期刊
TRANSPLANTATION
卷 101, 期 11, 页码 2713-2721出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/TP.0000000000001698
关键词
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资金
- Canadian National Transplant Research Program (CNTRP) Astellas Research Innovation - Astellas Pharma Canada, Inc.
- Astellas Pharma Canada, Inc.
- Canada's Stem Cell Network (Stem cell therapies acceleration grant)
- Council of Physicians, Dentists and Pharmacists of Hopital Maisonneuve-Rosemont
- Quebec Society of Nephrology
- Fonds de recherche du Quebec-Sante (FRQS)
Background. Polyomavirus-associated nephropathy (PVAN) after BK virus reactivation in kidney transplant recipients (KTR) can compromise graft survival. Lowering immunosuppression is the only established approach to prevent or treat PVAN but non-specifically increasing host immune competence also augments rejection risk. Ex vivo T cell stimulation/expansion offers the possibility to generate BK-specific T cell lines for adoptive immunotherapy. The objective of this study was to develop and characterize a clinical-scale protocol to generate BK-specific T cell lines from viremic KTR. Methods. Peripheral blood mononuclear cells from healthy controls and viremic KTR were stimulated using BK virus peptide libraries loaded or not on monocytes-derived dendritic cells. Cell counts, flow cytometry, and next-generation sequencing were used to assess T cell expansion, differentiation, and clonal diversity. Enzyme-linked immunospots, cytotoxicity assays as well as adoptive transfer in NOD/SCID/IL2R gamma(null) mice were used to assess for pathogen-specificity and evidence of nonspecific alloreactivity. Results. T cell lines from KTR and healthy control showed similar characteristics, implying that ongoing immunosuppression and chronic virus exposure do not compromise the differentiation, specificity, or clonal diversity of T cell lines after ex vivo production. Using antigen-loaded dendritic cells improved T cell expansion and favored central memory T cell differentiation. The T cell lines were antigen-specific and showed no nonspecific alloreactivity in vitro and in vivo. Conclusions. Using a rapid, clinically compliant culture system, we show that autologous BK virus-specific T cell lines can be reliably generated from viremic KTR. Our results pave the way for the treatment or prevention of PVAN with adoptive immunotherapy.
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