title: De novo alloreactive memory CD8+ T cells develop following allogeneic challenge when CNI immunosuppression is delayed.
abstract: Allospecific memory T cells are a recognized threat to the maintenance of solid-organ transplants. Limited information exists regarding the development of alloreactive memory T cells when post-transplant immunosuppression is present. The clinical practice of delaying calcineurin inhibitor (CNI) initiation post-transplant may permit the development of a de novo allospecific memory population. We investigated the development of de novo allospecific memory CD8+ T cells following the introduction of CNI immunosuppression in a murine model using allogeneic cell priming. Recipient mice alloprimed with splenocytes from fully mismatched donors received cyclosporine (CyA), initiated at 0, 2, 6, or 10days post-prime. Splenocytes from recipients were analyzed by flow cytometry or enzyme-linked immunosorbent assay for evidence of memory cell formation. Memory and effector CD8+ T cell development was prevented when CyA was initiated at 0day or 2days post-prime (p<0.001), but not 6days post-prime. Following a boost challenge, these memory CD8+ T cells were capable of producing a similarly sized population of secondary effectors as recipients not treated with CyA (p>0.05). Delaying CyA up to 6days or later post-prime permits the development of functional de novo allospecific memory CD8+ T cells. The development of this potentially detrimental T cell population in patients could be prevented by starting CNI immunosuppression early post-transplant.
authors.affiliation: Department of Pathology, Dalhousie University, Halifax, Nova Scotia B3H4R2, Canada. Electronic address: mike.hm@dal.ca.
authors.forename: M
authors.initials: M
authors.lastname: Hart-Matyas
authors.affiliation: Department of Pathology, Dalhousie University, Halifax, Nova Scotia B3H4R2, Canada.
authors.forename: A J
authors.initials: AJ
authors.lastname: Gareau
authors.affiliation: Department of Pathology, Dalhousie University, Halifax, Nova Scotia B3H4R2, Canada; Department of Surgery, Dalhousie University, Halifax, Nova Scotia B3H2Y9, Canada.
authors.forename: G M
authors.initials: GM
authors.lastname: Hirsch
authors.affiliation: Department of Pathology, Dalhousie University, Halifax, Nova Scotia B3H4R2, Canada; Department of Surgery, Dalhousie University, Halifax, Nova Scotia B3H2Y9, Canada; Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia B3H4R2, Canada.
authors.forename: T D G
authors.initials: TD
authors.lastname: Lee
mesh_terms: D064591:Allografts; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D065095:Calcineurin Inhibitors / Q000494:pharmacology*; D007156:Immunologic Memory / Q000187:drug effects*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D013154:Spleen / Q000276:immunology* / Q000637:transplantation*; D013997:Time Factors
chemical_list: D065095:Calcineurin Inhibitors
keywords: Calcineurin inhibitor immunosuppression; Cyclosporine; Memory CD8+ T cell development; Memory CD8+ T cell functionality; Post-transplant immunosuppression delay