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Review Article | DOI: https://doi.org/10.31579/2640-1053/066
1 Servei d’Immunologia, Hospital Clínic de Barcelona, University of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS). Barcelona, Spain.
1,2 Platform d’Immunoteràpia Hospital Sant Joan de Déu- Clínic. Platform d’Immunoteràpia Banc de Sang I Teixits-Clínic. Barcelona, Spain.
3 Functional Unit of Clinical Immunology, Sant Joan de Déu-Hospital Clinic, Barcelona, Spain.
*Corresponding Author: Manel Juan, Servei d’Immunologia, Hospital Clínic de Barcelona, University of Barcelona, Institut d'Investigacions Biomèdiques August. Barcelona, Spain
Citation: Muñoz-Sánchez G , Betriu S, Esteve-Solé A.3, Ortiz de Landázuri I, González-Navarro E.A, Español-Rego M, San Bartolomé C, Egri N, Palou E, Juan M. Tregs and Other Suppressive/Regulatory/Tolerogenic Cell Therapies in Transplantation, J. Cancer Research and Cellular Therapeutics. Doi: 10.31579/2640-1053/066
Copyright: © 2020 Manel Juan, This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium,provided the original author and source are credited.
Received: 30 December 2019 | Accepted: 06 January 2020 | Published: 07 January 2020
Keywords: treg; transplantation; rejection; cell therapy
Poor long-term graft outcome remains problematic because of the inability to prevent chronic allograft rejection. Strategies based on suppression/regulation/tolerance (3 different but similarly used concepts) of the immune system often leads to other concerns. New alternatives based on facilitating the induction of alloantigen tolerance by regulatory T cells (Tregs) and other immune-suppressor cells can restore the balance between inhibitory and effector arm. This review mainly summarizes results about the use of Tregs for the control of transplant rejection, commenting also other situations and potentially similar cell therapies.
Poor long-term graft outcome remains problematic because of the inability to prevent chronic allograft rejection. Strategies based on suppression/regulation/tolerance (3 different but similarly used concepts) of the immune system often leads to other concerns. New alternatives based on facilitating the induction of alloantigen tolerance by regulatory T cells (Tregs) and other immune-suppressor cells can restore the balance between inhibitory and effector arm. This review mainly summarizes results about the use of Tregs for the control of transplant rejection, commenting also other situations and potentially similar cell therapies.
Organ transplantation is currently a successful treatment for the majority of patients with end-stage organ failure. Fortunately, improvement in transplant technology, non-invasive biomarkers, better selection of donors and recipients by Human Leukocyte Antigen (HLA) typing/compatibility and the advance of immunosuppresive agents have enabled clear progress in transplantation outcomes ameliorating the graft survival, at least in the early post-transplant stage. However, the poor long-term graft outcome remains problematic because of the inability to prevent chronic allograft rejection (CR). In fact, half of all transplanted kidneys still fail within 15 years after transplantation[1]. In this context, the current treatment of transplantation focuses on the limitation of the effector arm of immune response with nonspecific immunosuppressive drugs (ISD) that perform by inhibiting non-specific T and B cell activation pathways or by depleting lymphocytes.
The mentioned strategy based on suppression of the immune system often leads to over immunosuppression. The lack of specificity of ISD frequently diminishes patient’s quality of life and gives rise to life-threatening infection episodes, malignancies, cardiovascular diseases or kidney failure causing graft loss or even death [2]. Due to the inconveniences caused in transplanted patients by this therapeutic approach, new alternatives that allow better results are being sought. In general, suppression, regulation or tolerance induction are different terms that often are interchangeably used. Although “Suppressor” cells suggest the blockage of responses, “Regulatory” should be a more flexible concept (increase or decrease functions) but just used under the meaning of suppression, and “Tolerogenic” cells are those cells that could induce specific recognition which would program no-response, the three concepts are often used as synonymous. Facilitating the induction of alloantigen tolerance by regulatory T cells (Tregs) and other immune-suppressor cells, restoring the balance between the inhibitory and the effector arm is the aim of a lot of novel strategies based on suppressive/regulatory/tolerogenic cells. Although this review mainly summarizes results about the use of Tregs as controllers of rejection in transplantation, other situations and potential similar cell therapies are also commented.
