Classical studies in cattle and rodents showed that mixed chimerism (MXC) established in fetuses and neonates was permanent, linked to immune tolerance and graft acceptance without immunosuppressive drugs (ISD). We determined whether persistent MXC in HLA-matched and -mismatched recipients of combined kidney and hematopoietic cell transplants from living donors followed the preclinical paradigm and allowed for permanent MXC and graft acceptance in the absence of ISD. Recipients were given a 10-day post-transplant conditioning regimen of total lymphoid irradiation and ATG.

Of 29 HLA-matched pts, 24 developed MXC for ≥1 yr and were withdrawn from ISD without subsequent rejection in 23 of the 24, up to 12 yrs of follow-up. MXC persisted after drug withdrawal in 10. However, 14 lost MXC during the 2nd yr while graft acceptance was maintained except in 1 pt with mild rejection 3 yrs off ISD. Pts with graft tolerance had specific unresponsiveness to donor cells in MLR even in the absence of MXC. There were 2 graft losses out of 29 during the 12-yr observation period, from disease recurrence. Biopsy obtained from mixed chimeric pts before discontinuation of ISD showed no rejection.

Of 22 HLA haplotype-mismatched pts, 18 have been followed for ≥1 yr, and 9 developed MXC that persisted at least 1 yr. MMF was withdrawn from the chimeric pts and they were maintained on tacrolimus (TAC) monotherapy at the end of the 1st yr. Biopsy showed no rejection. However, withdrawal of TAC in 6 during the 2nd yr resulted in loss of MXC with evidence of mild rejection in 3; they returned to ISD. MXC in these HLA-mismatched pts did not follow the “classical” paradigm – it was dependent on ISD. The remaining persistent chimeras have been maintained on TAC monotherapy. There has been no graft loss or chronic rejection in the 22 pts, with up to 7 yrs of follow-up. Neither severe or chronic infection, nor graft versus host disease, has been observed in the HLA-matched and -mismatched pts.

In conclusion, persistent MXC was associated with lack of rejection in both HLA-matched and -mismatched pts. Lack of rejection off ISD was observed even after loss of chimerism in HLA-matched pts, but not in HLA-mismatched pts. Persistent MXC in HLA-mismatched pts maintained on low-dose TAC monotherapy is a desirable outcome.

CITATION INFORMATION: Scandling J., Busque S., Lowsky R., Shizuru J., Jensen K., Shori A., Engleman E., Meyer E., Hoppe R., Strober S. Relationship between Mixed Chimerism and Acceptance of HLA-Matched and Mismatched Kidney Transplants after Withdrawal of Immunosuppressive Drugs Am J Transplant. 2017;17 (suppl 3).

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