Session Time: 3:15pm-4:45pm
Presentation Time: 3:51pm-4:03pm
*Purpose: Rodent studies have demonstrated the utility of regulatory T cell (Treg) infusion for the promotion of tolerance to organ allografts. Here, we evaluated the therapeutic potential of ex vivo-expanded autologous polyclonal Treg in rhesus monkeys with life-supporting kidney allografts.
*Methods: One week before transplantation (Tx), CD4+CD25+Treg were isolated from peripheral blood (using MACS), followed by polyclonal expansion using artificial APCs (L-cells) and IL-2. Recipients and donors were MHC-mismatched. Immunosuppression in the form of co-stimulation blockade (CTLA4Ig; 20mg/kg, with tapering until d180) and tacrolimus (trough levels 10-15ng/ml, with tapering until d60) was given to recipients without (n=3) or with (n=4) Treg infusion. Purity and phenotype of the expanded Treg were validated by flow cytometry. Treg infusions (total: 8 per graft recipient) were administered on d6 & d10 (10×106/kg per infusion), d13 & d16 (30×106/kg), and d20, d23, 27 & d30 (50×106/kg). Graft survival was determined by serum creatinine level, weight loss and urinary protein/creatinine ratio.
*Results: With no Treg infusion, graft survival times were 15, 35, and 40 days (median 35 days), compared to 38, 58, 86, and >165 days (median 72 days) with Treg infusion (p<0.05). In peripheral blood, no significant differences in memory CD4+ and CD8+T cell subsets were observed between recipients with or without Treg infusion. However, the percentages of CD4+CD28–CD95+ T cells in peripheral blood were significantly lower in recipients with Treg infusion (p<0.05). In both groups, no increase in donor-specific allo-antibodies was observed. With or without Treg infusion, the incidences of CD4+CD25hiFoxp3hi Treg in peripheral blood were markedly reduced after Tx. On the day of Tx (d0), the incidences of CD4+CD25hiFoxp3hi Treg in mesenteric lymph nodes (LN) were similar in both groups. However, on d35, mesenteric LN from Treg-infused monkeys exhibited significantly higher percentages of CD4+CD25hiFoxp3hi Treg than monkeys without Treg infusion (p<0.05).
*Conclusions: Multiple infusions of ex vivo-expanded polyclonal autologous Treg are safe and delay kidney allograft rejection in non-lymphodepleted monkeys treated with CTLA4Ig and tacrolimus. Furthermore, Treg were enriched in secondary lymphoid organs of recipients given Treg infusions.
To cite this abstract in AMA style:Sasaki K, Wang Y, Nakano R, Lu L, Hughes J, Vujevich V, Ganoza AJ, Wijkstrom M, Humar A, Thomson AW, Ezzelarab MB. Early Post-Transplant Infusion of Ex Vivo-Expanded Autologous Polyclonal Regulatory T Cells (Treg) Prolongs Kidney Allograft Survival in Non-Lymphodepleted, CTLA4Ig-Treated Rhesus Monkeys [abstract]. Am J Transplant. 2020; 20 (suppl 3). https://atcmeetingabstracts.com/abstract/early-post-transplant-infusion-of-ex-vivo-expanded-autologous-polyclonal-regulatory-t-cells-treg-prolongs-kidney-allograft-survival-in-non-lymphodepleted-ctla4ig-treated-rhesus-monkeys/. Accessed October 20, 2020.
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