Tregs: Regulatory T-cells; MSCs: Mesenchymal stromal cells; MMP: matrix metalloproteinase; Mregs: regulatory macrophages; MDSCs myeloid-derived suppressor cells; iNOs: inducible NO synthase; Tol-DCs: Tolerogenic DCs; Bregs: Regulatory B cells; CAR-Tregs: Treg cells expressing chimeric antigen receptor. Tregs induce apoptosis of alloreactive T cells via CTLA-4 and PD-1 engagement.
Besides, Tregs prevent APC’s ability to activate effector T cells by CTLA-4 and LAG-3 binding. Other mechanisms such as TGF-β expression, inducible cAMP early repressor (ICER), IL-10 and miRNA exosome transference are also involved. MSCs secrete MMP types 2 and 9 facilitating the cleavage of CD25 expressed on CD4+ T cells. Both Mregs and MDSCs have immunossupressive activity in an iNOS-dependent pathway. Tol-DCs are able to induce Treg development via CD80/86, ICOS-L, ILT3, ILT4 and PD-L1 binding. Bregs can modulate immune homeostasis in an IL-10 dependent pathway or by IL-10-independent mechanisms based on IL-35 or TGF-β
. CAR-Tregs recognize specific antigens such as HLA-A2 supressing allograft rejection.
1. - General concepts about Tregs
1.1. Characterization and Ontogeny
Tregs are a subset of CD4+ T cells (comprising 1-9% of blood CD4+ T cells) whose function is to limit immune responses by maintaining self-tolerance. Tregs are traditionally classified as natural Tregs (thymus-derived), or peripheral inducible Tregs (iTregs), which are the result of natural T-cells when exposed to cytokines such as TGF-β and IL-2p[3,4]. Tregs are distinguished by the high expression of both CD4+ and CD25+ (IL-2 alpha chain Receptor) and by the transcriptional regulator Forkhead Box P3 (FOXP3)[5], which is a reliable marker specially in mouse Tregs. However, FOXP3 is also expressed in human effector T cells when activated[6] and it is required the use of other markers such as CD4+/CD25+/CD127- to characterize them. Additionally, transcription factor FOXP3 demethylation serves to preserve Treg phenotype and related epigenetic changes are now used to identify Tregs in clinical research [7].
Thymic ontogeny of Tregs starts in CD4 single-positive stage (CD4+/CD8-). Upregulation of FOXP3 and consequent differentiation of Tregs depends on a great heterogeneity of paths and cytokines ruled by environmental conditions and is strongly influenced by inflammatory cues. Antigen Presenting Cells (APCs) in thymus promote FOXP3 upregulation in these thymocytes by self-antigen-presenting in the context of self-MHC class II8. This event together with a satisfactory interaction with CD28 in terms of strength, duration and affinity[9] activates nuclear factor-κB (NF-κB), forkhead box protein O (FOXO) and nuclear factor of activated T cells (NFAT)[10], which is required for FOXP3 expression.
Other factors, like the presence of high concentrations of TGF-β[11], Inducible Costimulator (ICOS/ICOSL) and thymic stromal lymphopoietin are also involved[12]. Also, FOXP3 upregulation event promotes Interleukin-2 receptor alpha chain (also called CD25) surface expression allowing cytokine signalling and consequently the development of fully functional Tregs [13].
1.2. Immunosuppressive drugs and Tregs
PI3K-mTOR (mammalian target of rapamycin) signalling pathway is recognized as one of the main targets of ISD used in transplantation. mTOR is a critical signalling molecule with a crucial role in transcribing immunological cues into a specific family of T cells. Extensive studies at the molecular level of this pathway are imperative for unravelling Tregs association with immunosuppresive drugs, cancer and autoimmunity.
