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Noguerol J, Laviolette K, Zahm M, Chaubet A, Sahal A, Détraves C, Torres R, Demont C, Adoue V, Joffre C, Cammas F, van Meerwijk JP, Joffre OP. Heterochromatic gene silencing controls CD4 + T cell susceptibility to regulatory T cell-mediated suppression in a murine allograft model. Nat Commun 2025; 16:566. [PMID: 39794349 PMCID: PMC11723947 DOI: 10.1038/s41467-025-55848-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Accepted: 01/02/2025] [Indexed: 01/13/2025] Open
Abstract
Protective immune responses require close interactions between conventional (Tconv) and regulatory T cells (Treg). The extracellular mediators and signaling events that regulate the crosstalk between these CD4+ T cell subsets have been extensively characterized. However, how Tconv translate Treg-dependent suppressive signals at the chromatin level remains largely unknown. Here we show, using a murine bone marrow allograft model in which graft rejection is coordinated by CD4+ T cells and can be inhibited by Treg, that Treg-mediated T cell suppression involves Heterochromatin Protein 1 α (HP1α)-dependent gene silencing. Unexpectedly, our screen also reveals that T cells deficient for HP1γ or the methyltransferase SUV39H1 are better repressed by Treg than their wild-type counterparts. Mechanistically, our transcriptional and epigenetic profiling identifies HP1γ as a negative regulator of a gene network functionally associated with T-cell exhaustion, including those encoding the inhibitory receptors PD-1 and LAG-3. In conclusion, we identify HP1 variants as rheostats that finely tune the balance between tolerance and immunity. While HP1α converts immunosuppressive signals into heterochromatin-dependent gene silencing mechanisms, HP1γ adjusts Tconv sensitivity to inhibitory environmental signals.
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Affiliation(s)
- Julie Noguerol
- Infinity, Toulouse Institute for Infectious and Inflammatory Diseases, University of Toulouse, Inserm U1291, CNRS U5051, Toulouse, France
| | - Karl Laviolette
- Infinity, Toulouse Institute for Infectious and Inflammatory Diseases, University of Toulouse, Inserm U1291, CNRS U5051, Toulouse, France
| | - Margot Zahm
- Infinity, Toulouse Institute for Infectious and Inflammatory Diseases, University of Toulouse, Inserm U1291, CNRS U5051, Toulouse, France
| | - Adeline Chaubet
- Infinity, Toulouse Institute for Infectious and Inflammatory Diseases, University of Toulouse, Inserm U1291, CNRS U5051, Toulouse, France
| | - Ambrine Sahal
- Centre de Recherche en Cancérologie de Toulouse, Université de Toulouse, Inserm U1037, CNRS U5071, Toulouse, France
| | - Claire Détraves
- Infinity, Toulouse Institute for Infectious and Inflammatory Diseases, University of Toulouse, Inserm U1291, CNRS U5051, Toulouse, France
| | - Romain Torres
- Infinity, Toulouse Institute for Infectious and Inflammatory Diseases, University of Toulouse, Inserm U1291, CNRS U5051, Toulouse, France
| | - Clothilde Demont
- Infinity, Toulouse Institute for Infectious and Inflammatory Diseases, University of Toulouse, Inserm U1291, CNRS U5051, Toulouse, France
| | - Véronique Adoue
- Infinity, Toulouse Institute for Infectious and Inflammatory Diseases, University of Toulouse, Inserm U1291, CNRS U5051, Toulouse, France
| | - Carine Joffre
- Centre de Recherche en Cancérologie de Toulouse, Université de Toulouse, Inserm U1037, CNRS U5071, Toulouse, France
| | - Florence Cammas
- Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Université Montpellier, 34298, Montpellier, France
- Institut Régional du Cancer Montpellier, Université Montpellier, 34298, Montpellier, France
- Institute of Human Genetics, CNRS UMR9002 University of Montpellier, 34396, Montpellier, France
| | - Joost Pm van Meerwijk
- Infinity, Toulouse Institute for Infectious and Inflammatory Diseases, University of Toulouse, Inserm U1291, CNRS U5051, Toulouse, France
| | - Olivier P Joffre
- Infinity, Toulouse Institute for Infectious and Inflammatory Diseases, University of Toulouse, Inserm U1291, CNRS U5051, Toulouse, France.
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2
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Liu Z, Baines KJ, Niessen NM, Heer MK, Clark D, Bishop GA, Trevillian PR. Characterizing Foxp3 + and Foxp3 - T cells in the homeostatic state and after allo-activation: resting CD4 +Foxp3 + Tregs have molecular characteristics of activated T cells. Front Immunol 2024; 15:1292158. [PMID: 38333213 PMCID: PMC10850883 DOI: 10.3389/fimmu.2024.1292158] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Accepted: 01/08/2024] [Indexed: 02/10/2024] Open
Abstract
Due to the intracellular expression of Foxp3 it is impossible to purify viable Foxp3+ cells on the basis of Foxp3 staining. Consequently CD4+Foxp3+ regulatory T cells (Tregs) in mice have mostly been characterized using CD4+CD25+ T cells or GFP-Foxp3 reporter T cells. However, these two populations cannot faithfully represent Tregs as the expression of CD25 and Foxp3 does not completely overlap and GFP+Foxp3+ reporter T cells have been reported to be functionally altered. The aim of this study was to characterize normal Tregs without separating Foxp3+ and Foxp3- cells for the expression of the main functional molecules and proliferation behaviors by flow cytometry and to examine their gene expression characteristics through differential gene expression. Our data showed that the expressions of Foxp3, CD25, CTLA-4 (both intracellular and cell surface) and PD-1 was mostly confined to CD4+ T cells and the expression of Foxp3 did not completely overlap with the expression of CD25, CTLA-4 or PD-1. Despite higher levels of expression of the T cell inhibitory molecules CTLA-4 and PD-1, Tregs maintained higher levels of Ki-67 expression in the homeostatic state and had greater proliferation in vivo after allo-activation than Tconv. Differential gene expression analysis revealed that resting Tregs exhibited immune activation markers characteristic of activated Tconv. This is consistent with the flow data that the T cell activation markers CD25, CTLA-4, PD-1, and Ki-67 were much more strongly expressed by Tregs than Tconv in the homeostatic state.
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Affiliation(s)
- Zilei Liu
- Transplant Unit, John Hunter Hospital, Newcastle, NSW, Australia
- Transplant and Surgical Immunology Theme, Immune Health Research Program, Hunter Medical Research Institute, The University of Newcastle, Newcastle, NSW, Australia
- School of Medicine and Public Health, College of Medicine, Health and Wellbeing, The University of Newcastle, Newcastle, NSW, Australia
| | - Katherine J. Baines
- Transplant and Surgical Immunology Theme, Immune Health Research Program, Hunter Medical Research Institute, The University of Newcastle, Newcastle, NSW, Australia
- School of Biomedical Sciences and Pharmacy, College of Medicine, Health and Wellbeing, The University of Newcastle, Newcastle, NSW, Australia
| | - Natalie M. Niessen
- Transplant and Surgical Immunology Theme, Immune Health Research Program, Hunter Medical Research Institute, The University of Newcastle, Newcastle, NSW, Australia
| | - Munish K. Heer
- Transplant Unit, John Hunter Hospital, Newcastle, NSW, Australia
| | - David Clark
- Transplant Unit, John Hunter Hospital, Newcastle, NSW, Australia
- School of Medicine and Public Health, College of Medicine, Health and Wellbeing, The University of Newcastle, Newcastle, NSW, Australia
| | - G. Alexander Bishop
- Transplantation Immunobiology Group, University of Sydney Central Clinical School, Charles Perkins Centre, Faculty of Medicine and Health, Sydney, NSW, Australia
| | - Paul R. Trevillian
- Transplant Unit, John Hunter Hospital, Newcastle, NSW, Australia
- Transplant and Surgical Immunology Theme, Immune Health Research Program, Hunter Medical Research Institute, The University of Newcastle, Newcastle, NSW, Australia
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Peng Q, Nowocin A, Ratnasothy K, Smith RA, Smyth LA, Lechler RI, Dorling A, Lombardi G. Inhibition of thrombin on endothelium enhances recruitment of regulatory T cells during IRI and when combined with adoptive Treg transfer, significantly protects against acute tissue injury and prolongs allograft survival. Front Immunol 2023; 13:980462. [PMID: 36793549 PMCID: PMC9924086 DOI: 10.3389/fimmu.2022.980462] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Accepted: 12/28/2022] [Indexed: 01/31/2023] Open
Abstract
Ischemia-reperfusion injury (IRI) amplifies T cell alloimmune responses after transplantation with thrombin playing a key pro-inflammatory role. To explore the influence of thrombin on regulatory T cell recruitment and efficacy we used a well-established model of IRI in the native murine kidney. Administration of the cytotopic thrombin inhibitor PTL060 inhibited IRI, and by skewing expression of chemokines (reducing CCL2 and CCL3 but increasing CCL17 and CCL22) increased the infiltration of M2 macrophages and Tregs. When PTL060 was combined with infusion of additional Tregs, these effects were further amplified. To test the benefits of thrombin inhibition in a transplant model, BALB/c hearts were transplanted into B6 mice with or without perfusion with PTL060 in combination with Tregs. Thrombin inhibition or Treg infusion alone led to small increments in allograft survival. However, the combined therapy led to modest graft prolongation by the same mechanisms as in renal IRI; graft survival was accompanied by increased numbers of Tregs and anti-inflammatory macrophages, and reduced expression of pro-inflammatory cytokines. While the grafts succumbed to rejection associated with the emergence of alloantibody, these data suggest that thrombin inhibition within the transplant vasculature enhances the efficacy of Treg infusion, a therapy that is currently entering the clinic to promote transplant tolerance.
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Affiliation(s)
- Qi Peng
- Centre for Nephrology, Urology and Transplantation, School of Immunology and Mucosal Biology, King’s College London, London, United Kingdom
| | - Anna Nowocin
- Centre for Nephrology, Urology and Transplantation, School of Immunology and Mucosal Biology, King’s College London, London, United Kingdom
| | - Kulachelvy Ratnasothy
- Centre for Nephrology, Urology and Transplantation, School of Immunology and Mucosal Biology, King’s College London, London, United Kingdom
| | - Richard A. Smith
- Centre for Nephrology, Urology and Transplantation, School of Immunology and Mucosal Biology, King’s College London, London, United Kingdom
| | - Lesley A. Smyth
- Centre for Nephrology, Urology and Transplantation, School of Immunology and Mucosal Biology, King’s College London, London, United Kingdom,School of Health, Sport and Bioscience, University of East London, London, United Kingdom
| | - Robert I. Lechler
- Centre for Nephrology, Urology and Transplantation, School of Immunology and Mucosal Biology, King’s College London, London, United Kingdom
| | - Anthony Dorling
- Centre for Nephrology, Urology and Transplantation, School of Immunology and Mucosal Biology, King’s College London, London, United Kingdom
| | - Giovanna Lombardi
- Centre for Nephrology, Urology and Transplantation, School of Immunology and Mucosal Biology, King’s College London, London, United Kingdom,*Correspondence: Giovanna Lombardi,
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Riether C. Regulation of hematopoietic and leukemia stem cells by regulatory T cells. Front Immunol 2022; 13:1049301. [PMID: 36405718 PMCID: PMC9666425 DOI: 10.3389/fimmu.2022.1049301] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Accepted: 10/20/2022] [Indexed: 01/25/2023] Open
Abstract
Adult bone marrow (BM) hematopoietic stem cells (HSCs) are maintained in a quiescent state and sustain the continuous production of all types of blood cells. HSCs reside in a specialized microenvironment the so-called HSC niche, which equally promotes HSC self-renewal and differentiation to ensure the integrity of the HSC pool throughout life and to replenish hematopoietic cells after acute injury, infection or anemia. The processes of HSC self-renewal and differentiation are tightly controlled and are in great part regulated through cellular interactions with classical (e.g. mesenchymal stromal cells) and non-classical niche cells (e.g. immune cells). In myeloid leukemia, some of these regulatory mechanisms that evolved to maintain HSCs, to protect them from exhaustion and immune destruction and to minimize the risk of malignant transformation are hijacked/disrupted by leukemia stem cells (LSCs), the malignant counterpart of HSCs, to promote disease progression as well as resistance to therapy and immune control. CD4+ regulatory T cells (Tregs) are substantially enriched in the BM compared to other secondary lymphoid organs and are crucially involved in the establishment of an immune privileged niche to maintain HSC quiescence and to protect HSC integrity. In leukemia, Tregs frequencies in the BM even increase. Studies in mice and humans identified the accumulation of Tregs as a major immune-regulatory mechanism. As cure of leukemia implies the elimination of LSCs, the understanding of these immune-regulatory processes may be of particular importance for the development of future treatments of leukemia as targeting major immune escape mechanisms which revolutionized the treatment of solid tumors such as the blockade of the inhibitory checkpoint receptor programmed cell death protein 1 (PD-1) seems less efficacious in the treatment of leukemia. This review will summarize recent findings on the mechanisms by which Tregs regulate stem cells and adaptive immune cells in the BM during homeostasis and in leukemia.
