Session Time: 3:15pm-4:45pm
Presentation Time: 3:51pm-4:03pm
*Purpose: Long-term survival of recipients of solid organ transplants is limited by chronic rejection, disease recurrence and immunosuppression-induced toxicity. Self-tolerance is established after autologous hematopoietic stem cell transplantation (aHSCT) for patients with autoimmune disease. We studied whether aHSCT can induce tolerance in liver transplant recipients.
*Methods: Patients enrolled had previously undergone liver transplantation for primary sclerosing cholangitis (PSC) and now had evidence of PSC recurrence. These patients were chosen given the poor outcomes associated with PSC recurrence. Eligible patients were greater than three months post-liver transplant and were between 18 to 55 years old. Hematopoietic stem cells were mobilized, isolated using CD34 cell immunomagnetic selection, and cryopreserved. Busulfan, cyclophosphamide and rabbit anti-thymocyte globulin were administered followed by aHSCT. Immunosuppressive medications were discontinued at the time of HSCT and everolimus was given to promote regulatory T cell (Treg) expansion for the first six months.
*Results: Twelve patients were evaluated and five were accepted for aHSCT. All five patients had evidence of recurrent PSC with moderate to severe ductopenia and fibrosis. Patients received a mean 7.21×106 purified CD34/kg. Of the five patients enrolled, three developed tolerance: two patients are off immunosuppression for greater than three years post-aHSCT; one patient died at 212 days post-aHSCT from right heart failure. The fourth patient died at day 87 post-aHSCT from sepsis, and the fifth patient developed sinusoidal obstruction syndrome and required repeat liver transplantation but is now on single agent immunosuppression with an mTOR inhibitor. In the three patients who developed tolerance, follow up liver biopsies showed regression of fibrosis and no evidence of rejection. Tolerance induced by aHSCT was associated with a partial deletion of T cell repertoire and replacement with new clones. There was evidence of enhanced peripheral regulation post-aHSCT with short-term (6 months) increases in Tregs and transitional B cells in the peripheral blood. While levels of Tregs returned to baseline in the blood, Tregs persisted in the liver allografts. aHSCT also led to deletion of autoantibodies that are commonly present in patients with PSC.
*Conclusions: These results suggest that aHSCT can induce tolerance in liver transplant recipients although toxicity is a significant problem that needs to be addressed. Tolerance induced by aHSCT likely involves both deletional events and enhanced peripheral regulation.
To cite this abstract in AMA style:Chruscinski A, Juvet S, Moshkelgosha S, Renner E, Lilly L, Selzner N, Bredeson C, Adeyi O, Fischer S, Demetris A, Zhang J, Epstein M, Clement A, Khalili K, Galvin Z, Humar A, Kim T, Tinckham K, Yi T, Levy G, Atkins H. A Proof-of-Principle Study to Evaluate Autologous Hematopoietic Stem Cell Transplantation for Allogeneic Organ Transplant Tolerance (ASCOTT) [abstract]. Am J Transplant. 2020; 20 (suppl 3). https://atcmeetingabstracts.com/abstract/a-proof-of-principle-study-to-evaluate-autologous-hematopoietic-stem-cell-transplantation-for-allogeneic-organ-transplant-tolerance-ascott/. Accessed June 15, 2021.
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