*Purpose: Lymphocyte depletion and subsequent homeostatic repopulation present opportunities to shape the alloreactive immune repertoire to favor tolerance. We tested if the addition of thymic irradiation (TI) and donor cell infusions can promote thymic output and foster antigen-specific activation induced cell death (AICD).

*Methods: Rhesus macaques underwent kidney allotransplantation from maximally MHC mismatched donors. All primates underwent T cell depletion with the rhesus-specific anti-thymocyte globulin. Maintenance immunosuppression consisted of belatacept and rapamycin that was weaned and ultimately discontinued after 1 year. Primates were divided in 3 groups: (1) control group (n=6), (2) 7Gy TI (n=5), and (3) 7Gy TI + Mesenchymal Stem Cell (MSC) infusions (n=6). We monitored homeostatic repopulation of peripheral blood mononuclear cells by flow cytometry.

*Results: All primates tolerated the procedures well and showed no treatment specific side effects. We observed no difference in overall survival (p=0.7). Primates in the treatment groups did not show graft tolerance after discontinuation of immunosuppression (POD364) and experienced graft rejection within 90 days (Figure 1a). We observed no significant effect of thymic irradiation on the rate of lymphocyte repopulation with similar absolute lymphocyte counts between the groups throughout the study period (Figure 1b). However, we observed a mild increase in the frequency of recent-thymic emigrant cells (RTEC) after thymic irradiation (p=0.06, Figure 1c). Clinically the addition of MSC infusion did not dampen the alloreactive immune response.

*Conclusions: Low dose thymic irradiation caused a mild increase in thymic output. However, this did not translate in faster homeostatic lymphocyte repopulation after depletional induction therapy. The addition of monthly MSC infusions did not induce tolerance in our NHP kidney allotransplantation model.

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