Background: We have previously reported donor specific expansion of regulatory T cells (Tregs) in nonhuman primate (NHP) recipients which achieved renal allograft tolerance after induction of transient mixed chimerism. In this study, we prospectively studied whether T cell immunomonitoring can be used to monitor/predict tolerance in NHP recipeints which received kidney or combined kidney/heart (KH) allografts and donor bone marrow transplantation (DBMT).

Method: Six NHP recipients which received DBMT either simultaneously or 2-4 months after kidney or combined K/H transplantation were studied. These recipients received a nonmyeloablative conditioning regimen that included low dose TBI, thymic irradiation, costimulatory blockade, T cell depleting antibodies and a one month course of CyA. We monitored T cell responses against donor and 3rd party cells by FACS using recipient PBMCs labeled with CFSE and monitored the proliferation of CD4+ (T helper and Treg cells) and CD8+ T cells and their secretion of INF-γ and IL-4 cytokines.

Results: All recipients developed transient mixed chimerism lasting for up to 2 months after DBMT. We performed CFSE-MLR assay at 113 ± 19 day after transplantation when these recipients had normal allograft function. Three kidney recipients later developed acute rejection (AR) and two kidney and one K/H recipients achieved long-term allograft survival without immunosuppression (>300 days) (TOL). Although CD8+ T cell hypo-responsiveness was observed in TOL recipients, these monkeys exhibited substantial anti-donor CD4+ T cell proliferation comparable to that observed in AR recipients. However, in TOL monkeys, proliferated CD4+ cells, contained significantly more FOXP3+ Tregs than CD4+ T cells of AR recipients (P<0.05). On the other hand, INF-γ+ and IL-4 secretions by CD4+ T cells were similar among the two groups.

Conclusion: T cell immunomonitoring including donor specific Treg expansion prospectively predicted the long-term outcome of the allografts in our mixed chimerism approach.

CITATION INFORMATION: Hotta K, Oura T, Dehnadi A, Huh K, Matsunami M, Benichou G, Madsen J, Cosimi A, Kawai T. Immune Tolerance Monitoring in Renal Allograft Tolerance Induced by Transient Mixed Chimerism in Nonhuman Primates. Am J Transplant. 2017;17 (suppl 3).

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