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Affiliation(s)
- Carsten Riether
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland,Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland,*Correspondence: Carsten Riether,
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Bernaldo-de-Quirós E, Pion M, Martínez-Bonet M, Correa-Rocha R. A New Generation of Cell Therapies Employing Regulatory T Cells (Treg) to Induce Immune Tolerance in Pediatric Transplantation. Front Pediatr 2022; 10:862807. [PMID: 35633970 PMCID: PMC9130702 DOI: 10.3389/fped.2022.862807] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Accepted: 04/25/2022] [Indexed: 11/13/2022] Open
Abstract
Kidney transplantation is the most common solid organ transplant and the preferred treatment for pediatric patients with end-stage renal disease, but it is still not a definitive solution due to immune graft rejection. Regulatory T cells (Treg) and their control over effector T cells is a crucial and intrinsic tolerance mechanism in limiting excessive immune responses. In the case of transplants, Treg are important for the survival of the transplanted organ, and their dysregulation could increase the risk of rejection in transplanted children. Chronic immunosuppression to prevent rejection, for which Treg are especially sensitive, have a detrimental effect on Treg counts, decreasing the Treg/T-effector balance. Cell therapy with Treg cells is a promising approach to restore this imbalance, promoting tolerance and thus increasing graft survival. However, the strategies used to date that employ peripheral blood as a Treg source have shown limited efficacy. Moreover, it is not possible to use this approach in pediatric patients due to the limited volume of blood that can be extracted from children. Here, we outline our innovative strategy that employs the thymus removed during pediatric cardiac surgeries as a source of therapeutic Treg that could make this therapy accessible to transplanted children. The advantageous properties and the massive amount of Treg cells obtained from pediatric thymic tissue (thyTreg) opens a new possibility for Treg therapies to prevent rejection in pediatric kidney transplants. We are recruiting patients in a clinical trial to prevent rejection in heart-transplanted children through the infusion of autologous thyTreg cells (NCT04924491). If its efficacy is confirmed, thyTreg therapy may establish a new paradigm in preventing organ rejection in pediatric transplants, and their allogeneic use would extend its application to other solid organ transplantation.
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Affiliation(s)
- Esther Bernaldo-de-Quirós
- Laboratory of Immune-Regulation, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
| | - Marjorie Pion
- Laboratory of Immune-Regulation, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
| | - Marta Martínez-Bonet
- Laboratory of Immune-Regulation, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
| | - Rafael Correa-Rocha
- Laboratory of Immune-Regulation, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
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Safinia N, Vaikunthanathan T, Lechler RI, Sanchez‐Fueyo A, Lombardi G. Advances in Liver Transplantation: where are we in the pursuit of transplantation tolerance? Eur J Immunol 2021; 51:2373-2386. [PMID: 34375446 PMCID: PMC10015994 DOI: 10.1002/eji.202048875] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 06/07/2021] [Accepted: 07/23/2021] [Indexed: 12/22/2022]
Abstract
Liver transplantation is the ultimate treatment option for end-stage liver disease. Breakthroughs in surgical practice and immunosuppression have seen considerable advancements in survival after transplantation. However, the intricate management of immunosuppressive regimens, balancing desired immunological quiescence while minimizing toxicity has proven challenging. Diminishing improvements in long-term morbidity and mortality have been inextricably linked with the protracted use of these medications. As such, there is now enormous interest to devise protocols that will allow us to minimize or completely withdraw immunosuppressants after transplantation. Immunosuppression withdrawal trials have proved the reality of tolerance following liver transplantation, however, without intervention will only occur after several years at the risk of potential cumulative immunosuppression-related morbidity. Focus has now been directed at accelerating this phenomenon through tolerance-inducing strategies. In this regard, efforts have seen the use of regulatory cell immunotherapy. Here we focus particularly on regulatory T cells, discussing preclinical data that propagated several clinical trials of adoptive cell therapy in liver transplantation. Furthermore, we describe efforts to further optimize the specificity and survival of regulatory cell therapy guided by concurrent immunomonitoring studies and the development of novel technologies including chimeric antigen receptors and co-administration of low-dose IL-2.
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Affiliation(s)
- Niloufar Safinia
- Division of Transplantation Immunology & Mucosal BiologyKing's College LondonLondonUK
| | | | - Robert Ian Lechler
- Division of Transplantation Immunology & Mucosal BiologyKing's College LondonLondonUK
| | | | - Giovanna Lombardi
- Division of Transplantation Immunology & Mucosal BiologyKing's College LondonLondonUK
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7
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Ozay EI, Shanthalingam S, Sherman HL, Torres JA, Osborne BA, Tew GN, Minter LM. Cell-Penetrating Anti-Protein Kinase C Theta Antibodies Act Intracellularly to Generate Stable, Highly Suppressive Regulatory T Cells. Mol Ther 2020; 28:1987-2006. [PMID: 32492367 PMCID: PMC7474270 DOI: 10.1016/j.ymthe.2020.05.020] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Revised: 04/21/2020] [Accepted: 05/19/2020] [Indexed: 01/27/2023] Open
Abstract
Regulatory T cells maintain immunological tolerance and dampen inflammatory responses. Administering regulatory T cells can prevent the immune-mediated tissue destruction of graft-versus-host disease, which frequently accompanies hematopoietic stem cell transfer. Neutralizing the T cell-specific kinase, protein kinase C theta, which promotes T cell effector functions and represses regulatory T cell differentiation, augments regulatory T cell immunosuppression and stability. We used a synthetic, cell-penetrating peptide mimic to deliver antibodies recognizing protein kinase C theta into primary human CD4 T cells. When differentiated ex vivo into induced regulatory T cells, treated cells expressed elevated levels of the regulatory T cell transcriptional regulator forkhead box P3, the surface-bound immune checkpoint receptor programmed death receptor-1, and pro-inflammatory interferon gamma, previously ascribed to a specific population of stable, highly suppressive human induced regulatory T cells. The in vitro suppressive capacity of these induced regulatory T cells was 10-fold greater than that of T cells differentiated without antibody delivery. When administered at the time of graft-versus-host disease induction, using a humanized mouse model, antibody-treated regulatory T cells were superior to non-treated T cells in attenuating lethal outcomes. This antibody delivery approach may overcome obstacles currently encountered using patient-derived regulatory T cells as a cell-based therapy for immune modulation.
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Affiliation(s)
- E Ilker Ozay
- Graduate Program in Molecular and Cellular Biology, University of Massachusetts Amherst, Amherst, MA 01003, USA
| | - Sudarvili Shanthalingam
- Department of Veterinary and Animal Sciences, University of Massachusetts Amherst, Amherst, MA 01003, USA
| | - Heather L Sherman
- Graduate Program in Molecular and Cellular Biology, University of Massachusetts Amherst, Amherst, MA 01003, USA
| | - Joe A Torres
- Graduate Program in Molecular and Cellular Biology, University of Massachusetts Amherst, Amherst, MA 01003, USA
| | - Barbara A Osborne
- Graduate Program in Molecular and Cellular Biology, University of Massachusetts Amherst, Amherst, MA 01003, USA; Department of Veterinary and Animal Sciences, University of Massachusetts Amherst, Amherst, MA 01003, USA
| | - Gregory N Tew
- Graduate Program in Molecular and Cellular Biology, University of Massachusetts Amherst, Amherst, MA 01003, USA; Department of Veterinary and Animal Sciences, University of Massachusetts Amherst, Amherst, MA 01003, USA; Department of Polymer Science and Engineering, University of Massachusetts Amherst, Amherst, MA 01003, USA
| | - Lisa M Minter
- Graduate Program in Molecular and Cellular Biology, University of Massachusetts Amherst, Amherst, MA 01003, USA; Department of Veterinary and Animal Sciences, University of Massachusetts Amherst, Amherst, MA 01003, USA.
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8
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Furlan SN, Singh K, Lopez C, Tkachev V, Hunt DJ, Hibbard J, Betz KM, Blazar BR, Trapnell C, Kean LS. IL-2 enhances ex vivo-expanded regulatory T-cell persistence after adoptive transfer. Blood Adv 2020; 4:1594-1605. [PMID: 32311015 PMCID: PMC7189290 DOI: 10.1182/bloodadvances.2019001248] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2019] [Accepted: 03/03/2020] [Indexed: 01/28/2023] Open
Abstract
As regulatory T cell (Treg) adoptive therapy continues to develop clinically, there is a need to determine which immunomodulatory agents pair most compatibly with Tregs to enable persistence and stabilize suppressor function. Prior work has shown that mechanistic target of rapamycin inhibition can increase the stability of thymic Tregs. In this study, we investigated the transcriptomic signatures of ex vivo-expanded Tregs after adoptive transfer in the setting of clinically relevant immunosuppression using a nonhuman primate (NHP) model as a prelude to future transplant studies. Here, we found that adding interleukin-2 (IL-2) to rapamycin in vivo supported a logarithmic increase in the half-life of adoptively transferred carboxyfluorescein diacetate succinimidyl ester-labeled, autologous NHP Tregs, effectively doubling the number of cells in the peripheral blood Treg compartment compared with Treg infusion when rapamycin was given alone. Using single-cell transcriptomics, we found that transferred ex vivo-expanded Tregs initially exhibit a gene expression signature consistent with an activated state. Moreover, those cells with the highest levels of activation also expressed genes associated with p53-mediated apoptosis. In contrast, transferred Tregs interrogated at day +20 posttransfer demonstrated a gene signature more similar to published profiles of resting Tregs. Together, these preclinical data further support combining IL-2 and rapamycin in vivo as adjunctive therapy for ex vivo-expanded adoptively transferred Tregs and suggest that the activation status of ex vivo-expanded Tregs is critical to their persistence.
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Affiliation(s)
- Scott N Furlan
- Fred Hutchinson Cancer Research Center and Department of Pediatrics, University of Washington, Seattle, WA
| | | | - Christina Lopez
- Seattle Children's Research Institute and Department of Pediatrics, University of Washington, Seattle, WA
| | - Victor Tkachev
- Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, MA
| | - Daniel Joel Hunt
- Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, MA
| | - James Hibbard
- Seattle Children's Research Institute and Department of Pediatrics, University of Washington, Seattle, WA
| | - Kayla M Betz
- Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, MA
| | - Bruce R Blazar
- Division of Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota, Minneapolis, MN; and
| | - Cole Trapnell
- Department of Genome Sciences, University of Washington, Seattle, WA
| | - Leslie S Kean
- Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, MA
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9
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Mixed chimerism established by hematopoietic stem cell transplantation is maintained by host and donor T regulatory cells. Blood Adv 2020; 3:734-743. [PMID: 30824417 DOI: 10.1182/bloodadvances.2018025502] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2018] [Accepted: 01/21/2019] [Indexed: 12/30/2022] Open
Abstract
Transplantation is an effective treatment of many clinical disorders, but the mechanisms that regulate immunological tolerance are uncertain and remain central to improving patient outcome. Hemopoietic stem cell transplantation (SCT) often establishes "mixed chimerism" in which immune cells from both the donor and patient coexist in vivo in a setting of immunological tolerance. We studied immune function in 69 patients within 2 months following SCT; 37 were fully donor and 32 displayed mixed chimerism. The proportion of T regulatory (Treg) cells was increased during mixed chimerism and comprised equal numbers of donor and host-derived regulatory cells. This was associated with a tolerogenic PD-L1+ profile on dendritic cells. Importantly, effector T cells from patients with mixed chimerism exhibited reduced cytotoxicity against host target cells in vitro, but this was restored following depletion of CD4+ Treg cells. These data show that Treg cells play a major role in sustaining immunological tolerance during mixed chimerism. These insights should help to guide novel interventions to improve clinical transplantation.
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10
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Baek H, Park SY, Ku SJ, Ryu K, Kim Y, Bae H, Lee YS. Bee Venom Phospholipase A2 Induces Regulatory T Cell Populations by Suppressing Apoptotic Signaling Pathway. Toxins (Basel) 2020; 12:toxins12030198. [PMID: 32235689 PMCID: PMC7150970 DOI: 10.3390/toxins12030198] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Revised: 03/13/2020] [Accepted: 03/20/2020] [Indexed: 12/20/2022] Open
Abstract
Bee venom phospholipase A2 is a lipolytic enzyme in bee venom that catalyzes hydrolysis of the sn-2 ester bond of membrane phospholipids to produce free fatty acid and lysophospholipids. Current evidence suggests that bee venom phospholipase A2 (bvPLA2) induces regulatory T cell expansion and attenuates several immune system-related diseases, including Alzheimer's disease. The induction of Treg cells is directly mediated by binding to mannose receptors on dendritic cells. This interaction induces the PGE2-EP2 signaling pathway, which promotes Treg induction in CD4+ T cells. In this study, we investigated the effects of bvPLA2 treatment on the apoptotic signaling pathway in Treg populations. Flow cytometry was performed to identify early apoptotic cells. As a result, early apoptotic cells were dramatically decreased in bvPLA2-treated splenocytes, whereas rapamycin-treated cells showed levels of apoptotic cells similar to those of PBS-treated cells. Furthermore, bvPLA2 treatment increased expression of anti-apoptotic molecules including CTLA-4 and PD-1. The survival rate increased in bvPLA2-treated Tregs. Our findings indicate that bvPLA2-mediated modulation of apoptotic signaling is strongly associated with the Treg induction, which exhibits protective effects against various immune-related diseases. To our knowledge, this study is the first to demonstrate that bvPLA2 is the major bee venom (BV) compound capable of inducing Treg expansion through altering apoptotic signal.
