Background: Successful induction of allograft tolerance in MHC-mismatched kidney transplantation has been achieved after induction of transient chimerism in both nonhuman primates (NHP) and humans. However, development of a reliable assay to monitor tolerance is critically important to safely taper immunosuppression.

Method: Six NHP and four human recipients of combined kidney and bone marrow transplantation (CKBMT) who achieved long-term renal allograft survival without immunosuppression were studied. Differential T-cell responses were evaluated by CFSE-MLR co-stained for CD4, CD8 and Foxp3.

Results: NHP tolerant recipients evaluated at 2.1±0.9 years after transplantation showed donor-specific CD8+ T cell hyporesponsiveness but displayed vigorous anti-donor CD4+ T cell proliferation. Interestingly, among these proliferated CD4+ cells, significantly higher Foxp3+ cell proliferation was observed against donor, compared with third party stimulators (Fig. A). In contrast, consistently high anti-donor CD8+ and CD4+ T cell responses with limited Treg expansion were observed in rejectors (data not shown). In humans, although assays were performed at markedly later time points (4.7±1.8 years), tolerant patients displayed much greater loss of anti-donor CD8+ and CD4+ T cells responses. However, unlike NHPs, Treg expansion was not significant and CD4+ T cell responses were limited (Fig. B). Finally, we prospectively monitored T cell responses in one recent human CKBMT recipient who achieved renal allograft tolerance. Although anti-donor CD8+ T cell responses gradually disappeared, significant CD4+ responses and Treg expansion were observed at day 325 as observed in most NHP recipients. However, anti-donor Treg responses eventually disappeared by day 727, as observed in other human tolerant recipients (Fig. C).

Conclusion: Regulatory mechanisms were suggested in NHPs at 2 years. More robust loss of anti-donor T cell responses was observed in human tolerant recipients, although these recipients were tested at later time points than the NHP.

CITATION INFORMATION: Hotta K, Oura T, Crisalli K, Sachs D, Cosim B, Kawai T. Immune Tolerance Monitoring in Renal Allograft Tolerance Induced by Transient Mixed Chimerism in Nonhuman Primates and Humans. Am J Transplant. 2016;16 (suppl 3).

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