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

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Tiong Y. Lim, Elena Perpiñán, Maria-carlota Londoño, Rosa Miquel, Paula Ruiz, Ada S. Kurt, Elisavet Kodela, Amy R. Cross, Claudia Berlin, Joanna Hester, Fadi Issa, Abdel Douiri, Felix H. Volmer, Richard Taubert, Evangelia Williams, Anthony J. Demetris, Lesniak Andrew, Bensimon Gilbert, Juan José Lozano, Marc Martinez-llordella & 2 more Tim Tree, Alberto Sánchez-fueyo

Original languageEnglish
JournalJournal of Hepatology
DOIs
Accepted/In press17 Aug 2022
Published7 Sep 2022

King's Authors

Abstract

BACKGROUND & AIMS
CD4+CD25+Foxp3+ regulatory T cells (Tregs) are essential to maintain immunological tolerance and have been shown to promote liver allograft tolerance both in rodents and in humans. Low dose interleukin-2 (LDIL-2) can expand human endogenous circulating Tregs in vivo, but its role in suppressing antigen-specific responses and promoting Treg trafficking to the sites of inflammation is unknown. Likewise, whether LDIL-2 facilitates the induction of allograft tolerance has not been investigated in humans.

METHODS
We conducted a clinical trial in stable liver recipients 2-6 years post-transplant to determine the capacity of LDIL-2 to suppress allospecific immune responses and allow for the complete discontinuation of maintenance immunosuppression (clinicaltrials.gov NCT02949492). One month after initiating LDIL-2, patients exhibiting at least a 2-fold increase in circulating Tregs gradually discontinued immunosuppression over a 4-month period while continuing LDIL-2 for a total treatment duration of 6 months.

RESULTS
All patients achieved a marked and sustained increase in circulating Tregs. However, this was not associated with the preferential expansion of donor-reactive Tregs and did not promote the accumulation of intra-hepatic Tregs. Furthermore, LDIL-2 induced a marked interferon-gamma orchestrated transcriptional response in the liver even before immunosuppression weaning was initiated. The trial was terminated after the first six participants failed to reach the primary endpoint due to rejection requiring immunosuppression reinstitution.

CONCLUSIONS
The expansion of circulating Tregs in response to LDIL-2 is not sufficient to control alloimmunity and to promote liver allograft tolerance, due, at least in part, to off-target effects that increase the liver immunogenicity. Our trial provides unique insight into the mechanisms of action of immunomodulatory therapies such as LDIL-2 and their limitations in promoting alloantigen-specific effects and immunological tolerance.

Lay Summary
The administration of low-dose interleukin-2 to liver transplant patients increased the number of circulating lymphocytes with immunosuppressive properties (regulatory T cells), but did not promote their trafficking into the transplanted liver and failed to induce transplantation tolerance.

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