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Affiliation(s)
- Hyunjung Baek
- Department of Physiology, College of Korean Medicine, Kyung Hee University, Seoul 02447, Korea; (H.B.); (S.-Y.P.); (K.R.)
| | - Seon-Young Park
- Department of Physiology, College of Korean Medicine, Kyung Hee University, Seoul 02447, Korea; (H.B.); (S.-Y.P.); (K.R.)
| | - Su Jeong Ku
- Department of Anatomy and Acupoint, College of Korean Medicine, Gachon University, Seongnam 13120, Korea; (S.J.K.); (Y.K.)
| | - Kihyun Ryu
- Department of Physiology, College of Korean Medicine, Kyung Hee University, Seoul 02447, Korea; (H.B.); (S.-Y.P.); (K.R.)
| | - Younsub Kim
- Department of Anatomy and Acupoint, College of Korean Medicine, Gachon University, Seongnam 13120, Korea; (S.J.K.); (Y.K.)
| | - Hyunsu Bae
- Department of Physiology, College of Korean Medicine, Kyung Hee University, Seoul 02447, Korea; (H.B.); (S.-Y.P.); (K.R.)
- Correspondence: (H.B.); (Y.-S.L.)
| | - Ye-Seul Lee
- Department of Anatomy and Acupoint, College of Korean Medicine, Gachon University, Seongnam 13120, Korea; (S.J.K.); (Y.K.)
- Correspondence: (H.B.); (Y.-S.L.)
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11
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Mancusi A, Piccinelli S, Velardi A, Pierini A. CD4 +FOXP3 + Regulatory T Cell Therapies in HLA Haploidentical Hematopoietic Transplantation. Front Immunol 2019; 10:2901. [PMID: 31921162 PMCID: PMC6927932 DOI: 10.3389/fimmu.2019.02901] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2019] [Accepted: 11/26/2019] [Indexed: 12/11/2022] Open
Abstract
Since their discovery CD4+FOXP3+ regulatory T cells (Tregs) represented a promising tool to induce tolerance in allogeneic hematopoietic cell transplantation. Preclinical models proved that adoptive transfer of Tregs or the use of compounds that can favor their function in vivo are effective for prevention and treatment of graft-vs.-host disease (GvHD). Following these findings, Treg-based therapies have been employed in clinical trials. Adoptive immunotherapy with Tregs effectively prevents GvHD induced by alloreactive T cells in the setting of one HLA haplotype mismatched hematopoietic transplantation. The absence of post transplant pharmacologic immunosuppression unleashes T-cell mediated graft-vs.-tumor (GvT) effect, which results in an unprecedented, almost complete control of leukemia relapse in this setting. In the present review, we will report preclinical studies and clinical trials that demonstrate Treg ability to promote donor engraftment, protect from GvHD and improve GvT effect. We will also discuss new strategies to further enhance in vivo efficacy of Treg-based therapies.
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Affiliation(s)
- Antonella Mancusi
- Hematology and Clinical Immunology and Bone Marrow Transplant Program, Department of Medicine, University of Perugia, Perugia, Italy
| | - Sara Piccinelli
- Hematology and Clinical Immunology and Bone Marrow Transplant Program, Department of Medicine, University of Perugia, Perugia, Italy
| | - Andrea Velardi
- Hematology and Clinical Immunology and Bone Marrow Transplant Program, Department of Medicine, University of Perugia, Perugia, Italy
| | - Antonio Pierini
- Hematology and Clinical Immunology and Bone Marrow Transplant Program, Department of Medicine, University of Perugia, Perugia, Italy
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12
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Bollinger AL, Bollinger T, Rupp J, Shima K, Gross N, Padayachy L, Chicheportiche R, Puga Yung GL, Seebach JD. Annexin V expression on CD4 + T cells with regulatory function. Immunology 2019; 159:205-220. [PMID: 31642515 DOI: 10.1111/imm.13140] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2019] [Revised: 09/28/2019] [Accepted: 10/04/2019] [Indexed: 12/22/2022] Open
Abstract
Regulatory T (Treg) cells induce immunologic tolerance by suppressing effector functions of conventional lymphocytes in the periphery. On the other hand, immune silencing is mediated by recognition of phosphatidylserine (PS) on apoptotic cells by phagocytes. Here we describe expression of the PS-binding protein Annexin V (ANXA5) in CD4+ CD25hi Treg cells at the mRNA and protein levels. CD4+ ANXA5+ T cells constitute about 0·1%-0·6% of peripheral blood CD3+ T cells, exhibit co-expression of several Treg markers, such as Forkhead box P3, programmed cell death protein-1, cytotoxic T-lymphocyte antigen-4 and CD38. In vitro, ANXA5+ Treg cells showed enhanced adhesion to PS+ endothelial cells. Stimulated by anti-CD3 and PS+ syngeneic antigen-presenting cells CD4+ ANXA5+ T cells expanded in the absence of exogenous interleukin-2. CD4+ ANXA5+ T cells suppressed CD4+ ANXA5- T-cell proliferation and mammalian target of rapamycin phosphorylation, partially dependent on cell contact. CD4+ ANXA5+ T-cell-mediated suppression was allo-specific and accompanied by an increased production of anti-inflammatory mediators. In vivo, using a model of delayed type hypersensitivity, murine CD4+ ANXA5+ T cells inhibited T helper type 1 responses. In conclusion, we report for the first time expression of ANXA5 on a subset of Treg cells that might bridge classical regulatory Treg function with immune silencing.
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Affiliation(s)
- Anna-Lena Bollinger
- Division of Immunology and Allergology, Department of Medicine, University Hospitals and Medical Faculty, Geneva, Switzerland
| | - Thomas Bollinger
- Department of Molecular Biology, University of Geneva, Geneva, Switzerland
| | - Jan Rupp
- Department of Infectious Diseases and Microbiology, University of Lübeck, Lübeck, Germany
| | - Kensuke Shima
- Department of Infectious Diseases and Microbiology, University of Lübeck, Lübeck, Germany
| | - Natalie Gross
- Lübeck Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany
| | - Laura Padayachy
- Division of Immunology and Allergology, Department of Medicine, University Hospitals and Medical Faculty, Geneva, Switzerland
| | - Rachel Chicheportiche
- Division of Immunology and Allergology, Department of Medicine, University Hospitals and Medical Faculty, Geneva, Switzerland
| | - Gisella L Puga Yung
- Division of Immunology and Allergology, Department of Medicine, University Hospitals and Medical Faculty, Geneva, Switzerland
| | - Jörg Dieter Seebach
- Division of Immunology and Allergology, Department of Medicine, University Hospitals and Medical Faculty, Geneva, Switzerland
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13
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Abstract
Regulatory T cells (Treg cells) represent a CD4+ T-cell lineage that plays a critical role in restraining immune responses to self and foreign antigens and associated inflammation. Due to the suppressive function of Treg cells, inhibition or ablation of these cells can be used to boost the immunity against malignant cells. On the other hand, augmenting the activity of Treg cells can be employed for the treatment of inflammatory or autoimmune diseases and allogeneic conflicts associated with transplantation. Graft-versus-host disease (GvHD) is a leading cause of morbidity and mortality after haematopoietic stem cell transplantation (HSCT). In this review, we describe basic biological properties of Treg cells and their role in GvHD. We focus on the application of adoptive transfer of Treg cells and the therapeutic modulation of their activity for the prevention and treatment of GvHD in pre-clinical models and in clinical settings. We also discuss the main obstacles to applying Treg cell-based therapies for GvHD in clinical practice.
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Affiliation(s)
- Shlomo Elias
- Howard Hughes Medical Institute and Immunology Program, Sloan-Kettering Institute, and Ludwig Center at Memorial Sloan-Kettering Cancer Center, New York, New York, USA
| | - Alexander Y. Rudensky
- Howard Hughes Medical Institute and Immunology Program, Sloan-Kettering Institute, and Ludwig Center at Memorial Sloan-Kettering Cancer Center, New York, New York, USA
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14
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Lalfer M, Chappert P, Carpentier M, Urbain D, Davoust JM, Gross DA. Foxp3 + Regulatory and Conventional CD4 + T Cells Display Similarly High Frequencies of Alloantigen-Reactive Cells. Front Immunol 2019; 10:521. [PMID: 30941146 PMCID: PMC6434998 DOI: 10.3389/fimmu.2019.00521] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2018] [Accepted: 02/26/2019] [Indexed: 01/22/2023] Open
Abstract
Foxp3+ regulatory T cells (Tregs) play a major role in acquired immune tolerance to allogenic transplants. Their suppressive activity is thought to require T cell receptor (TCR)-driven antigen recognition; little, however, is known about the fraction of Tregs able to recognize alloantigens within this T cell subset primarily educated against self-antigens. Performing transfer experiments of Tregs or conventional T cells (Tconv) into both lymphoreplete and lymphopenic mice, we observed a similarly high proportion of cells signaling through their TCR and proliferating in allogenic hosts. Furthermore, using an in vivo proliferation assay with limited T cell numbers infused into lymphopenic mice, we found that the overall frequency of alloreactive Tregs was similar if not higher to that of alloreactive Tconv. Overall our study highlights a noticeably high level of alloreactive Foxp3+ regulatory T cells accounting for their predominant role in transplantation tolerance.
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Affiliation(s)
- Mélanie Lalfer
- Institut National de la Santé et de la Recherche Médicale U1151 - Centre National de la Recherche Scientifique UMR 8253, Institut Necker-Enfants Malades, Paris, France.,Université Paris Descartes, Sorbonne Paris Cité, Paris, France
| | - Pascal Chappert
- Institut National de la Santé et de la Recherche Médicale U1151 - Centre National de la Recherche Scientifique UMR 8253, Institut Necker-Enfants Malades, Paris, France.,Université Paris Descartes, Sorbonne Paris Cité, Paris, France
| | - Maxime Carpentier
- Institut National de la Santé et de la Recherche Médicale U1151 - Centre National de la Recherche Scientifique UMR 8253, Institut Necker-Enfants Malades, Paris, France.,Université Paris Descartes, Sorbonne Paris Cité, Paris, France
| | - Dominique Urbain
- Institut National de la Santé et de la Recherche Médicale U1151 - Centre National de la Recherche Scientifique UMR 8253, Institut Necker-Enfants Malades, Paris, France.,Université Paris Descartes, Sorbonne Paris Cité, Paris, France
| | - Jean M Davoust
- Institut National de la Santé et de la Recherche Médicale U1151 - Centre National de la Recherche Scientifique UMR 8253, Institut Necker-Enfants Malades, Paris, France.,Université Paris Descartes, Sorbonne Paris Cité, Paris, France
| | - David-Alexandre Gross
- Institut National de la Santé et de la Recherche Médicale U1151 - Centre National de la Recherche Scientifique UMR 8253, Institut Necker-Enfants Malades, Paris, France.,Université Paris Descartes, Sorbonne Paris Cité, Paris, France
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15
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Tahvildari M, Inomata T, Amouzegar A, Dana R. Regulatory T cell modulation of cytokine and cellular networks in corneal graft rejection. CURRENT OPHTHALMOLOGY REPORTS 2018; 6:266-274. [PMID: 31807370 PMCID: PMC6894425] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
PURPOSE OF REVIEW Corneal allografts placed in vascularized or inflamed host beds are at increased risk of graft rejection due to the preponderance of activated immune cells in the host bed. Regulatory T cells (Tregs) are master regulators of the adaptive immune response and play a key role in the induction of immune tolerance. The aim of this review is to discuss mechanisms through which Tregs mediate tolerance in corneal transplantation and the novel therapeutic approaches that target Tregs to promote transplant survival. RECENT FINDINGS The inflammatory environment of high-risk allografts not only promotes activation of effector T cells and their infiltration to graft site, but also impairs Treg immunomodulatory function. Recent studies have shown that expansion of Tregs and enhancing their modulatory function significantly improve graft survival. SUMMARY As our understanding of the cellular and molecular pathways in corneal transplantation has deepened, novel therapeutic strategies have been developed to improve allograft survival. In this review, we discuss therapeutic approaches that focus on Tregs to promote corneal allograft survival.
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Affiliation(s)
- Maryam Tahvildari
- Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, MA
- Kresge Eye Institute, Department of ophthalmology, Wayne State University, Detroit, MI
| | - Takenori Inomata
- Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, MA
- Juntendo University Faculty of Medicine, Department of Ophthalmology, Tokyo, Japan
- Juntendo University Faculty of Medicine, Department of Strategic Operative Room, Management and Improvement, Tokyo, Japan
| | - Afsaneh Amouzegar
- Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, MA
| | - Reza Dana
- Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, MA
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16
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Tahvildari M, Inomata T, Amouzegar A, Dana R. Regulatory T Cell Modulation of Cytokine and Cellular Networks in Corneal Graft Rejection. CURRENT OPHTHALMOLOGY REPORTS 2018. [DOI: 10.1007/s40135-018-0191-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
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17
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Kawai K, Uchiyama M, Hester J, Wood K, Issa F. Regulatory T cells for tolerance. Hum Immunol 2018; 79:294-303. [DOI: 10.1016/j.humimm.2017.12.013] [Citation(s) in RCA: 71] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2017] [Revised: 12/16/2017] [Accepted: 12/26/2017] [Indexed: 12/29/2022]
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18
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Pilat N, Granofszky N, Wekerle T. Combining Adoptive Treg Transfer with Bone Marrow Transplantation for Transplantation Tolerance. CURRENT TRANSPLANTATION REPORTS 2017; 4:253-261. [PMID: 29201599 PMCID: PMC5691126 DOI: 10.1007/s40472-017-0164-7] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
PURPOSE OF REVIEW The mixed chimerism approach is an exceptionally potent strategy for the induction of donor-specific tolerance in organ transplantation and so far the only one that was demonstrated to work in the clinical setting. Regulatory T cells (Tregs) have been shown to improve chimerism induction in experimental animal models. This review summarizes the development of innovative BMT protocols using therapeutic Treg transfer for tolerance induction. RECENT FINDINGS Treg cell therapy promotes BM engraftment in reduced conditioning protocols in both, mice and non-human primates. In mice, transfer of polyclonal recipient Tregs was sufficient to substitute cytotoxic recipient conditioning. Treg therapy prevented chronic rejection of skin and heart allografts related to tissue-specific antigen disparities, in part by promoting intragraft Treg accumulation. SUMMARY Adoptive Treg transfer is remarkably effective in facilitating BM engraftment in reduced-intensity protocols in mice and non-human primates. Furthermore, it promotes regulatory mechanisms that prevent chronic rejection.
