Session Time: 2:30pm-4:00pm
Presentation Time: 3:42pm-3:54pm
Location: Room 208
*Purpose: Long-term survival of recipients of solid organ transplants is hampered by chronic rejection, disease recurrence and immunosuppression-induced toxicity. Self-tolerance is re-established after autologous hematopoietic stem cell transplantation (HSCT) for patients with autoimmune disease. We are now studying whether HSCT can induce tolerance in liver transplant recipients with recurrent primary sclerosis cholangitis (PSC).
*Methods: Patients with recurrent PSC treated with liver transplantation who are > 3 months post-transplant and 18 to 55 yrs old were eligible for the trial. Hematopoietic stem cells were mobilized, isolated using CD34 cell immunomagnetic selection, and cryopreserved. Busulfan, cyclophosphamide and rabbit αntithymocyte globulin were administered to ablate auto- and allo-reactivity followed by HSCT. Immunosuppressive medications were discontinued at the time of HSCT and everolimus was given to promote regulatory T cell expansion for the first 6 months. Patients were followed for evidence of tolerance or rejection. Immune studies including autoantibody profiling, TCR sequencing, and CyTOF were performed on patient samples.
*Results: 75 liver transplant patients were screened and 13 patients were evaluated. One patient declined participation, liver disease was too advanced in 4 patients and too mild in 2 patients. 6 patients were enrolled and 5 have undergone HSCT. All patients had evidence of recurrent PSC with moderate to severe ductopenia and fibrosis at a median of 98 months (15-233 mo.) prior to HSCT. The median age was 40 (36-44) yrs. 4 patients were male, 3 patients received living and 2 patients received cadaveric liver grafts and 1 patient had two liver transplants. 4 patients had ulcerative colitis. Patients received a mean 7.21×106 purified CD34+ cells/kg. Grade 3-4 non-hematologic toxicity was seen in all patients. Immunosuppression was discontinued in 3 patients post HSCT: 2 are alive at greater than 2 years after HSCT and one died at 212 days post-HSCT of heart failure. Of the other two patients who received HSCT, one patient developed veno-occlusive disease and required repeat liver transplantation, and one patient died of hemophagocytosis. Tolerance induction with HSCT was associated with both deletional events and evidence of peripheral regulation. HSCT led to deletion of T cell clones and autoantibodies while promoting circulating Treg and transitional B cells.
*Conclusions: These results suggest that HSCT can induce tolerance in liver transplant recipients although toxicity is a significant problem that needs to be addressed.
To cite this abstract in AMA style:Chruscinski A, Atkins H, Clement A, Grant D, Bredsen C, Renner E, Zhang J, Epstein M, Lilly L, Selzner N, Adeyi O, Smith R, Moshkelgosha S, Humar A, Juvet S, Levy G. An Open-Label Proof-of-Principle Phase 2A Study to Evaluate Autologous Hematopoietic Stem Cell Transplantation for Allogeneic Organ Transplant Tolerance (ASCOTT) [abstract]. Am J Transplant. 2019; 19 (suppl 3). https://atcmeetingabstracts.com/abstract/an-open-label-proof-of-principle-phase-2a-study-to-evaluate-autologous-hematopoietic-stem-cell-transplantation-for-allogeneic-organ-transplant-tolerance-ascott-2/. Accessed February 24, 2020.
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