How mTOR regulates Treg phenotype and metabolism is not fully understood. mTOR is formed by two complexes named mTOR1(Raptor), the principal target of rapamycin (RAPA), and mTOR2 (Rictor). T cells lacking whole mTOR complex differentiate preferentially into FOXP3+ Treg rather than Th1, Th2 or Th17 effector cells [14] and expand more efficiently in the presence of IL-2 compared with normal-mTOR T cells. It has been suggested that TGF-β mediated induction of Foxp3+ regulatory cells in deficient mTOR T-cells could explain this divergence given that Tregs development is regulated by a protein named Smad3, which is more likely to be stimulated by TGF-β in mTOR-deficient Treg cells. However, mice containing Treg specific deletion of Raptor (mTOR1) lose their Treg function in vivo [15] and develop fatal autoimmune inflammatory state [16].
Many immunosuppressive drugs currently used base their mechanism on the mTOR pathway determining Tregs function and transplantation outcome. For instance, calcineurin inhibitors have shown a negative effect on Tregs generation and function [17] while there is substantial evidence that rapamycin favours Treg survival and function [18]. The effects of mycophenolic acid are variable [19,20] and regarding basiliximab, due to its anti-CD25 effect, may have a deleterious effect on Treg cells [21]. Nonetheless, either via mTOR or by another alternative mechanism there is a widespread observation that the percentage of circulating CD25+ CD4+ FOXP3 cells decreases after transplantation [22]. This way, the balance between immunoreactive and immunosuppressive status gets compromised concluding in the adverse events or reactions described above. That is the main reason why new approaches focusing on tolerance induction via Tregs or other promising methods such as regulatory macrophages or mixed chimerism should be considered.
2. - Tregs in transplantation
As regulatory T cells are essential for the induction and preservation of peripheral tolerance and hence for preventing graft rejection, they have been deeply studied and seriously taken into consideration as a new therapeutic tool. Data suggest that Tregs could exert a tolerant state to alloantigens in vivo by inducing a regulatory profile in alloreactive T cells. Before describing the therapeutic approaches by which we could take profit of Tregs, it is convenient to describe briefly the main steps where Tregs get involved suppressing allorejection to understand the multiple pathways that could be affected by manipulating these cells.
In the setting of any solid organ transplantation, donor APCs migrate to the lymph nodes and present allogeneic class I or class II MHC molecules to the recipient’s CD8+ and CD4+ T cells, respectively (direct presentation). Host dendritic cells can also display and present graft alloantigens to T lymphocytes (indirect presentation) resulting in naive T cells differentiation and proliferation into effector helper T cells and cytotoxic T lymphocytes. These effector T cells migrate back into the graft and mediate cellular rejection. The usefulness of Tregs resides in their capability of regulating this rejection process in different ways.
Tregs are able to induce cytotoxic T lymphocyte apoptosis via engagement of CTLA-4 (cytotoxic T lymphocyte antigen-4) and PD1 (Programmed cell death 1), granzyme A/B, TNF related apoptosis-inducing ligand (TRAIL), FAS/FAS-ligand pathway, the galectin/TIM-3 pathway and through IL-2 deprivation. On the other hand, Treg’s CTLA-4 binds with CD80/86 on APCs leading to the induction of indolamine-2,3-dioxygenase (IDO)[23,24] and LAG-3 binds with MHC-II preventing APC’s ability to activate effector T cells[25]. Other mechanisms mediated by Tregs as TGF-β membrane-bound active expression, upregulation of ICER (inducible cAMP early repressor)[26] and the consequent inhibition of NFAT and IL-2 transcription by cAMP transference from Tregs to effector T cells, IL-10/IL-35/TGF-β production and miRNA exosome[27] transference are also suppressive physiological cues focused on diminishing immune response and rejection.
3. - T-immunotherapies (from Tregs to CARTregs)
Diverse therapies based on the use of immune-related cells to induce tolerance are currently undergoing clinical trials. Tolerance induction could be advantageous in different circumstances such as autoimmunity, in which control of self-reactive lymphocytes is defective, or transplantation. Even though Tregs are the cornerstone of this review, other cell strains are being considered and studied as tolerance inductors like myeloid-derived suppressor cells (MSDC), Mesenchymal Stem Cells (MSC), regulatory macrophages (Mreg), tolerogenic Dendritic Cells (Tol-DCs) or regulatory B lymphocytes (Breg).