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Affiliation(s)
- Nina Pilat
- Section of Transplantation Immunology, Department of Surgery, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
| | - Nicolas Granofszky
- Section of Transplantation Immunology, Department of Surgery, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
| | - Thomas Wekerle
- Section of Transplantation Immunology, Department of Surgery, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
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19
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Vaikunthanathan T, Safinia N, Boardman D, Lechler RI, Lombardi G. Regulatory T cells: tolerance induction in solid organ transplantation. Clin Exp Immunol 2017; 189:197-210. [PMID: 28422316 DOI: 10.1111/cei.12978] [Citation(s) in RCA: 56] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/31/2017] [Indexed: 02/06/2023] Open
Abstract
The concept of regulatory T cell (Treg ) therapy in transplantation is now a reality. Significant advances in science and technology have enabled us to isolate human Tregs , expand them to clinically relevant numbers and infuse them into human transplant recipients. With several Phase I/II trials under way investigating Treg safety and efficacy it is now more crucial than ever to understand their complex biology. However, our journey is by no means complete; results from these trials will undoubtedly provoke both further knowledge and enquiry which, alongside evolving science, will continue to drive the optimization of Treg therapy in the pursuit of transplantation tolerance. In this review we will summarize current knowledge of Treg biology, explore novel technologies in the setting of Treg immunotherapy and address key prerequisites surrounding the clinical application of Tregs in transplantation.
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Affiliation(s)
- T Vaikunthanathan
- MRC Centre for Transplantation, Division of Transplantation Immunology and Mucosal Biology, King's College London, London, UK
| | - N Safinia
- MRC Centre for Transplantation, Division of Transplantation Immunology and Mucosal Biology, King's College London, London, UK
| | - D Boardman
- MRC Centre for Transplantation, Division of Transplantation Immunology and Mucosal Biology, King's College London, London, UK
| | - R I Lechler
- MRC Centre for Transplantation, Division of Transplantation Immunology and Mucosal Biology, King's College London, London, UK
| | - G Lombardi
- MRC Centre for Transplantation, Division of Transplantation Immunology and Mucosal Biology, King's College London, London, UK
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20
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Zwang NA, Leventhal JR. Cell Therapy in Kidney Transplantation: Focus on Regulatory T Cells. J Am Soc Nephrol 2017; 28:1960-1972. [PMID: 28465379 DOI: 10.1681/asn.2016111206] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Renal transplantation is the renal replacement modality of choice for suitable candidates with advanced CKD or ESRD. Prevention of rejection, however, requires treatment with nonspecific pharmacologic immunosuppressants that carry both systemic and nephrologic toxicities. Use of a patient's own suppressive regulatory T cells (Tregs) is an attractive biologic approach to reduce this burden. Here, we review the immunologic underpinnings of Treg therapy and technical challenges to developing successful cell therapy. These issues include the selection of appropriate Treg subsets, ex vivo Treg expansion approaches, how many Tregs to administer and when, and how to care for patients after Treg administration.
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Affiliation(s)
| | - Joseph R Leventhal
- Comprehensive Transplant Center, Northwestern Memorial Hospital, Chicago, Illinois
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21
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da Silva MB, da Cunha FF, Terra FF, Camara NOS. Old game, new players: Linking classical theories to new trends in transplant immunology. World J Transplant 2017; 7:1-25. [PMID: 28280691 PMCID: PMC5324024 DOI: 10.5500/wjt.v7.i1.1] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2016] [Revised: 11/16/2016] [Accepted: 12/07/2016] [Indexed: 02/05/2023] Open
Abstract
The evolutionary emergence of an efficient immune system has a fundamental role in our survival against pathogenic attacks. Nevertheless, this same protective mechanism may also establish a negative consequence in the setting of disorders such as autoimmunity and transplant rejection. In light of the latter, although research has long uncovered main concepts of allogeneic recognition, immune rejection is still the main obstacle to long-term graft survival. Therefore, in order to define effective therapies that prolong graft viability, it is essential that we understand the underlying mediators and mechanisms that participate in transplant rejection. This multifaceted process is characterized by diverse cellular and humoral participants with innate and adaptive functions that can determine the type of rejection or promote graft acceptance. Although a number of mediators of graft recognition have been described in traditional immunology, recent studies indicate that defining rigid roles for certain immune cells and factors may be more complicated than originally conceived. Current research has also targeted specific cells and drugs that regulate immune activation and induce tolerance. This review will give a broad view of the most recent understanding of the allogeneic inflammatory/tolerogenic response and current insights into cellular and drug therapies that modulate immune activation that may prove to be useful in the induction of tolerance in the clinical setting.
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22
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Single CD28 stimulation induces stable and polyclonal expansion of human regulatory T cells. Sci Rep 2017; 7:43003. [PMID: 28223693 PMCID: PMC5320448 DOI: 10.1038/srep43003] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2016] [Accepted: 01/18/2017] [Indexed: 12/17/2022] Open
Abstract
CD4+FOXP3+ Treg are essential for immune tolerance. Phase-1 clinical trials of Treg-therapy to treat graft-versus-host-disease reported safety and potential therapeutic efficacy. Treg-based trials have started in organ-transplant patients. However, efficient ex vivo expansion of a stable Treg population remains a challenge and exploring novel ways for Treg expansion is a pre-requisite for successful immunotherapy. Based on the recent finding that CD28-signaling is crucial for survival and proliferation of mouse Treg, we studied single-CD28 stimulation of human Treg, without T cell receptor stimulation. Single-CD28 stimulation of human Treg in the presence of recombinant human IL-2(rhIL-2), as compared to CD3/CD28/rhIL-2 stimulation, led to higher expression levels of FOXP3. Although the single-CD28 expanded Treg population was equally suppressive to CD3/CD28 expanded Treg, pro-inflammatory cytokine (IL-17A/IFNγ) production was strongly inhibited, indicating that single-CD28 stimulation promotes Treg stability. As single-CD28 stimulation led to limited expansion rates, we examined a CD28-superagonist antibody and demonstrate a significant increased Treg expansion that was more efficient than standard anti-CD3/CD28-bead stimulation. CD28-superagonist stimulation drove both naïve and memory Treg proliferation. CD28-superagonist induction of stable Treg appeared both PI3K and mTOR dependent. Regarding efficient and stable expansion of Treg for adoptive Treg-based immunotherapy, application of CD28-superagonist stimulation is of interest.
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23
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Ogonek J, Kralj Juric M, Ghimire S, Varanasi PR, Holler E, Greinix H, Weissinger E. Immune Reconstitution after Allogeneic Hematopoietic Stem Cell Transplantation. Front Immunol 2016; 7:507. [PMID: 27909435 PMCID: PMC5112259 DOI: 10.3389/fimmu.2016.00507] [Citation(s) in RCA: 301] [Impact Index Per Article: 33.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2016] [Accepted: 11/02/2016] [Indexed: 12/17/2022] Open
Abstract
The timely reconstitution and regain of function of a donor-derived immune system is of utmost importance for the recovery and long-term survival of patients after allogeneic hematopoietic stem cell transplantation (HSCT). Of note, new developments such as umbilical cord blood or haploidentical grafts were associated with prolonged immunodeficiency due to delayed immune reconstitution, raising the need for better understanding and enhancing the process of immune reconstitution and finding strategies to further optimize these transplant procedures. Immune reconstitution post-HSCT occurs in several phases, innate immunity being the first to regain function. The slow T cell reconstitution is regarded as primarily responsible for deleterious infections with latent viruses or fungi, occurrence of graft-versus-host disease, and relapse. Here we aim to summarize the major steps of the adaptive immune reconstitution and will discuss the importance of immune balance in patients after HSCT.
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Affiliation(s)
- Justyna Ogonek
- Transplantation Biology, Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany
| | - Mateja Kralj Juric
- BMT, Department of Internal Medicine I, Medical University of Vienna, Vienna, Austria
| | - Sakhila Ghimire
- Department of Hematology and Oncology, University of Regensburg, Regensburg, Germany
| | - Pavankumar Reddy Varanasi
- Transplantation Biology, Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany
| | - Ernst Holler
- Department of Hematology and Oncology, University of Regensburg, Regensburg, Germany
| | | | - Eva Weissinger
- Transplantation Biology, Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany
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24
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Shen XF, Jiang JP, Yang JJ, Wang WZ, Guan WX, Du JF. Donor-Specific Regulatory T Cells Acquired from Tolerant Mice Bearing Cardiac Allograft Promote Mixed Chimerism and Prolong Intestinal Allograft Survival. Front Immunol 2016; 7:511. [PMID: 27909438 PMCID: PMC5113131 DOI: 10.3389/fimmu.2016.00511] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2016] [Accepted: 11/02/2016] [Indexed: 12/17/2022] Open
Abstract
The induction of donor-specific transplant tolerance has always been a central problem for small bowel transplantation (SBT), which is thought to be the best therapy for end-stage bowel failure. With the development of new tolerance-inducing strategies, mixed chimerism induced by co-stimulation blockade has become most potent for tolerance of allografts, such as skin, kidney, and heart. However, a lack of clinically available co-stimulation blockers has hindered efficient application in humans. Furthermore, unlike those for other types of solid organ transplantation, strategies to induce robust mixed chimerism for intestinal allografts have not been fully developed. To improve current mixed chimerism induction protocols for future clinical application, we developed a new protocol using donor-specific regulatory T (Treg) cells from mice with heart allograft tolerance, immunosuppressive drugs which could be used clinically and low doses of irradiation. Our results demonstrated that donor-specific Treg cells acquired from tolerant mice after in vitro expansion generate stable chimerism and lead to acceptance of intestinal allograft. Increased intragraft Treg cells and clonal deletion contribute to the development of SBT tolerance.
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Affiliation(s)
- Xiao-Fei Shen
- Department of General Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School , Nanjing , China
| | - Jin-Peng Jiang
- Department of Rehabilitation Medicine, PLA Army General Hospital , Beijing , China
| | - Jian-Jun Yang
- Division of Digestive Surgery, Xijing Hospital of Digestive Diseases, Fourth Military Medical University , Xi'an , China
| | - Wei-Zhong Wang
- Division of Digestive Surgery, Xijing Hospital of Digestive Diseases, Fourth Military Medical University , Xi'an , China
| | - Wen-Xian Guan
- Department of General Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School , Nanjing , China
| | - Jun-Feng Du
- Department of General Surgery, PLA Army General Hospital , Beijing , China
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25
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Bone marrow chimerism as a strategy to produce tolerance in solid organ allotransplantation. Curr Opin Organ Transplant 2016; 21:595-602. [PMID: 27805947 DOI: 10.1097/mot.0000000000000366] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
PURPOSE OF REVIEW Clinical transplant tolerance has been most successfully achieved combining hematopoietic chimerism with kidney transplantation. This review outlines this strategy in animal models and human transplantation, and possible clinical challenges. RECENT FINDINGS Kidney transplant tolerance has been achieved through chimerism in several centers beginning with Massachusetts General Hospital's success with mixed chimerism in human leukocyte antigen (HLA)-mismatched patients and the Stanford group with HLA-matched patients, and the more recent success of the Northwestern protocol achieving full chimerism. This has challenged the original view that stable mixed chimerism is necessary for organ graft tolerance. However, among the HLA-mismatched kidney transplant-tolerant patients, loss of mixed chimerism does not lead to renal-graft rejection, and the development of host Foxp3+ regulatory T cells has been observed. Recent animal models suggest that graft tolerance through bone marrow chimerism occurs through both clonal deletion and regulatory immune cells. Further, Tregs have been shown to improve chimerism in animal models. SUMMARY Animal studies continue to suggest ways to improve our current clinical strategies. Advances in chimerism protocols suggest that tolerance may be clinically achievable with relative safety for HLA-mismatched kidney transplants.
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26
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Combining Exosomes Derived from Immature DCs with Donor Antigen-Specific Treg Cells Induces Tolerance in a Rat Liver Allograft Model. Sci Rep 2016; 6:32971. [PMID: 27640806 PMCID: PMC5027549 DOI: 10.1038/srep32971] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2016] [Accepted: 08/18/2016] [Indexed: 12/20/2022] Open
Abstract
Allograft tolerance is the ultimate goal in the field of transplantation immunology. Immature dendritic cells (imDCs) play an important role in establishing tolerance but have limitations, including potential for maturation, short lifespan in vivo and short storage times in vitro. However, exosomes (generally 30–100 nm) from imDCs (imDex) retain many source cell properties and may overcome these limitations. In previous reports, imDex prolonged the survival time of heart or intestine allografts. However, tolerance or long-term survival was not achieved unless immune suppressants were used. Regulatory T cells (Tregs) can protect allografts from immune rejection, and our previous study showed that the effects of imDex were significantly associated with Tregs. Therefore, we incorporated Tregs into the treatment protocol to further reduce or avoid suppressant use. We defined the optimal exosome dose as approximately 20 μg (per treatment before, during and after transplantation) in rat liver transplantation and the antigen-specific role of Tregs in protecting liver allografts. In the co-treatment group, recipients achieved long-term survival, and tolerance was induced. Moreover, imDex amplified Tregs, which required recipient DCs and were enhanced by IL-2. Fortunately, the expanded Tregs retained their regulatory ability and donor-specificity. Thus, imDex and donor-specific Tregs can collaboratively induce graft tolerance.
