Session Time: 2:30pm-4:00pm
Presentation Time: 3:18pm-3:30pm
Location: Room 208
*Purpose: Previously we reported a novel biomarker gene set for the identification of tolerance in murine models of rapamycin-induced cardiac tolerance and spontaneous hepatic tolerance. GeXP multiplex RT-PCR as used to amplify 22 prominent immunoregulatory genes, in cardiac and liver grafts, that were then correlated with the pathological and biochemical parameters of transplanted organs. Subsequently, an eight -gene expression panel, consisting of increased expression of 6 immunoregulatory genes (fgl2, foxp3, il10, lag3, tgfb, tigit) and decreased expression of 2 pro-inflammatory genes (ifng, gzmb) was found to be predictive of tolerance.
*Methods: In this Phase 2A single center study, we examined whether an 8 target and 5 housekeeping gene expression panel in peripheral blood mononuclear cells (PBMC) and liver allografts could identify operationally tolerant liver transplant recipients. We first measured the panel in PBMC from 60 adult liver transplant recipients who were a minimum of 3 months post-transplant and who had no biochemical evidence of rejection. Patients with a putative tolerant gene profile in PBMC underwent a liver biopsy and were then weaned off immunosuppression (IS) to confirm that the gene profile identified a tolerant state. PBMC gene expression was monitored at 3, 6, and 12 months post IS withdrawal.
*Results: Of the 60 patients studied, 16 had the putative tolerance gene profile in their PBMC. Age, gender, indication for transplant, and CNI choice did not correlate with having the tolerant profile. Twelve patients agreed to enter the withdrawal phase of the study. Prior to withdrawal, a liver biopsy was performed, and 3 patients were excluded as their biopsies showed recurrent disease and/or rejection. Of the 9 remaining patients, 5 have now been weaned off of IS and are >2 years post IS withdrawal, 2 are undergoing withdrawal and 2 developed acute cellular rejection, which was easily reversed. Five of 5 patients who had the gene expression profile both in liver and PBMC were successfully weaned off immunosuppression. In patients who achieved tolerance, patterns of the tolerance gene profile were similar to what was seen in mice that achieved tolerance: levels of fgl2 remained stable over time, foxp3 gene expression increased at 3 months and then then returned to baseline and tigit gene expression in tolerant patients increased at 6 months post-IS withdrawal and remained elevated at 1 year.
*Conclusions: These data suggest that a combination of gene expression monitoring in PBMC and the liver allograft may identify operationally tolerant recipients, allowing for withdrawal of immunosuppression. Recruitment of additional patients into the trial is now ongoing.
To cite this abstract in AMA style:Chruscinski A, Rojas-Luengas V, Moshkelgosha S, Luo J, Yowanto H, Galvin Z, Lilly L, Smith R, Renner E, Zhang J, Grant D, Adeyi O, Atkins H, Juni P, Selzner N, Juvet S, Levy G. Results of Litmus (nct 02541916): The Liver Immune Tolerance Bio Marker Utilization Study [abstract]. Am J Transplant. 2019; 19 (suppl 3). https://atcmeetingabstracts.com/abstract/results-of-litmus-nct-02541916-the-liver-immune-tolerance-bio-marker-utilization-study-2/. Accessed May 9, 2021.
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