Twenty-eight fully HLA-matched and 18 HLA haplotype- matched recipients were given combined kidney and hematopoietic cell transplants using a completely post-transplant conditioning regimen consisting of 10 doses of total lymphoid irradiation (TLI, total dose 120cGy) and 5 doses of rabbit anti-thymocyte globulin (total dose 7.5mg/kg) over 11 days.

After the last dose of TLI, HLA-matched recipients received 4 to 10 x10⁶ CD34 cells/kg purified on a Miltenyi column, and 1 x10⁶ CD3 T cells/kg contained in the column flow-through cells. Donor cells were collected from G-CSF mobilized blood and cryopreserved about 6 weeks before kidney transplantation. Twenty-one recipients were given one month of mycophenolate mofetil (MMF) and 9 to 12 months of cyclosporine before discontinuation. Of the 21, seven have been stable mixed chimeras for up to 8 years, and 14 lost chimerism in the second year. Follow-up in the 21 is now up to nearly 9 years, with no acute rejection aside from one case at 4 years off drug in a single individual who had lost chimerism in the second year. Five patients did not meet drug withdrawal criteria, and two are in taper. Death-censored kidney graft survival in the matched recipients is 100%, with up to nearly 12 years of observation.

The haplotype-matched recipients were given escalating dose of T cells, and persistent chimerism for at least one year has been achieved in 5 patients despite discontinuation of MMF and taper of tacrolimus to a trough blood level of 3 to 5ng/mL (minimum effective dose; MED). In contrast to the fully HLA-matched patients, two of the haplotype-matched patients developed acute rejection after the loss of chimerism when tacrolimus was tapered to discontinuation during the second year. These episodes of acute rejection were rapidly reversed. When chimerism has been lost during drug taper in subsequent patients, they have been maintained on MED of tacrolimus, without acute rejection. Death-censored kidney graft survival in the mismatched recipients is 100%, with up to six years of observation.

In conclusion, in this protocol stable mixed chimerism appears to be an important biomarker correlated with tolerance in the HLA-mismatched but not in the fully HLA-matched. We are currently determining the fraction of HLA-mismatched patients who develop stable chimerism and tolerance after immunosuppression is completely discontinued in year two.

CITATION INFORMATION: Busque S, Scandling J, Shizuru J, Lowsky R, Shori A, Kent J, Engleman E, Strober S. Relationship Between Mixed Chimerism and Tolerance in HLA-Matched and -Mismatched Recipients of Kidney and Hematopoietic Cell Transplants. Am J Transplant. 2017;17 (suppl 3).

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