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27
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Hu M, Wang YM, Wang Y, Zhang GY, Zheng G, Yi S, O'Connell PJ, Harris DCH, Alexander SI. Regulatory T cells in kidney disease and transplantation. Kidney Int 2016; 90:502-514. [PMID: 27263492 DOI: 10.1016/j.kint.2016.03.022] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2015] [Revised: 03/06/2016] [Accepted: 03/17/2016] [Indexed: 01/03/2023]
Abstract
Regulatory T cells (Tregs) have been shown to be important in maintaining immune homeostasis and preventing autoimmune disease, including autoimmune kidney disease. It is also likely that they play a role in limiting kidney transplant rejection and potentially in promoting transplant tolerance. Although other subsets of Tregs exist, the most potent and well-defined Tregs are the Foxp3 expressing CD4(+) Tregs derived from the thymus or generated peripherally. These CD4(+)Foxp3(+) Tregs limit autoimmune renal disease in animal models, especially chronic kidney disease, and kidney transplantation. Furthermore, other subsets of Tregs, including CD8 Tregs, may play a role in immunosuppression in kidney disease. The development and protective mechanisms of Tregs in kidney disease and kidney transplantation involve multiple mechanisms of suppression. Here we review the development and function of CD4(+)Foxp3(+) Tregs. We discuss the specific application of Tregs as a therapeutic strategy to prevent kidney disease and to limit kidney transplant rejection and detail clinical trials in this area of transplantation.
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Affiliation(s)
- Min Hu
- Centre for Transplantation and Renal Research, The Westmead Institute for Medical Research, University of Sydney, Westmead, New South Wales, Australia; Centre for Kidney Research, The Children's Hospital at Westmead, University of Sydney, Westmead, New South Wales, Australia
| | - Yuan Min Wang
- Centre for Kidney Research, The Children's Hospital at Westmead, University of Sydney, Westmead, New South Wales, Australia
| | - Yiping Wang
- Centre for Transplantation and Renal Research, The Westmead Institute for Medical Research, University of Sydney, Westmead, New South Wales, Australia
| | - Geoff Y Zhang
- Centre for Kidney Research, The Children's Hospital at Westmead, University of Sydney, Westmead, New South Wales, Australia
| | - Guoping Zheng
- Centre for Transplantation and Renal Research, The Westmead Institute for Medical Research, University of Sydney, Westmead, New South Wales, Australia
| | - Shounan Yi
- Centre for Transplantation and Renal Research, The Westmead Institute for Medical Research, University of Sydney, Westmead, New South Wales, Australia
| | - Philip J O'Connell
- Centre for Transplantation and Renal Research, The Westmead Institute for Medical Research, University of Sydney, Westmead, New South Wales, Australia
| | - David C H Harris
- Centre for Transplantation and Renal Research, The Westmead Institute for Medical Research, University of Sydney, Westmead, New South Wales, Australia
| | - Stephen I Alexander
- Centre for Kidney Research, The Children's Hospital at Westmead, University of Sydney, Westmead, New South Wales, Australia.
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Alsuliman A, Appel SH, Beers DR, Basar R, Shaim H, Kaur I, Zulovich J, Yvon E, Muftuoglu M, Imahashi N, Kondo K, Liu E, Shpall EJ, Rezvani K. A robust, good manufacturing practice-compliant, clinical-scale procedure to generate regulatory T cells from patients with amyotrophic lateral sclerosis for adoptive cell therapy. Cytotherapy 2016; 18:1312-24. [PMID: 27497700 DOI: 10.1016/j.jcyt.2016.06.012] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2016] [Revised: 05/21/2016] [Accepted: 06/16/2016] [Indexed: 01/01/2023]
Abstract
Regulatory T cells (Tregs) play a fundamental role in the maintenance of self-tolerance and immune homeostasis. Defects in Treg function and/or frequencies have been reported in multiple disease models. Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting upper and lower motor neurons. Compelling evidence supports a neuroprotective role for Tregs in this disease. Indeed, rapid progression in ALS patients is associated with decreased FoxP3 expression and Treg frequencies. Thus, we propose that strategies to restore Treg number and function may slow disease progression in ALS. In this study, we developed a robust, Good Manufacturing Practice (GMP)-compliant procedure to enrich and expand Tregs from ALS patients. Tregs isolated from these patients were phenotypically similar to those from healthy individuals but were impaired in their ability to suppress T-cell effector function. In vitro expansion of Tregs for 4 weeks in the presence of GMP-grade anti-CD3/CD28 beads, interleukin (IL)-2 and rapamcyin resulted in a 25- to 200-fold increase in their number and restored their immunoregulatory activity. Collectively, our data facilitate and support the implementation of clinical trials of adoptive therapy with ex vivo expanded and highly suppressive Tregs in patients with ALS.
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Affiliation(s)
- Abdullah Alsuliman
- Stem Cell Transplantation and Cellular Therapy, MD Anderson Cancer Center, Houston, Texas, USA; Stem Cell & Tissue Re-engineering Program, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Stanley H Appel
- Peggy and Gary Edwards ALS Laboratory, Department of Neurology, Houston Methodist Neurological Institute, Houston Methodist Research Institute, Houston Methodist Hospital, Houston, Texas, USA
| | - David R Beers
- Peggy and Gary Edwards ALS Laboratory, Department of Neurology, Houston Methodist Neurological Institute, Houston Methodist Research Institute, Houston Methodist Hospital, Houston, Texas, USA
| | - Rafet Basar
- Stem Cell Transplantation and Cellular Therapy, MD Anderson Cancer Center, Houston, Texas, USA
| | - Hila Shaim
- Stem Cell Transplantation and Cellular Therapy, MD Anderson Cancer Center, Houston, Texas, USA
| | - Indresh Kaur
- Stem Cell Transplantation and Cellular Therapy, MD Anderson Cancer Center, Houston, Texas, USA
| | - Jane Zulovich
- Stem Cell Transplantation and Cellular Therapy, MD Anderson Cancer Center, Houston, Texas, USA
| | - Eric Yvon
- Stem Cell Transplantation and Cellular Therapy, MD Anderson Cancer Center, Houston, Texas, USA
| | - Muharrem Muftuoglu
- Stem Cell Transplantation and Cellular Therapy, MD Anderson Cancer Center, Houston, Texas, USA
| | - Nobuhiko Imahashi
- Stem Cell Transplantation and Cellular Therapy, MD Anderson Cancer Center, Houston, Texas, USA
| | - Kayo Kondo
- Stem Cell Transplantation and Cellular Therapy, MD Anderson Cancer Center, Houston, Texas, USA
| | - Enli Liu
- Stem Cell Transplantation and Cellular Therapy, MD Anderson Cancer Center, Houston, Texas, USA
| | - Elizabeth J Shpall
- Stem Cell Transplantation and Cellular Therapy, MD Anderson Cancer Center, Houston, Texas, USA
| | - Katayoun Rezvani
- Stem Cell Transplantation and Cellular Therapy, MD Anderson Cancer Center, Houston, Texas, USA.
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29
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Vuddamalay Y, Attia M, Vicente R, Pomié C, Enault G, Leobon B, Joffre O, Romagnoli P, van Meerwijk JPM. Mouse and human CD8(+) CD28(low) regulatory T lymphocytes differentiate in the thymus. Immunology 2016; 148:187-96. [PMID: 26924728 DOI: 10.1111/imm.12600] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2015] [Revised: 02/20/2016] [Accepted: 02/22/2016] [Indexed: 12/22/2022] Open
Abstract
Regulatory T (Treg) lymphocytes play a central role in the control of immune responses and so maintain immune tolerance and homeostasis. In mice, expression of the CD8 co-receptor and low levels of the co-stimulatory molecule CD28 characterizes a Treg cell population that exerts potent suppressive function in vitro and efficiently controls experimental immunopathology in vivo. It has remained unclear if CD8(+) CD28(low) Treg cells develop in the thymus or represent a population of chronically activated conventional T cells differentiating into Treg cells in the periphery, as suggested by their CD28(low) phenotype. We demonstrate that functional CD8(+) CD28(low) Treg cells are present in the thymus and that these cells develop locally and are not recirculating from the periphery. Differentiation of CD8(+) CD28(low) Treg cells requires MHC class I expression on radioresistant but not on haematopoietic thymic stromal cells. In contrast to other Treg cells, CD8(+) CD28(low) Treg cells develop simultaneously with CD8(+) CD28(high) conventional T cells. We also identified a novel homologous naive CD8(+) CD28(low) T-cell population with immunosuppressive properties in human blood and thymus. Combined, our data demonstrate that CD8(+) CD28(low) cells can develop in the thymus of mice and suggest that the same is true in humans.
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Affiliation(s)
- Yirajen Vuddamalay
- Institut National de la Santé et de la Recherche Médicale (Inserm) U1043, Toulouse, France.,Centre National de la Recherche Scientifique (CNRS) U5282, Toulouse, France.,Centre de Physiopathologie de Toulouse Purpan (CPTP), Université de Toulouse, Université Paul Sabatier, Toulouse, France
| | - Mehdi Attia
- Institut National de la Santé et de la Recherche Médicale (Inserm) U1043, Toulouse, France.,Centre National de la Recherche Scientifique (CNRS) U5282, Toulouse, France.,Centre de Physiopathologie de Toulouse Purpan (CPTP), Université de Toulouse, Université Paul Sabatier, Toulouse, France
| | - Rita Vicente
- Institut National de la Santé et de la Recherche Médicale (Inserm) U1043, Toulouse, France.,Centre National de la Recherche Scientifique (CNRS) U5282, Toulouse, France.,Centre de Physiopathologie de Toulouse Purpan (CPTP), Université de Toulouse, Université Paul Sabatier, Toulouse, France
| | - Céline Pomié
- Institut National de la Santé et de la Recherche Médicale (Inserm) U1043, Toulouse, France.,Centre National de la Recherche Scientifique (CNRS) U5282, Toulouse, France.,Centre de Physiopathologie de Toulouse Purpan (CPTP), Université de Toulouse, Université Paul Sabatier, Toulouse, France
| | - Geneviève Enault
- Institut National de la Santé et de la Recherche Médicale (Inserm) U1043, Toulouse, France.,Centre National de la Recherche Scientifique (CNRS) U5282, Toulouse, France.,Centre de Physiopathologie de Toulouse Purpan (CPTP), Université de Toulouse, Université Paul Sabatier, Toulouse, France
| | - Bertrand Leobon
- Department of Pediatric Cardiology and Cardiovascular surgery, Children Hospital, University Hospital of Toulouse, Toulouse, France
| | - Olivier Joffre
- Institut National de la Santé et de la Recherche Médicale (Inserm) U1043, Toulouse, France.,Centre National de la Recherche Scientifique (CNRS) U5282, Toulouse, France.,Centre de Physiopathologie de Toulouse Purpan (CPTP), Université de Toulouse, Université Paul Sabatier, Toulouse, France
| | - Paola Romagnoli
- Institut National de la Santé et de la Recherche Médicale (Inserm) U1043, Toulouse, France.,Centre National de la Recherche Scientifique (CNRS) U5282, Toulouse, France.,Centre de Physiopathologie de Toulouse Purpan (CPTP), Université de Toulouse, Université Paul Sabatier, Toulouse, France
| | - Joost P M van Meerwijk
- Institut National de la Santé et de la Recherche Médicale (Inserm) U1043, Toulouse, France.,Centre National de la Recherche Scientifique (CNRS) U5282, Toulouse, France.,Centre de Physiopathologie de Toulouse Purpan (CPTP), Université de Toulouse, Université Paul Sabatier, Toulouse, France
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30
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Villa NY, Rahman MM, McFadden G, Cogle CR. Therapeutics for Graft-versus-Host Disease: From Conventional Therapies to Novel Virotherapeutic Strategies. Viruses 2016; 8:85. [PMID: 27011200 PMCID: PMC4810275 DOI: 10.3390/v8030085] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2015] [Revised: 03/09/2016] [Accepted: 03/09/2016] [Indexed: 02/06/2023] Open
Abstract
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) has a curative potential for many hematologic malignancies and blood diseases. However, the success of allo-HSCT is limited by graft-versus-host disease (GVHD), an immunological syndrome that involves inflammation and tissue damage mediated by donor lymphocytes. Despite immune suppression, GVHD is highly incident even after allo-HSCT using human leukocyte antigen (HLA)-matched donors. Therefore, alternative and more effective therapies are needed to prevent or control GVHD while preserving the beneficial graft-versus-cancer (GVC) effects against residual disease. Among novel therapeutics for GVHD, oncolytic viruses such as myxoma virus (MYXV) are receiving increased attention due to their dual role in controlling GVHD while preserving or augmenting GVC. This review focuses on the molecular basis of GVHD, as well as state-of-the-art advances in developing novel therapies to prevent or control GVHD while minimizing impact on GVC. Recent literature regarding conventional and the emerging therapies are summarized, with special emphasis on virotherapy to prevent GVHD. Recent advances using preclinical models with oncolytic viruses such as MYXV to ameliorate the deleterious consequences of GVHD, while maintaining or improving the anti-cancer benefits of GVC will be reviewed.
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Affiliation(s)
- Nancy Y Villa
- Division of Hematology and Oncology, Department of Medicine, University of Florida, Gainesville, FL 32610, USA.
| | - Masmudur M Rahman
- Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL 32610, USA.
| | - Grant McFadden
- Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL 32610, USA.
| | - Christopher R Cogle
- Division of Hematology and Oncology, Department of Medicine, University of Florida, Gainesville, FL 32610, USA.
