Chimerism and Tolerance Without GVHD in Mismatched Recipients of Combined Hematopoietic Stem Cell/Kidney Transplants: Donor-Specific Hyporeactivity Is Not a Reliable Biomarker for Tolerance.

We recently reported low-intensity conditioning combined with facilitating cell (FC)-enriched hematopoietic stem cell transplantation (FCRx) can safely achieve high levels of durable chimerism in unrelated and related mismatched kidney transplant (KTx) recipients. This is associated with stable renal function, absence of GVHD, and successful withdrawal of immunosuppression (IS). We herein present interim follow-up on 19 subjects and present data to demonstrate that donor specific hypoactivity does not correlate with tolerance to the renal allograft if durable chimerism is not present. HLA-mismatched related (n = 12) and unrelated (n = 7) living donor KTx recipients were conditioned with fludarabine (days -5,-4,-3), cyclophosphamide (50 mg/kg day -3, +3), 200 cGy TBI, (day -1), KTx (day 0), followed by infusion of cryopreserved G-CSF mobilized FCRx (day +1). Multilineage chimerism was assessed by STR analysis. Mixed lymphocyte reaction (MLR) assays were performed to assess donor-specific hyporeactivity. 18 of 19 patients demonstrated peripheral blood macrochimerism at 1 month post-transplant (6% - 100%). The one patient who failed to engraft was highly sensitized (Class I PRA > 40%). No subjects developed GVHD or “engraftment syndrome.” Durable whole blood and T cell chimerism was achieved in 12 subjects. All patients demonstrated in vitro donor-specific hyporesponsiveness (DSH) by MLR +/- CML post-transplant regardless of chimerism status. However, DSH in patients who lost chimerism was not predictive of successful IS weaning, as 3 transiently chimeric patients with DSH had subclinical Banff 1A rejection on protocol biopsy while on IS monotherapy. Recurrence of underlying autoimmune disease has only occurred in subjects who were transiently chimeric. Protocol biopsies in chimeric subjects have exhibited normal histology for up to 3 years. 12 chimeric subjects are completely off IS from 3-42 months. The presence of durable, high level whole blood and T cell chimerism in combined kidney + FCRx recipients is a robust biomarker of tolerance. DSH without donor chimerism does not predict successful IS withdrawal or tolerance. DISCLOSURES:Gallon, L.: Grant/Research Support, NOvartis. Tollerud, D.: Other, regenerex LLC, COO. Elliot, M.: Employee, REGENEREX LLC. Ildstad, S.: Other, regenerex LLC, CEO.