundamentally possible. However, translating the reconstitution of immune tolerance into the clinical setting is a daunting challenge fraught with the complexities of multiple interacting mechanisms overlaid on a background of variation in disease. In this article, we explore the basic science underlying mechanisms of tolerance and review the latest clinical advances in the quest for transplantation tolerance.


Assuntos
Imunologia de Transplantes , Tolerância ao Transplante , Animais , Humanos
19.
Eur J Immunol ; 42(12): 3322-33, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22996319

RESUMO

Chronic graft-versus-host disease (cGVHD) is characterised by a complex etiology of both alloimmune- and autoimmune-mediated disease progression and pathology, and is consequently difficult to control. The therapeutic potential of regulatory T (Treg) cells for cGVHD is currently being investigated; however, the relative ability of Treg cells with defined antigen specificities for auto- and alloantigen to prevent disease has not been previously examined. In this study, we show that donor-derived Treg-cell lines generated with self-MHC H-2(b) specificity or specificity for BALB/c H-2(d) alloantigen presented via the direct or indirect pathways are able to mediate an equal protection against cGVHD immune pathology in a disease model associated with recipient B-cell-driven humoral autoimmunity and glomerulonephritis. Mechanistically, autospecific Treg cells prevented disease induction by blocking donor T-cell engraftment whereas allospecific Treg cells permitted long-term engraftment of donor T cells. Donor T cells, while unresponsive to auto- and recipient alloantigens, retained the capacity to respond to third party alloantigens on ex vivo stimulation. These findings indicate that allospecific Treg cells may therefore be more clinically relevant as a cell therapy for cGVHD in the context of haplo-identical hematopoietic transplantation, as they allow persistence of donor T cells capable of responding to foreign antigens whilst preventing cGVHD-mediated autoimmunity.


Assuntos
Autoimunidade , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/prevenção & controle , Antígenos H-2/imunologia , Isoantígenos/imunologia , Linfócitos T Reguladores/imunologia , Animais , Doença Crônica , Modelos Animais de Doenças , Feminino , Glomerulonefrite/imunologia , Glomerulonefrite/prevenção & controle , Doença Enxerto-Hospedeiro/patologia , Transplante de Células-Tronco Hematopoéticas , Imunidade Humoral , Camundongos , Camundongos Endogâmicos BALB C , Linfócitos T Reguladores/transplante , Transplante Homólogo
20.
Haematologica ; 98(8): 1291-9, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23242600

RESUMO

Adoptive transfer of ex vivo expanded CD4(+)CD25(+)FOXP3(+) regulatory T cells is a successful therapy for autoimmune diseases and transplant rejection in experimental models. In man, equivalent manipulations in bone marrow transplant recipients appear safe, but questions regarding the stability of the transferred regulatory T cells during inflammation remain unresolved. In this study, protocols for the expansion of clinically useful numbers of functionally suppressive and stable human regulatory T cells were investigated. Regulatory T cells were expanded in vitro with rapamycin and/or all-trans retinoic acid and then characterized under inflammatory conditions in vitro and in vivo in a humanized mouse model of graft-versus-host disease. Addition of rapamycin to regulatory T-cell cultures confirms the generation of high numbers of suppressive regulatory T cells. Their stability was demonstrated in vitro and substantiated in vivo. In contrast, all-trans retinoic acid treatment generates regulatory T cells that retain the capacity to secrete IL-17. However, combined use of rapamycin and all-trans retinoic acid abolishes IL-17 production and confers a specific chemokine receptor homing profile upon regulatory T cells. The use of purified regulatory T-cell subpopulations provided direct evidence that rapamycin can confer an early selective advantage to CD45RA(+) regulatory T cells, while all-trans retinoic acid favors CD45RA(-) regulatory T-cell subset. Expansion of regulatory T cells using rapamycin and all-trans retinoic acid drug combinations provides a new and refined approach for large-scale generation of functionally potent and phenotypically stable human regulatory T cells, rendering them safe for clinical use in settings associated with inflammation.


Assuntos
Linfócitos T CD4-Positivos/efeitos dos fármacos , Fatores de Transcrição Forkhead , Subunidade alfa de Receptor de Interleucina-2 , Sirolimo/farmacologia , Subpopulações de Linfócitos T/efeitos dos fármacos , Tretinoína/farmacologia , Transferência Adotiva/métodos , Animais , Linfócitos T CD4-Positivos/imunologia , Fatores de Transcrição Forkhead/imunologia , Humanos , Subunidade alfa de Receptor de Interleucina-2/imunologia , Camundongos , Subpopulações de Linfócitos T/imunologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia
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