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31
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Arefanian H, Tredget EB, Mok DCM, Ramji Q, Rafati S, Rodriguez-Barbosa J, Korbutt GS, Rajotte RV, Gill RG, Rayat GR. Porcine Islet-Specific Tolerance Induced by the Combination of Anti-LFA-1 and Anti-CD154 mAbs is Dependent on PD-1. Cell Transplant 2016; 25:327-42. [DOI: 10.3727/096368915x688506] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
We previously demonstrated that short-term administration of a combination of anti-LFA-1 and anti-CD154 monoclonal antibodies (mAbs) induces tolerance to neonatal porcine islet (NPI) xenografts that is mediated by regulatory T cells (Tregs) in B6 mice. In this study, we examined whether the coinhibitory molecule PD-1 is required for the induction and maintenance of tolerance to NPI xenografts. We also determined whether tolerance to NPI xenografts could be extended to allogeneic mouse or xenogeneic rat islet grafts since we previously demonstrated that tolerance to NPI xenografts could be extended to second-party NPI xenografts. Finally, we determined whether tolerance to NPI xenografts could be extended to allogeneic mouse or second-party porcine skin grafts. Diabetic B6 mice were transplanted with 2,000 NPIs under the kidney capsule and treated with short-term administration of a combination of anti-LFA-1 and anti-CD154 mAbs. Some of these mice were also treated simultaneously with anti-PD-1 mAb at >150 days posttransplantation. Spleen cells from some of the tolerant B6 mice were used for proliferation assays or were injected into B6 rag-/- mice with established islet grafts from allogeneic or xenogeneic donors. All B6 mice treated with anti-LFA-1 and anti-CD154 mAbs achieved and maintained normoglycemia until the end of the study; however, some mice that were treated with anti-PD-1 mAb became diabetic. All B6 rag-/- mouse recipients of first- and second-party NPIs maintained normoglycemia after reconstitution with spleen cells from tolerant B6 mice, while all B6 rag-/- mouse recipients of allogeneic mouse or xenogeneic rat islets rejected their grafts after cell reconstitution. Tolerant B6 mice rejected their allogeneic mouse or xenogeneic second-party porcine skin grafts while remaining normoglycemic until the end of the study. These results show that porcine islet-specific tolerance is dependent on PD-1, which could not be extended to skin grafts.
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Affiliation(s)
- Hossein Arefanian
- Alberta Diabetes Institute, Surgical-Medical Research Institute, Department of Surgery, Faculty of Medicine and Dentistry University of Alberta, Edmonton, Alberta, Canada
- Endocrinology and Metabolism Research Center, Tehran University of Medical Sciences, Tehran, Iran
- Pancreatic Islet Biology and Transplantation Unit, Dasman Diabetes Institute, Kuwait, Dasman, Kuwait
| | - Eric B. Tredget
- Alberta Diabetes Institute, Surgical-Medical Research Institute, Department of Surgery, Faculty of Medicine and Dentistry University of Alberta, Edmonton, Alberta, Canada
| | - Dereck C. M. Mok
- Alberta Diabetes Institute, Surgical-Medical Research Institute, Department of Surgery, Faculty of Medicine and Dentistry University of Alberta, Edmonton, Alberta, Canada
| | - Qahir Ramji
- Alberta Diabetes Institute, Surgical-Medical Research Institute, Department of Surgery, Faculty of Medicine and Dentistry University of Alberta, Edmonton, Alberta, Canada
| | - Shahin Rafati
- Alberta Diabetes Institute, Surgical-Medical Research Institute, Department of Surgery, Faculty of Medicine and Dentistry University of Alberta, Edmonton, Alberta, Canada
| | - Jose Rodriguez-Barbosa
- Institute of Biomedicine (Immunobiology), University of Leon, Campus de Vegazana s/n, Leon, Spain
| | - Gregory S. Korbutt
- Alberta Diabetes Institute, Surgical-Medical Research Institute, Department of Surgery, Faculty of Medicine and Dentistry University of Alberta, Edmonton, Alberta, Canada
| | - Ray V. Rajotte
- Alberta Diabetes Institute, Surgical-Medical Research Institute, Department of Surgery, Faculty of Medicine and Dentistry University of Alberta, Edmonton, Alberta, Canada
| | - Ron G. Gill
- Barbara Davis Center for Childhood Diabetes, University of Colorado, Aurora, CO, USA
| | - Gina R. Rayat
- Alberta Diabetes Institute, Surgical-Medical Research Institute, Department of Surgery, Faculty of Medicine and Dentistry University of Alberta, Edmonton, Alberta, Canada
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32
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Chera M, Hamel Y, Baillou C, Touil S, Guillot-Delost M, Charlotte F, Kossir L, Simonin G, Maury S, Cohen JL, Lemoine FM. Generation of Human Alloantigen-Specific Regulatory T Cells under Good Manufacturing Practice-Compliant Conditions for Cell Therapy. Cell Transplant 2015; 24:2527-40. [DOI: 10.3727/096368914x683566] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Natural regulatory T cells (Tregs) may have a great therapeutic potential to induce tolerance in allogeneic cells and organ transplantations. In mice, we showed that alloantigen-specific Tregs (spe-Tregs) were more efficient than polyclonal Tregs (poly-Tregs) in controlling graft-versus-host disease (GVHD). Here we describe a clinical-grade compliant method for generating human spe-Tregs. Tregs were enriched from leukapheresis products with anti-CD25 immunomagnetic beads, primed twice by allogeneic mature monocyte-derived dendritic cells (mDCs), and cultured during 3 weeks in medium containing interleukin 2 (IL-2), IL-15, and rapamycin. After 3 weeks of culture, final cell products were expanded 8.3-fold from the initial CD25+ purifications. Immunophenotypic analyses of final cells indicate that they were composed of 88 ± 2.6% of CD4+ T cells, all expressing Treg-specific markers (FOXP3, Helios, GARP, LAP, and CD152). Spe-Tregs were highly suppressive in vitro and also in vivo using a xeno-GVHD model established in immunodeficient mice. The specificity of their suppressive activity was demonstrated on their ability to significantly suppress the proliferation of autologous effector T cells stimulated by the same mDCs compared to third-party mDCs. Our data provide evidence that functional alloantigen Tregs can be generated under clinical-grade compliant conditions. Taking into account that 130 × 106 CD25+ cells can be obtained at large scale from standard leukapheresis, our cell process may give rise to a theoretical final number of 1 × 109 spe-Tregs. Thus, using our strategy, we can propose to prepare spe-Tregs for clinical trials designed to control HLA-mismatched GVHD or organ transplantation rejection.
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Affiliation(s)
- Mustapha Chera
- AP-HP, University Hospital La Pitié-Salpêtrière, Department of Biotherapies, Paris, France
- Center of Clinical Investigation in Biotherapies 1420, University Hospital La Pitié-Salpêtrière, Paris, France
| | - Yamina Hamel
- Sorbonne Universités, UPMC Univ Paris 06, UMR-S CR7, CIMI-Paris, Paris, France
| | - Claude Baillou
- Sorbonne Universités, UPMC Univ Paris 06, UMR-S CR7, CIMI-Paris, Paris, France
- INSERM, UMR S 1135, CIMI-Paris, Paris, France
| | - Soumia Touil
- CNRS, UMR 7211, Immunology Immunopathology and Immunotherapy, Paris, France
| | - Maude Guillot-Delost
- Sorbonne Universités, UPMC Univ Paris 06, UMR-S CR7, CIMI-Paris, Paris, France
- INSERM, UMR S 1135, CIMI-Paris, Paris, France
| | - Frédéric Charlotte
- AP-HP, University Hospital La Pitié-Salpêtrière, Department of Pathology, Paris, France
| | - Laila Kossir
- AP-HP, University Hospital La Pitié-Salpêtrière, Department of Biotherapies, Paris, France
- Center of Clinical Investigation in Biotherapies 1420, University Hospital La Pitié-Salpêtrière, Paris, France
| | - Ghislaine Simonin
- AP-HP, University Hospital La Pitié-Salpêtrière, Department of Biotherapies, Paris, France
- Center of Clinical Investigation in Biotherapies 1420, University Hospital La Pitié-Salpêtrière, Paris, France
| | - Sébastien Maury
- AP-HP, Henri-Mondor Hospital, Department of Clinical Hematology, Créteil, France
- Université Paris-Est, UMR-S955, UPEC, Créteil, France
- INSERM, U955, Team 21, Créteil, France
| | - José L. Cohen
- Université Paris-Est, UMR-S955, UPEC, Créteil, France
- INSERM, U955, Team 21, Créteil, France
- AP-HP, Henri-Mondor - A. Chenevier Hospital, CIC-BT-504, Créteil, France
| | - François M. Lemoine
- AP-HP, University Hospital La Pitié-Salpêtrière, Department of Biotherapies, Paris, France
- Center of Clinical Investigation in Biotherapies 1420, University Hospital La Pitié-Salpêtrière, Paris, France
- Sorbonne Universités, UPMC Univ Paris 06, UMR-S CR7, CIMI-Paris, Paris, France
- INSERM, UMR S 1135, CIMI-Paris, Paris, France
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33
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Safinia N, Scotta C, Vaikunthanathan T, Lechler RI, Lombardi G. Regulatory T Cells: Serious Contenders in the Promise for Immunological Tolerance in Transplantation. Front Immunol 2015; 6:438. [PMID: 26379673 PMCID: PMC4553385 DOI: 10.3389/fimmu.2015.00438] [Citation(s) in RCA: 98] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2015] [Accepted: 08/12/2015] [Indexed: 01/12/2023] Open
Abstract
Regulatory T cells (Tregs) play an important role in immunoregulation and have been shown in animal models to promote transplantation tolerance and curb autoimmunity following their adoptive transfer. The safety and potential therapeutic efficacy of these cells has already been reported in Phase I trials of bone-marrow transplantation and type I diabetes, the success of which has motivated the broadened application of these cells in solid-organ transplantation. Despite major advances in the clinical translation of these cells, there are still key questions to be addressed to ensure that Tregs attest their reputation as ideal candidates for tolerance induction. In this review, we will discuss the unique traits of Tregs that have attracted such fame in the arena of tolerance induction. We will outline the protocols used for their ex vivo expansion and discuss the future directions of Treg cell therapy. In this regard, we will review the concept of Treg heterogeneity, the desire to isolate and expand a functionally superior Treg population and report on the effect of differing culture conditions. The relevance of Treg migratory capacity will also be discussed together with methods of in vivo visualization of the infused cells. Moreover, we will highlight key advances in the identification and expansion of antigen-specific Tregs and discuss their significance for cell therapy application. We will also summarize the clinical parameters that are of importance, alongside cell manufacture, from the choice of immunosuppression regimens to the number of injections in order to direct the success of future efficacy trials of Treg cell therapy. Years of research in the field of tolerance have seen an accumulation of knowledge and expertise in the field of Treg biology. This perpetual progression has been the driving force behind the many successes to date and has put us now within touching distance of our ultimate success, immunological tolerance.
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Affiliation(s)
- Niloufar Safinia
- MRC Centre for Transplantation, Division of Transplantation Immunology and Mucosal Biology, Faculty of Life Sciences and Medicine, King's College London , London , UK
| | - Cristiano Scotta
- MRC Centre for Transplantation, Division of Transplantation Immunology and Mucosal Biology, Faculty of Life Sciences and Medicine, King's College London , London , UK
| | - Trishan Vaikunthanathan
- MRC Centre for Transplantation, Division of Transplantation Immunology and Mucosal Biology, Faculty of Life Sciences and Medicine, King's College London , London , UK
| | - Robert I Lechler
- MRC Centre for Transplantation, Division of Transplantation Immunology and Mucosal Biology, Faculty of Life Sciences and Medicine, King's College London , London , UK
| | - Giovanna Lombardi
- MRC Centre for Transplantation, Division of Transplantation Immunology and Mucosal Biology, Faculty of Life Sciences and Medicine, King's College London , London , UK
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34
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Zhang H, Guo H, Lu L, Zahorchak AF, Wiseman RW, Raimondi G, Cooper DKC, Ezzelarab MB, Thomson AW. Sequential monitoring and stability of ex vivo-expanded autologous and nonautologous regulatory T cells following infusion in nonhuman primates. Am J Transplant 2015; 15:1253-66. [PMID: 25783759 PMCID: PMC4773915 DOI: 10.1111/ajt.13113] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2014] [Revised: 10/24/2014] [Accepted: 11/17/2014] [Indexed: 01/25/2023]
Abstract
Ex vivo-expanded cynomolgus monkey CD4(+)CD25(+)CD127(-) regulatory T cells (Treg) maintained Foxp3 demethylation status at the Treg-specific demethylation region, and potently suppressed T cell proliferation through three rounds of expansion. When carboxyfluorescein succinimidyl ester- or violet proliferation dye 450-labeled autologous (auto) and nonautologous (non-auto)-expanded Treg were infused into monkeys, the number of labeled auto-Treg in peripheral blood declined rapidly during the first week, but persisted at low levels in both normal and anti-thymocyte globulin plus rapamycin-treated (immunosuppressed; IS) animals for at least 3 weeks. By contrast, MHC-mismatched non-auto-Treg could not be detected in normal monkey blood or in blood of two out of the three IS monkeys by day 6 postinfusion. They were also more difficult to detect than auto-Treg in peripheral lymphoid tissue. Both auto- and non-auto-Treg maintained Ki67 expression early after infusion. Sequential monitoring revealed that adoptively transferred auto-Treg maintained similarly high levels of Foxp3 and CD25 and low CD127 compared with endogenous Treg, although Foxp3 staining diminished over time in these nontransplanted recipients. Thus, infused ex vivo-expanded auto-Treg persist longer than MHC-mismatched non-auto-Treg in blood of nonhuman primates and can be detected in secondary lymphoid tissue. Host lymphodepletion and rapamycin administration did not consistently prolong the persistence of non-auto-Treg in these sites.
