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, some recipients developed acute rejection (AR) despite of development of chimerism. Therefore, development of a reliable assay to monitor tolerance is critically important to safely taper immunosuppression. In this study, we prospectively studied whether T cell immunomonitoring is useful to predict transplant outcome in recipients of combined kidney and donor bone marrow transplantation (DBMT).

Method: Eleven NHP recipients who received DBMT either simultaneously or 2-4 months after kidney transplantation were studied. These recipients received a nonmyeloablative conditioning regimen that included low dose TBI and/or thymic irradiation, costimulatory blockade, ATG and a one month course of CyA. Five monkeys received a Bcl-2 inhibiter. We monitored T cell responses against donor and 3rd party cells using CFSE-MLR co-stained for CD4, CD8 Foxp3, INF-γ and IL-4.

Results: All recipients developed transient mixed chimerism up to 2 months after DBMT. We performed CFSE-MLR assay at 114±40 day after transplantation when these recipients had normal kidney function. Seven recipients later developed AR and four achieved long-term renal allograft survival without immunosuppression (>300 days) (LTS). Although CD8+ T cell hypo-responsiveness was observed in LTS recipients, the exhibited substantial anti-donor CD4+ T cell proliferation comparable to that observed in AR recipients. However, among these proliferated CD4+ cells, Foxp3+ Tregs were significantly higher in LTS recipients comparing with AR recipients (P<0.05). In ROC curve analysis, AUC for percentage of proliferating Treg is 0.92 (P<0.05). On the other hand, INF-γ+ and IL-4 CD4+ cell proliferation was similar between two groups.

Conclusion: Immunomonitoring of donor specific Treg expansion may reliably predict renal allograft tolerance.

CITATION INFORMATION: Hotta K., Oura T., Dehnadi A., Huh K., Matsunami M., Sasaki H., Benichou G., Madsen J., Cosimi A., Kawai T. T Cell Immunomonitoring Including Donor Specific Treg Expansion Prospectively Predicts Renal Allograft Tolerance Induced by Transient Mixed Chimerism Am J Transplant. 2017;17 (suppl 3).

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