Low dose interleukin-2 selectively expands circulating regulatory T cells but fails to promote liver allograft tolerance in humans

Lim, Tiong Yeng; Perpiñán, Elena; Londoño, María-Carlota; Miquel, Rosa; Ruiz, Paula; Kurt, Ada; Kodela, Elisavet; Cross, Amy; Berlin, Claudia; Hester, Joanna; Issa, Fadi; Douiri, Abdel; Volmer, Felix H; Taubert, Richard; Williams, Evangelia; Demetris, Anthony J.; Lesniak, Andrew; Bensimon, G.; Lozano, Juan José; Martínez‐Llordella, Marc; Tree, Timothy; Sánchez‐Fueyo, Alberto

doi:10.1016/j.jhep.2022.08.035

Cited by 36 publications

(54 citation statements)

References 36 publications

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“…Although the response of T regs to the addition of these cytokines did not change, the proliferation of CD8 + T cells markedly increased. These results echo the lack of donor-specific T reg expansion following the in vivo administration of low-dose IL-2 to liver transplant recipients in a clinical trial (LITE, NCT02949492) that has a very similar design to ARTEMIS ( 52 ). Together, these results suggest that reduced IL-2 in transplant recipients maintained on calcineurin inhibitors may pose a substantial challenge to exogenous T reg therapy and tolerance induction.…”

Section: Discussionsupporting

confidence: 58%

Selective decrease of donor-reactive T _regs after liver transplantation limits T _reg therapy for promoting allograft tolerance in humans

et al. 2022

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Promoting immune tolerance to transplanted organs can minimize the amount of immunosuppressive drugs that patients need to take, reducing lifetime risks of mortality and morbidity. Regulatory T cells (T regs ) are essential for immune tolerance, and preclinical studies have shown their therapeutic efficacy in inducing transplantation tolerance. Here, we report the results of a phase 1/2 trial (ARTEMIS, NCT02474199) of autologous donor alloantigen–reactive T reg (darT reg ) therapy in individuals 2 to 6 years after receiving a living donor liver transplant. The primary efficacy endpoint was calcineurin inhibitor dose reduction by 75% with stable liver function tests for at least 12 weeks. Among 10 individuals who initiated immunosuppression withdrawal, 1 experienced rejection before planned darT reg infusion, 5 received darT regs , and 4 were not infused because of failure to manufacture the minimal infusible dose of 100 × 10 6 cells. darT reg infusion was not associated with adverse events. Two darT reg -infused participants reached the primary endpoint, but an insufficient number of recipients were treated for assessing the efficacy of darT regs . Mechanistic studies revealed generalized T reg activation, senescence, and selective reduction of donor reactivity after liver transplantation. Overall, the ARTEMIS trial features a design concept for evaluating the efficacy of T reg therapy in transplantation. The mechanistic insight gained from the study may help guide the design of future trials.

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Section: Discussionsupporting

confidence: 58%

Selective decrease of donor-reactive T _regs after liver transplantation limits T _reg therapy for promoting allograft tolerance in humans

et al. 2022

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“…Our group and others previously described the use of short courses of low-dose recombinant IL-2 to increase circulating Tregs in patients with autoimmune hepatitis (5) (48). In contrast to the results observed in autoimmunity, an additional study from our group in human liver transplantation revealed that low-dose IL-2 increased the immunogenicity of the liver allograft, facilitating rather than preventing allograft rejection (49). These somehow unexpected clinical results observed in liver transplant recipients are reminiscent of what has been described in murine models of intra-hepatic T cell priming, in which IL-2 reverts the inactivation of CD8+ T cells that takes place when they recognize cognate antigens expressed by hepatocytes (50).…”

Section: Discussionmentioning

confidence: 79%

IL-2 availability regulates the tissue specific phenotype of murine intra-hepatic Tregs

