The following is a summary of the “Low dose interleukin-2 selectively expands circulating regulatory T cells but fails to promote liver allograft tolerance in humans,” published in the January 2023 issue of Hepatology by Lim, et al.
To test LDIL-2’s ability to inhibit allospecific immune responses and permit the eventual withdrawal of maintenance immunosuppression, a clinical trial was conducted in healthy liver transplant patients 2-6 years after the procedure (ClinicalTrials.gov NCT02949492). Those who experienced a 2-fold increase in circulating CD4+CD25+Foxp3+ regulatory T cells (Tregs) or more after 1 month of LDIL-2 treatment eventually tapered off immunosuppression over 4 months while continuing LDIL-2 for a total of 6 months.
The number of circulating Tregs increased dramatically and stayed high for everyone participating. This, however, was not linked to the formation of donor-reactive Tregs within the liver or a preference for their growth. In addition, LDIL-2 triggered a robust IFN-orchestrated transcriptional response in the liver before the initiation of immunosuppressive weaning. As the first 6 trial participants experienced rejection requiring reinstitution of immunosuppression, the study was stopped before it could reach its primary aim.
Nevertheless, off-target effects that increase liver immunogenicity mean that the increase in circulating Tregs in response to LDIL-2 is not enough to control alloimmunity and induce liver allograft tolerance. Their study is the first to shed light on how immunomodulatory medications like LDIL-2 work to promote alloantigen-specific effects and immunological tolerance, as well as the limitations of such treatments.