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EFFICIENT GENERATION OF DONOR-SPECIFIC TR1 CELLS FROM PATIENTS ON HEMODIALYSIS

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Abstract

Background. Achievement of graft tolerance and withdrawal of chronic immunosuppression is the holy grail of transplant immunologists. The One Study is an European founded clinical trial where ex vivo generated/expanded T regulatory cells (Tregs) are infused in the recipient of a kidney transplant from a living donor with the ultimate goal of minimizing/discontinuing immunosuppression. Thus far, few data are available on the immunophenotype of patients on hemodialysis and on the ex vivo generation of functional donor-specific T Regulatory Type 1 (Tr1) cells.

Materials and methods. Peripheral whole blood was collected from patients on hemodialysis (HD, n=6) and healthy controls (HC, n=6). Flow cytometry (FACS) was performed to investigate the frequency of T, B, Dendritic Cells (DC), FOXP3+ Tregs, Tr1 cells and cytokine-producing cells. Donor-specific Tr1 cells were generated following the standard protocol developed in our lab (Bacchetta et al., Haematologica 2010). Briefly, PBMC from HD patients (i.e., the kidney transplant recipients) were co-cultured with donor derived DC generated in the presence of IL-10 (named DC-10) for 10 days.

Results. HD patients and HC showed similar peripheral frequency of naïve and effector CD4+ and CD8+ T-cells, of B-cells and plasma cells. Similar number of IL-4- and IL-17-producing CD4+ T cells was evident as well as no differences were found in the frequency of FOXP3+ Tregs and Tr1 cells. HD patients had higher circulating CD11c+CD14- dendritic cells (DC), which were mainly CD11chigh and highly activated (i.e., CD86hi HLA-DR+) as compared to those in HC donors. Tr1 cells were efficiently generated in 5 out of the 6 HD patients tested as shown by their anergic phenotype when re-stimulated in vitro with donor-derived mature dendritic cells.

Conclusions. HD patients have a peripheral immune system comparable to that of HC except for the frequency of activated DC. Moreover, Tr1 cells can be efficiently generated from the peripheral blood of these patients, rendering these subjects eligible for the One Study.

A. Petrelli(1), E. Tresoldi(2), R. Caldara(1), R. Bacchetta(3), M.G. Roncarolo(3, 4), A. Secchi(1, 4)
((1)Transplantation Medicine, San Raffaele Scientific Institute Milan , (2)Immunotolerance Unit, San Raffaele Scientific Institute Milan , (3)HSR-TIGET, Division of Regenerative Medicine, Stem Cells and Gene Therapy, San Raffaele Scientific Institute Milan , (4)Vita Salute San Raffaele University Milan )
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Realizzazione: Tesi S.p.A.

Per assistenza contattare: Claudia Ingrassia, Tesi S.p.A.
0172 476301 — claudia.ingrassia@gruppotesi.com