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Affiliation(s)
- H. Zhang
- Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA
| | - H. Guo
- Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA
| | - L. Lu
- Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA
| | - A. F. Zahorchak
- Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA
| | - R. W. Wiseman
- Wisconsin National Primate Research Center, University of Wisconsin-Madison, Madison, WI
| | - G. Raimondi
- Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA
| | - D. K. C. Cooper
- Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA
| | - M. B. Ezzelarab
- Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA
| | - A. W. Thomson
- Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA,Corresponding author: Angus W. Thomson,
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35
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Overcoming immunological barriers in regenerative medicine. Nat Biotechnol 2015; 32:786-94. [PMID: 25093888 DOI: 10.1038/nbt.2960] [Citation(s) in RCA: 103] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2014] [Accepted: 06/14/2014] [Indexed: 02/06/2023]
Abstract
Regenerative therapies that use allogeneic cells are likely to encounter immunological barriers similar to those that occur with transplantation of solid organs and allogeneic hematopoietic stem cells (HSCs). Decades of experience in clinical transplantation hold valuable lessons for regenerative medicine, offering approaches for developing tolerance-induction treatments relevant to cell therapies. Outside the field of solid-organ and allogeneic HSC transplantation, new strategies are emerging for controlling the immune response, such as methods based on biomaterials or mimicry of antigen-specific peripheral tolerance. Novel biomaterials can alter the behavior of cells in tissue-engineered constructs and can blunt host immune responses to cells and biomaterial scaffolds. Approaches to suppress autoreactive immune cells may also be useful in regenerative medicine. The most innovative solutions will be developed through closer collaboration among stem cell biologists, transplantation immunologists and materials scientists.
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Abstract
There is a clear need to develop strategies to induce tolerance without the need of chronic immunosuppression in transplant recipient and in patients with autoimmunity. Adoptive T regulatory cell (Treg) therapy offers the potential of long-lasting protection. However, based on results of clinical trials so far with ex vivo expanded autologous Tregs in type 1 diabetic (T1D) patients, it seems unlikely that single immunotherapy with Treg infusion without immunomodulation regimens that promote stable donor Treg engraftment and persistence would afford truly significant clinical benefit. Combination therapies could provide improved outcomes with consideration of the fundamental factors required for Treg generation, homeostasis, and function to promote long-term donor Treg persistence to provoke beneficial therapeutic outcomes.
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Restimulation After Cryopreservation and Thawing Preserves the Phenotype and Function of Expanded Baboon Regulatory T Cells. Transplant Direct 2015; 1:1-7. [PMID: 27019869 DOI: 10.1097/txd.0000000000000511] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Regulatory T cells (Treg) are being explored for their tolerance-inducing capabilities. Freezing and banking Treg for future use makes this strategy more clinically applicable. We aimed to devise an improved method of expanding and cryopreserving Treg to maximize yield, purity, and function for use in xenotransplantation. METHODS Baboon peripheral blood mononuclear cells (PBMC) were isolated from whole blood. CD4+/CD25hi cells were isolated by flow cytometric sorting and expanded for 26 days in culture with IL-2, anti-CD3 antibody, artificial APCs transfected with human CD58, CD32, and CD80, and rapamycin with weekly restimulations. Expanded Treg were frozen for 2 months then thawed and cultured for 48 hours in medium plus 1) no additives, 2) IL-2, 3) anti-CD3 antibody, 4) IL-2 + anti-CD3 antibody, and 5) IL-2 + anti-CD3 antibody + L cells. Phenotype and suppression were assessed after expansion, immediately after thawing, and after culturing. RESULTS We expanded purified baboon Treg more than 10,000-fold. Expanded Treg exhibited excellent suppression in functional assays. Cryopreservation decreased suppressive function without changing phenotype, but increasing amounts of reactivation after thawing produced significantly better viability and suppressive function with a trend towards greater Treg purity. CONCLUSIONS We produced numbers of expanded Tregs consistent with clinical use. In contrast to some previous reports, both Treg phenotype and suppressive function were preserved or even enhanced by increasing amounts of restimulation after thawing. Thus, banking of expanded recipient Tregs for in vivo infusion should be possible.
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D'Addio F, Margonato D, Pensato U, Borgese L, Potena L, Fiorina P. Novel therapeutic and diagnostic management of heart transplant patients. HEART, LUNG AND VESSELS 2015; 7:198-207. [PMID: 26495265 PMCID: PMC4593017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/03/2022]
Abstract
Heart transplantation was performed for the first time 40 years ago and it is now universally considered the "gold standard" treatment for individuals suffering from end-stage heart failure. The increased understanding of the molecular mechanisms and of the role of the immune system in allograft rejection led to an overall improvement of graft survival, which is now around 10 years. The introduction of novel immunosuppressive drugs reduced the rate of acute allograft rejection but did not improve significantly the long-term graft survival. In addition, adverse effects (e.g. infections, cancer and renal failure) associated with immunosuppressive drugs are increasing over time and may affect post-transplantation outcomes. An immunosuppression-free protocol based on tolerance induction is the Holy Grail for heart transplant recipients, but it is still far beyond our reach. In this review, we discuss the landscape of immunological challenges that heart transplanted individuals face and we critically review the novel immunological approaches available to overcome these remaining issues. Some of the novel approaches, successfully tested in preclinical and clinical models, may lead to a prolongation of patient's and heart allograft survival.
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Affiliation(s)
- Francesca D'Addio
- Transplant Medicine, IRCCS, Ospedale San Raffaele, Milan, Italy,Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | | | - Umberto Pensato
- Transplant Medicine, IRCCS, Ospedale San Raffaele, Milan, Italy
| | - Laura Borgese
- Cardiovascular Department, University of Bologna and S. Orsola-Malpighi Hospital, Bologna, Italy
| | - Luciano Potena
- Cardiovascular Department, University of Bologna and S. Orsola-Malpighi Hospital, Bologna, Italy
| | - Paolo Fiorina
- Transplant Medicine, IRCCS, Ospedale San Raffaele, Milan, Italy,Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
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Moore C, Tejon G, Fuentes C, Hidalgo Y, Bono MR, Maldonado P, Fernandez R, Wood KJ, Fierro JA, Rosemblatt M, Sauma D, Bushell A. Alloreactive regulatory T cells generated with retinoic acid prevent skin allograft rejection. Eur J Immunol 2014; 45:452-63. [PMID: 25381698 DOI: 10.1002/eji.201444743] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2014] [Revised: 10/06/2014] [Accepted: 11/06/2014] [Indexed: 12/24/2022]
Abstract
CD4(+) CD25(+) Foxp3(+) regulatory T (Treg) cells mediate immunological self-tolerance and suppress immune responses. Retinoic acid (RA), a natural metabolite of vitamin A, has been reported to enhance the differentiation of Treg cells in the presence of TGF-β. In this study, we show that the co-culture of naive T cells from C57BL/6 mice with allogeneic antigen-presenting cells (APCs) from BALB/c mice in the presence of TGF-β, RA, and IL-2 resulted in a striking enrichment of Foxp3(+) T cells. These RA in vitro-induced regulatory T (RA-iTreg) cells did not secrete Th1-, Th2-, or Th17-related cytokines, showed a nonbiased homing potential, and expressed several cell surface molecules related to Treg-cell suppressive potential. Accordingly, these RA-iTreg cells suppressed T-cell proliferation and inhibited cytokine production by T cells in in vitro assays. Moreover, following adoptive transfer, RA-iTreg cells maintained Foxp3 expression and their suppressive capacity. Finally, RA-iTreg cells showed alloantigen-specific immunosuppressive capacity in a skin allograft model in immunodeficient mice. Altogether, these data indicate that functional and stable allogeneic-specific Treg cells may be generated using TGF-β, RA, and IL-2. Thus, RA-iTreg cells may have a potential use in the development of more effective cellular therapies in clinical transplantation.
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Affiliation(s)
- Carolina Moore
- Departamento de Biologia, Facultad de Ciencias, Universidad de Chile, Santiago, Chile; Facultad de Ciencias Biologicas, Universidad Andres Bello, Santiago, Chile
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40
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Leveque L, Le Texier L, Lineburg KE, Hill GR, MacDonald KPA. Autophagy and haematopoietic stem cell transplantation. Immunol Cell Biol 2014; 93:43-50. [DOI: 10.1038/icb.2014.95] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2014] [Revised: 10/07/2014] [Accepted: 10/08/2014] [Indexed: 12/17/2022]
Affiliation(s)
- Lucie Leveque
- Department of Immunology, QIMR Berghofer Medical Research InstituteBrisbaneAustralia
| | - Laetitia Le Texier
- Department of Immunology, QIMR Berghofer Medical Research InstituteBrisbaneAustralia
| | - Katie E Lineburg
- Department of Immunology, QIMR Berghofer Medical Research InstituteBrisbaneAustralia
| | - Geoffrey R Hill
- Department of Immunology, QIMR Berghofer Medical Research InstituteBrisbaneAustralia
| | - Kelli PA MacDonald
- Department of Immunology, QIMR Berghofer Medical Research InstituteBrisbaneAustralia
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41
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Henig I, Zuckerman T. Hematopoietic stem cell transplantation-50 years of evolution and future perspectives. Rambam Maimonides Med J 2014; 5:e0028. [PMID: 25386344 PMCID: PMC4222417 DOI: 10.5041/rmmj.10162] [Citation(s) in RCA: 117] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
Hematopoietic stem cell transplantation is a highly specialized and unique medical procedure. Autologous transplantation allows the administration of high-dose chemotherapy without prolonged bone marrow aplasia. In allogeneic transplantation, donor-derived stem cells provide alloimmunity that enables a graft-versus-tumor effect to eradicate residual disease and prevent relapse. The first allogeneic transplantation was performed by E. Donnall Thomas in 1957. Since then the field has evolved and expanded worldwide. New indications beside acute leukemia and aplastic anemia have been constantly explored and now include congenital disorders of the hematopoietic system, metabolic disorders, and autoimmune disease. The use of matched unrelated donors, umbilical cord blood units, and partially matched related donors has dramatically extended the availability of allogeneic transplantation. Transplant-related mortality has decreased due to improved supportive care, including better strategies to prevent severe infections and with the incorporation of reduced-intensity conditioning protocols that lowered the toxicity and allowed for transplantation in older patients. However, disease relapse and graft-versus-host disease remain the two major causes of mortality with unsatisfactory progress. Intense research aiming to improve adoptive immunotherapy and increase graft-versus-leukemia response while decreasing graft-versus-host response might bring the next breakthrough in allogeneic transplantation. Strategies of graft manipulation, tumor-associated antigen vaccinations, monoclonal antibodies, and adoptive cellular immunotherapy have already proved clinically efficient. In the following years, allogeneic transplantation is likely to become more complex, more individualized, and more efficient.
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Affiliation(s)
- Israel Henig
- Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus, Haifa, Israel
| | - Tsila Zuckerman
- Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus, Haifa, Israel ; Bruce Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, Israel
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42
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Yin Y, Cai X, Chen X, Liang H, Zhang Y, Li J, Wang Z, Chen X, Zhang W, Yokoyama S, Wang C, Li L, Li L, Hou D, Dong L, Xu T, Hiroi T, Yang F, Ji H, Zhang J, Zen K, Zhang CY. Tumor-secreted miR-214 induces regulatory T cells: a major link between immune evasion and tumor growth. Cell Res 2014; 24:1164-80. [PMID: 25223704 PMCID: PMC4185347 DOI: 10.1038/cr.2014.121] [Citation(s) in RCA: 220] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2014] [Revised: 07/18/2014] [Accepted: 08/05/2014] [Indexed: 12/30/2022] Open
Abstract
An increased population of CD4(+)CD25(high)Foxp3(+) regulatory T cells (Tregs) in the tumor-associated microenvironment plays an important role in cancer immune evasion. However, the underlying mechanism remains unclear. Here we observed an increased secretion of miR-214 in various types of human cancers and mouse tumor models. Tumor-secreted miR-214 was sufficiently delivered into recipient T cells by microvesicles (MVs). In targeted mouse peripheral CD4(+) T cells, tumor-derived miR-214 efficiently downregulated phosphatase and tensin homolog (PTEN) and promoted Treg expansion. The miR-214-induced Tregs secreted higher levels of IL-10 and promoted tumor growth in nude mice. Furthermore, in vivo studies indicated that Treg expansion mediated by cancer cell-secreted miR-214 resulted in enhanced immune suppression and tumor implantation/growth in mice. The MV delivery of anti-miR-214 antisense oligonucleotides (ASOs) into mice implanted with tumors blocked Treg expansion and tumor growth. Our study reveals a novel mechanism through which cancer cell actively manipulates immune response via promoting Treg expansion.