et al. 2022

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CD4+CD25+Foxp3+ Tregs are known to acquire tissue-specific features and exert cytoprotective and regenerative functions. The extent to which this applies to liver-resident Tregs is unknown. In this study, we aimed to explore the phenotypic and functional characteristics of adult murine liver resident Tregs during homeostasis. Additionally, we investigated their role in ameliorating liver inflammation and tissue damage. Quantification of Foxp3+CD4+CD25+ cells comparing different tissues showed that the liver contained significantly fewer resident Tregs. A combination of flow cytometry phenotyping and microarray analysis of intra-hepatic and splenic Tregs under homeostatic conditions revealed that, although intra-hepatic Tregs exhibited the core transcriptional Treg signature, they expressed a distinct transcriptional profile. This was characterized by reduced CD25 expression and increased levels of pro-inflammatory Th1 transcripts Il1b and Ifng. In vivo ablation of Tregs in the Foxp3-DTR mouse model showed that Tregs had a role in reducing the magnitude of systemic and intra-hepatic inflammatory responses following acute carbon tetrachloride (CCl₄) injury, but their absence did not impact the development of hepatocyte necrosis. Conversely, the specific expansion of Tregs by administration of IL-2 complexes increased the number of intra-hepatic Tregs and significantly ameliorated tissue damage following CCl₄ administration in C57BL/6 mice. The cytoprotective effect observed in response to IL-2c was associated with the increased expression of markers known to regulate Treg suppressive function. Our results offer insight into the transcriptome and complex immune network of intra-hepatic Tregs and suggest that strategies capable of selectively increasing the pool of intra-hepatic Tregs could constitute effective therapies in inflammatory liver diseases.

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“…Unexpectedly, however, although levels of Tregs were increased in the blood, intrahepatic expansion of Tregs was not seen. After initiation of weaning, all patients failed to reach the first endpoint due to rejection and requirement of immunosuppression restoration, resulting in termination of the trial [ 24 ].…”

Section: Current Status and Ongoing Studiesmentioning

confidence: 99%

“…Nevertheless, low-dose IL-2 treatment has emerged as a promising method for tolerance induction, both in rodent models and in clinical trials [ 60 ]. A concern, however, is that this procedure can be associated with an increased risk of T-cell-mediated rejection [ 24 ]. Thus, in a liver transplantation trial, low-dose IL-2 was shown to elicit an IFNγ-dependent inflammatory response within the allograft.…”

Section: Future Strategiesmentioning

confidence: 99%

Treg Therapy for the Induction of Immune Tolerance in Transplantation—Not Lost in Translation?

Pilat

Steiner

Sprent

2023

IJMS

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The clinical success of solid organ transplantation is still limited by the insufficiency of immunosuppressive regimens to control chronic rejection and late graft loss. Moreover, serious side effects caused by chronic immunosuppressive treatment increase morbidity and mortality in transplant patients. Regulatory T cells (Tregs) have proven to be efficient in the induction of allograft tolerance and prolongation of graft survival in numerous preclinical models, and treatment has now moved to the clinics. The results of the first Treg-based clinical trials seem promising, proving the feasibility and safety of Treg therapy in clinical organ transplantation. However, many questions regarding Treg phenotype, optimum dosage, antigen-specificity, adjunct immunosuppressants and efficacy remain open. This review summarizes the results of the first Treg-based clinical trials for tolerance induction in solid organ transplantation and recapitulates what we have learnt so far and which questions need to be resolved before Treg therapy can become part of daily clinical practice. In addition, we discuss new strategies being developed for induction of donor-specific tolerance in solid organ transplantation with the clinical aims of prolonged graft survival and minimization of immunosuppression.

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Low dose interleukin-2 selectively expands circulating regulatory T cells but fails to promote liver allograft tolerance in humans

Cited by 36 publications

References 36 publications

Selective decrease of donor-reactive T _regs after liver transplantation limits T _reg therapy for promoting allograft tolerance in humans

Selective decrease of donor-reactive T _regs after liver transplantation limits T _reg therapy for promoting allograft tolerance in humans

IL-2 availability regulates the tissue specific phenotype of murine intra-hepatic Tregs

Treg Therapy for the Induction of Immune Tolerance in Transplantation—Not Lost in Translation?

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Low dose interleukin-2 selectively expands circulating regulatory T cells but fails to promote liver allograft tolerance in humans

Cited by 36 publications

References 36 publications

Selective decrease of donor-reactive T regs after liver transplantation limits T reg therapy for promoting allograft tolerance in humans

Selective decrease of donor-reactive T regs after liver transplantation limits T reg therapy for promoting allograft tolerance in humans

IL-2 availability regulates the tissue specific phenotype of murine intra-hepatic Tregs

Treg Therapy for the Induction of Immune Tolerance in Transplantation—Not Lost in Translation?

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Selective decrease of donor-reactive T _regs after liver transplantation limits T _reg therapy for promoting allograft tolerance in humans

Selective decrease of donor-reactive T _regs after liver transplantation limits T _reg therapy for promoting allograft tolerance in humans