| Title: |
Low dose interleukin-2 selectively expands circulating regulatory T cells but fails to promote liver allograft tolerance in humans |
| Authors: |
Lim, TY; Perpinan, E; Carlota Londono, M; Miquel, R; Ruiz, P; Kurt, A; Codela, E; Cross, A; Berlin, C; Hester, J; Issa, F; Douiri, A; Volmer, F; Taubert, R; Williams, E; Demetris, J; Lesniak, A; Bensimon, G; Lozano, J; Martinez-Llordella, M; Tree, T; Sanchez-Fueyo, A |
| Publisher Information: |
Elsevier |
| Publication Year: |
2022 |
| Collection: |
Oxford University Research Archive (ORA) |
| Description: |
Background & Aims: CD4+CD25+Foxp3+ regulatory T cells (Tregs) are essential to maintain immunological tolerance and have been shown to promote liver allograft tolerance in both rodents and humans. Low-dose IL-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 transplant 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 LDIL-2 was initiated, those 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 participants 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 intrahepatic Tregs. Furthermore, LDIL-2 induced a marked IFNγ-orchestrated transcriptional response in the liver even before immunosuppression weaning was initiated. The trial was terminated after the first 6 participants failed to reach the primary endpoint owing to rejection requiring reinstitution of immunosuppression. 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 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. Clinical Trials ... |
| Document Type: |
conference object |
| Language: |
English |
| Relation: |
https://doi.org/10.1016/j.jhep.2022.08.035 |
| DOI: |
10.1016/j.jhep.2022.08.035 |
| Availability: |
https://doi.org/10.1016/j.jhep.2022.08.035; https://ora.ox.ac.uk/objects/uuid:9c00f998-730e-40ae-84e5-db0a1cfbb37f |
| Rights: |
info:eu-repo/semantics/openAccess ; CC Attribution (CC BY) |
| Accession Number: |
edsbas.B3A47E91 |
| Database: |
BASE |