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Affiliation(s)
- Yuan Yin
- 1] Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology (JERC-MBB), State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Hankou Road, Nanjing, Jiangsu 210093, China [2] Wuxi Oncology Institute, the Affiliated Hospital of Jiang Nan University, Wuxi, Jiangsu 214062, China
| | - Xing Cai
- Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology (JERC-MBB), State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Hankou Road, Nanjing, Jiangsu 210093, China
| | - Xi Chen
- Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology (JERC-MBB), State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Hankou Road, Nanjing, Jiangsu 210093, China
| | - Hongwei Liang
- Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology (JERC-MBB), State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Hankou Road, Nanjing, Jiangsu 210093, China
| | - Yujing Zhang
- Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology (JERC-MBB), State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Hankou Road, Nanjing, Jiangsu 210093, China
| | - Jing Li
- Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology (JERC-MBB), State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Hankou Road, Nanjing, Jiangsu 210093, China
| | - Zuoyun Wang
- State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue-Yang Road, Shanghai 200031, China
| | - Xiulan Chen
- Key Laboratory of Protein and Peptide Pharmaceuticals & Laboratory of Proteomics, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
| | - Wen Zhang
- Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology (JERC-MBB), State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Hankou Road, Nanjing, Jiangsu 210093, China
| | - Seiji Yokoyama
- Department of Allergy and Immunology, The Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan
| | - Cheng Wang
- Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology (JERC-MBB), State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Hankou Road, Nanjing, Jiangsu 210093, China
| | - Liang Li
- Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology (JERC-MBB), State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Hankou Road, Nanjing, Jiangsu 210093, China
| | - Limin Li
- Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology (JERC-MBB), State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Hankou Road, Nanjing, Jiangsu 210093, China
| | - Dongxia Hou
- Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology (JERC-MBB), State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Hankou Road, Nanjing, Jiangsu 210093, China
| | - Lei Dong
- Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology (JERC-MBB), State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Hankou Road, Nanjing, Jiangsu 210093, China
| | - Tao Xu
- National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
| | - Takachika Hiroi
- Department of Allergy and Immunology, The Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan
| | - Fuquan Yang
- Key Laboratory of Protein and Peptide Pharmaceuticals & Laboratory of Proteomics, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
| | - Hongbin Ji
- State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue-Yang Road, Shanghai 200031, China
| | - Junfeng Zhang
- Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology (JERC-MBB), State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Hankou Road, Nanjing, Jiangsu 210093, China
| | - Ke Zen
- Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology (JERC-MBB), State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Hankou Road, Nanjing, Jiangsu 210093, China
| | - Chen-Yu Zhang
- Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology (JERC-MBB), State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Hankou Road, Nanjing, Jiangsu 210093, China
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Mechanistic and therapeutic role of regulatory T cells in tolerance through mixed chimerism. Curr Opin Organ Transplant 2014; 15:725-30. [PMID: 20881493 DOI: 10.1097/mot.0b013e3283401755] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
PURPOSE OF REVIEW Although substantial advances in transplantation medicine have improved short-term graft survival, long-term outcome after organ transplantation is unsatisfactory. The induction of donor-specific tolerance as a potential solution remains an unmet need. Mixed chimerism established through transplantation of donor bone marrow is an appealing tolerance strategy, but widespread clinical application is prevented by the toxicity of recipient conditioning, which is required for achieving bone marrow engraftment. Clonal deletion - both central and peripheral - has long been recognized as a cardinal mechanism in experimental mixed chimerism models. RECENT FINDINGS Several recent studies have delineated the importance of nondeletional, regulatory mechanisms for the induction of tolerance through mixed chimerism. Moreover, the therapeutic application of recipient regulatory T cells (Tregs) has been combined with the transplantation of donor bone marrow. Such a 'Treg-chimerism' protocol leads to engraftment of conventional doses of fully allogeneic bone marrow and to donor-specific tolerance without the need for any cytotoxic conditioning. SUMMARY Regulatory mechanisms play a major role in mixed chimerism protocols. Treg therapy is exceptionally effective in achieving bone marrow engraftment without cytotoxic recipient treatment, thereby eliminating a major toxic factor preventing widespread application of the mixed chimerism strategy.
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Cabello-Kindelan C, de la Barrera A, Malek TR, Bayer AL. In vivo environment necessary to support transplanted donor mouse T regulatory cells. Am J Transplant 2014; 14:1032-45. [PMID: 24618297 DOI: 10.1111/ajt.12650] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2013] [Revised: 12/06/2013] [Accepted: 12/26/2013] [Indexed: 01/25/2023]
Abstract
CD4(+) Foxp3(+) T regulatory cells (Tregs ) are essential for maintaining immunological tolerance, which could be harnessed for novel cell-based therapies to prevent allograft rejection and control autoimmunity. However, the use of Tregs for therapy is hindered by the inability to generate sufficient cell numbers to inhibit desired immune response(s) and achieve stable engraftment of the donor-Treg cell inoculums. The present study was undertaken to investigate the in vivo requirements to promote engraftment of adoptively transferred Tregs and induce tolerance. We established that not only is peripheral space required, but competition from endogenous Tregs must be minimized for successful donor-Treg engraftment with IL-2 critical for driving their proliferation and survival. Moreover, these studies revealed a critical level of donor-Treg engraftment was required for tolerance induction to skin transplants. These mouse studies lay the foundation for development of novel Treg approaches for tolerance induction in the clinic involving not only organ or cellular transplantation, but also to re-establish self-tolerance in autoimmune settings.
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Affiliation(s)
- C Cabello-Kindelan
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL
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45
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Yan G, Xi Y, Xu S, Lin Y, Chen J, Dai H, Xia J, Li C, Li Q, Li Z, Qi Z. Inhibition of accelerated rejection mediated by alloreactive CD4⁺ memory T cells and prolonged allograft survival by arsenic trioxide. Immunol Invest 2014; 42:438-54. [PMID: 23802174 DOI: 10.3109/08820139.2013.801986] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
The aim of this study was to evaluate and determine the potential mechanisms of As₂O₃ in accelerated rejection mediated by alloreactive CD4⁺ memory T cells. Vascularized heterotopic cardiac transplantation from C57BL/6 mice to nude mice (pre-transferred CD4⁺ memory T cells) was performed on Day 0, and As₂O₃ was administered to recipient mice from Day 0 to 10. As a result, As₂O₃ could reduce the proliferation of allo-primed CD4⁺ memory T cells in vitro in MLR and the baseline rate of proliferation was restored by the addition of exogenous IL-2. In vivo, compared with the control[+] group, the mean survival time of cardiac allografts in the As₂O₃ group was prolonged from 5.8 ± 0.7 to 14.2 ± 2.5 days. Five days after transplantation, the relative gene expression of IL-2, IFN-γ and Foxp3 was reduced in the grafts by As₂O₃ treatment, but the expression of IL-10 and TGF-β was increased. Correspondingly, the proportions of CD4⁺ T cells, CD4⁺ memory T cells and regulatory T cells (Tregs), both in recipient spleens and lymph nodes, were lowered. These results indicate the potential of As2O3 as a novel immunosuppressant targeting CD4⁺ memory T cells.
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Affiliation(s)
- Guoliang Yan
- Basic Medical Department of Medical College, Xiamen University, Xiamen City, Fujian Province, P. R. China
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Safinia N, Leech J, Hernandez-Fuentes M, Lechler R, Lombardi G. Promoting transplantation tolerance; adoptive regulatory T cell therapy. Clin Exp Immunol 2013; 172:158-68. [PMID: 23574313 DOI: 10.1111/cei.12052] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/10/2012] [Indexed: 01/09/2023] Open
Abstract
Transplantation is a successful treatment for end-stage organ failure. Despite improvements in short-term outcome, long-term survival remains suboptimal because of the morbidity and mortality associated with long-term use of immunosuppression. There is, therefore, a pressing need to devise protocols that induce tolerance in order to minimize or completely withdraw immunosuppression in transplant recipients. In this review we will discuss how regulatory T cells (T(regs)) came to be recognized as an attractive way to promote transplantation tolerance. We will summarize the preclinical data, supporting the importance of these cells in the induction and maintenance of immune tolerance and that provide the rationale for the isolation and expansion of these cells for cellular therapy. We will also describe the data from the first clinical trials, using T(regs) to inhibit graft-versus-host disease (GVHD) after haematopoietic stem cell transplantation and will address both the challenges and opportunities in human T(reg) cell therapy.
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Affiliation(s)
- N Safinia
- MRC Centre for Transplantation, Guy's and St Thomas' NHS Foundation Trust, London, UK
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47
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Long-term prevention of chronic allograft rejection by regulatory T-cell immunotherapy involves host Foxp3-expressing T cells. Blood 2013; 121:4303-10. [DOI: 10.1182/blood-2012-08-452037] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Key Points
Administration of donor-specific regulatory T cells prevents chronic rejection of BM and skin allografts in the mouse. Injected regulatory T cells induce the emergence of host regulatory T cells with similar specificity thus ensuring persistence of tolerance.
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Ruiz P, Maldonado P, Hidalgo Y, Gleisner A, Sauma D, Silva C, Saez JJ, Nuñez S, Rosemblatt M, Bono MR. Transplant tolerance: new insights and strategies for long-term allograft acceptance. Clin Dev Immunol 2013; 2013:210506. [PMID: 23762087 PMCID: PMC3665173 DOI: 10.1155/2013/210506] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2013] [Revised: 04/12/2013] [Accepted: 04/13/2013] [Indexed: 02/08/2023]
Abstract
One of the greatest advances in medicine during the past century is the introduction of organ transplantation. This therapeutic strategy designed to treat organ failure and organ dysfunction allows to prolong the survival of many patients that are faced with no other treatment option. Today, organ transplantation between genetically dissimilar individuals (allogeneic grafting) is a procedure widely used as a therapeutic alternative in cases of organ failure, hematological disease treatment, and some malignancies. Despite the potential of organ transplantation, the administration of immunosuppressive drugs required for allograft acceptance induces severe immunosuppression in transplanted patients, which leads to serious side effects such as infection with opportunistic pathogens and the occurrence of neoplasias, in addition to the known intrinsic toxicity of these drugs. To solve this setback in allotransplantation, researchers have focused on manipulating the immune response in order to create a state of tolerance rather than unspecific immunosuppression. Here, we describe the different treatments and some of the novel immunotherapeutic strategies undertaken to induce transplantation tolerance.
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Affiliation(s)
- Paulina Ruiz
- Departamento de Biologia, Facultad de Ciencias, Universidad de Chile, 7800024 Santiago, Chile
- Programa de Ciencias Biomedicas, Facultad de Medicina, Universidad de Chile, 8380453 Santiago, Chile
| | - Paula Maldonado
- Departamento de Biologia, Facultad de Ciencias, Universidad de Chile, 7800024 Santiago, Chile
| | - Yessia Hidalgo
- Departamento de Biologia, Facultad de Ciencias, Universidad de Chile, 7800024 Santiago, Chile
| | - Alejandra Gleisner
- Departamento de Biologia, Facultad de Ciencias, Universidad de Chile, 7800024 Santiago, Chile
| | - Daniela Sauma
- Departamento de Biologia, Facultad de Ciencias, Universidad de Chile, 7800024 Santiago, Chile
- Fundacion Ciencia y Vida, 7780272 Santiago, Chile
| | - Cinthia Silva
- Departamento de Biologia, Facultad de Ciencias, Universidad de Chile, 7800024 Santiago, Chile
| | - Juan Jose Saez
- Departamento de Biologia, Facultad de Ciencias, Universidad de Chile, 7800024 Santiago, Chile
| | - Sarah Nuñez
- Departamento de Biologia, Facultad de Ciencias, Universidad de Chile, 7800024 Santiago, Chile
| | - Mario Rosemblatt
- Departamento de Biologia, Facultad de Ciencias, Universidad de Chile, 7800024 Santiago, Chile
- Fundacion Ciencia y Vida, 7780272 Santiago, Chile
- Facultad de Ciencias Biologicas, Universidad Andres Bello, 8370146 Santiago, Chile
| | - Maria Rosa Bono
- Departamento de Biologia, Facultad de Ciencias, Universidad de Chile, 7800024 Santiago, Chile
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Regulatory T cells in allogeneic stem cell transplantation. Clin Dev Immunol 2013; 2013:608951. [PMID: 23737813 PMCID: PMC3662184 DOI: 10.1155/2013/608951] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2013] [Accepted: 04/15/2013] [Indexed: 01/02/2023]
Abstract
Growing evidence suggests that cellular adoptive immunotherapy is becoming an attractive though challenging approach in regulating tumor immunity and alloresponses in clinical transplantation. Naturally arising CD4+CD25+Foxp3+ regulatory T cells (Treg) have emerged as a key component in this regard. Over the last decade, a large body of evidence from preclinical models has demonstrated their crucial role in auto- and tumor immunity and has opened the door to their “first-in-man” clinical application. Initial studies in clinical allogeneic stem cell transplantation are very encouraging and may pave the way for other applications. Further improvements in Treg ex vivo or in vivo expansion technologies will simplify their global clinical application. In this review, we discuss the current knowledge of Treg biology and their potential for cell-based immunotherapy in allogeneic stem cell transplantation.
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Horch M, Nguyen VH. Regulatory T-cell immunotherapy for allogeneic hematopoietic stem-cell transplantation. Ther Adv Hematol 2013; 3:29-44. [PMID: 23556110 DOI: 10.1177/2040620711422266] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
From mouse studies to recently published clinical trials, evidence has accumulated on the potential use of regulatory T cells (Treg) in preventing and treating graft-versus-host disease following hematopoietic-cell transplantation (HCT). However, controversies remain as to the phenotype and stability of various Treg subsets and their respective roles in vivo, the requirement of antigen-specificity of Treg to reduce promiscuous suppression, and the molecular mechanisms by which Treg suppress, particularly in humans. In this review, we discuss recent findings that support a heterogeneous population of human Treg, address advances in understanding how Treg function in the context of HCT, and present data on recent clinical trials that highlight the feasibility and limitations on Treg immunotherapy for graft-versus-host disease.
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