3.1. Polyclonal Treg cells
Polyclonal Treg cells are non-antigen-specific cells (in contrast with antigen-specific Tregs we will describe later). Regulatory T cells are a well-defined subset that can be cultivated and expanded ex vivo and returned safely to patients. The low rate of Tregs in adults (less than 9% of CD4+) requires their expansion ex vivo before clinical use. Polyclonal expansion generates large numbers of Tregs from peripheral blood with potential use as adoptive cell therapy. First of all, cells can be sourced directly from the patient (autologous) or a third-party unrelated donor (allogeneic). The source of autologous Treg cells is limiting and current manufacturing conditions are demanding and costly. On the other hand, allogeneic Tregs offer exceptional opportunities when immune host-mediated elimination of transferred cells is overcome, allowing a durable response.
In terms of production and isolation, the best marker to characterize Treg cells is a nuclear transcription factor (FOXP3) and therefore is not suitable for isolation by flow cytometry since it is an intracellular complex. As described above, CD25 is highly expressed in most Treg cells but is transiently shared with effector T cells, so cannot be used by itself to avoid unwanted T-cells [28].
In the present day, there are different protocols for regulatory Treg production. One option is to use CD8, CD14, CD19 and CD127 negative selection to discard non-CD4 T-cells followed by CD25 positive selection[28]. Instead of selection, Treg induction protocol is based on FOXP3 expression promoters (IL-2, TGF-β activation and use of mTOR inhibitors). By using mentioned promoters together with TCR activation we could selectively stimulate Treg development[28]. Once we have selected/induced Treg subset, expansion and proliferation is required; IL-2 is used as a growth factor promoting expansion and survival of Tregs previously isolated [29].
Clinical trials to determine the safety and stability of this cell therapy have been carried out. In solid organ transplantation, the ONE study (NCT02129881) has shown that Treg cells can be grown and are safe for administration to transplant recipients in a dose-escalating approach from 0.5-3.0x106 cells/kg. There is an attractive argument for combining Treg with rapamycin (RAPA) monotherapy, since rapamycin may facilitate the survival of Tregs. Starting from ONE study, the so-called TWO study (MR/N027930/1), which started in 2017 and will end in 2023, aims to elucidate if nTreg can actually control rejection. For this purpose, 34 renal transplant recipients will be recruited over three years and each receptor will be treated with conventional immunosuppressive drugs. However, after transplant, cellular therapy of Treg isolated from their own blood (autologous) will be administered. Then, the immunosuppressive drug dose will be reduced while renal function monitoring is carried out. Thus, evidence of nTreg role in protecting grafts from damage could be tested[30].
3.2 Antigen-specific Treg therapies
Efficacy of antigen-specific Tregs should be higher than polyclonal Tregs [31,32] but their expansion is challenging due to low precursor rates. Some studies suggest that these alloantigen-expanded Tregs are 100-fold more potent at suppressing alloantigen-stimulated proliferation in vitro than polyclonal Tregs [33]. Different approaches to obtain antigen-specific Tregs should be taken into account: 1) purified antigen-specific Tregs; 2) specific TCR transduction; 3) CAR Tregs, in which the CAR (Chimeric Antigen Receptor) recognizes specific targets; and 4) specific effector T cells reconverted into Treg cells by FOXP3 overexpression.
1. Purified antigen-specific Tregs
The frequency of direct allo-reactive Tregs (darTregs) has been estimated to be between 1% and 10% [33]. Proof-of-principle researches have shown that antigen-specific Tregs can be cultured and expanded using donor APCs such as DCs, B lymphocytes[34] and mononuclear cells. Qizhi et al[35] group estimated that 5 × 109 polyclonal Tregs would be necessary to induce tolerance when combined with 90
In summary, new cell immunotherapies are appearing as options for control rejection in transplantation; probably the use of Tregs seems to be most promising, although other similar cell therapies are arriving to boost this option. The promise of a durable tolerance without unwanted immuno suppression is now a clear possibility in the near future.
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