Renal Allograft Survival in Nonhuman Primates Infused With Donor Antigen-Pulsed Autologous Regulatory Dendritic Cells

Abstract

Systemic administration of autologous regulatory dendritic cells (DCreg; unpulsed or pulsed with donor antigen [Ag]), prolongs allograft survival and promotes transplant tolerance in rodents. Here, we demonstrate that nonhuman primate (NHP) monocyte-derived DCreg pre-loaded with cell membrane vesicles from allogeneic PBMC, induce T cell hyporesponsiveness to donor alloAg in vitro. These donor alloAg-pulsed autologous DCreg (1.4–3.6 x 106/kg) were administered intravenously, one day before MHC-mismatched renal transplantation to rhesus monkeys treated with costimulation blockade (cytotoxic T lymphocyte Ag 4 [CTLA4] Ig) and tapered rapamycin. Prolongation of graft median survival time from 39.5 days (no DCreg infusion; n=6 historical controls) and 29 days with control unpulsed DCreg (n=2), to 56 days with donor Ag-pulsed DCreg (n=5), was associated with evidence of modulated host CD4+ and CD8+ T cell responses to donor Ag and attenuation of systemic IL-17 production. Circulating anti-donor antibody (Ab) was not detected until CTLA4Ig withdrawal. One monkey treated with donor Ag-pulsed DCreg rejected its graft in association with progressively elevated anti-donor Ab, 525 days post-transplant (160 days after withdrawal of immunosuppression). These findings indicate a modest but not statistically significant beneficial effect of donor Ag-pulsed autologous DCreg infusion on NHP graft survival when administered with a minimal immunosuppressive drug regimen.

Tolerogenic Dendritic Cells: The Pearl of Immunotherapy in Organ Transplantation

“…In addition to donor-derived Tol-DC, the effect of autologous Tol-DC is also evaluated in a preclinical trial of rhesus monkey. Autologous Tol-DC are incubated with vesicles generated from prospective transplant donor PBMC, and these Tol-DC could effectively capture vesicles without changing their own phenotype ( 88 ). IL-17 is a proinflammatory cytokine, which plays an important role in organ rejection.…”

“…However, the number of donor-reactive CTLA4 + IL-17 + T cells did not change pre- and post-transplantation in the donor antigen-pulsed autologous Tol-DC treated group. In addition to the inhibition of donor-reactive CTLA4 + IL-17 + T cells, donor antigen-pulsed autologous Tol-DC also modulated the expression of PD-1 and CTLA4 in donor reactive T cells ( 88 ). In conclusion, the efficacy of Tol-DC in preclinical trials of kidney transplantation has been proven.…”

“…Compared to non-Tol-DC treated group, the administration of donor-derived Tol-DC significantly prolonged the graft survival period ranging from 50 to 300 days (median=113.5). Graft median survival time of donor-antigen-pulsed autologous Tol-DC was 56 days ( 88 ). Additionally, there was no adverse effect observed in these preclinical trials.…”

Memory T cells are significantly increased in rejected liver allografts of rhesus monkeys

“…Many preclinical studies of kidney and islet allotransplantation have provided effective guidelines or developed broadly accepted therapeutic strategies, which have then been moved into the clinic . There are also many reports of biomarkers and new drug applications especially in kidney transplantation that quite readily could be tested in such preclinical models …”

“…(7,10) There are also many reports of biomarkers and new drug applications especially in kidney transplantation that quite readily could be tested in such preclinical models. (11)(12)(13) However, there are relatively few LT models of NHPs (14)(15)(16)(17) that have been undertaken for such. This is especially true when it comes to investigating immune cell populations, which are important in monitoring the immune status of the recipient following LT.…”