Importance of Hematopoietic Mixed Chimerism for Induction of Renal Allograft Tolerance in Nonhuman Primates

BACKGROUND Although induction of durable mixed chimerism is required for murine skin allograft tolerance, renal allograft tolerance has been achieved after induction of only transient mixed chimerism in nonhuman primates (NHPs) and humans. To better define the level/duration of chimerism required for stable renal allograft tolerance, we retrospectively analyzed these parameters and compared them with transplant outcomes in NHP combined kidney and bone marrow transplant (CKBMT) recipients. METHODS Peripheral blood levels and duration of myeloid or lymphoid chimerism were retrospectively analyzed in 34 NHP CKBMT recipients which were divided into 3 groups: Tolerance (TOL), n=10; chronic antibody-mediated rejection (CAMR), n=12; and T cell-mediated rejection (TCMR), n=12. RESULTS All 4 of the recipients that failed to develop any chimerism lost their allografts due to TCMR after discontinuation of immunosuppression (56 ± 3 days). Among 30 recipients who successfully developed multilineage chimerism, 10 achieved immunosuppression-free survival (1258 ± 388 days), 12 eventually developed CAMR (932 ± 155 days), and 8 developed TCMR (82 ± 10 days). The maximum level but not duration of lymphoid chimerism was significantly higher in TOL recipients compared with both CAMR (p=0.0159) and TCMR (p=0.0074). Conversely, the maximum myeloid chimerism was significantly higher in TOL than in TCMR (p=0.0469), but not in CAMR. ROC analyses revealed that lymphoid chimerism levels of 3.1% or greater could reliably predict long-term immunosuppression-free renal allograft survival (p

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