title: Post-transplant repopulation of naïve and memory T cells in blood and lymphoid tissue after alemtuzumab-mediated depletion in heart-transplanted cynomolgus monkeys.
abstract: Repopulation of memory T cells (Tmem) in allograft recipients after lymphodepletion is a major barrier to transplant tolerance induction. Ineffective depletion of naïve T cells (Tn) and Tmem may predispose to repopulation of Tmem after transplantation. Cynomolgus macaque monkeys given heart allografts were lymphodepleted using Alemtuzumab (Campath-1H; anti-CD52). Peripheral blood (PB) and lymph nodes (LN) were analyzed for CD95(-) (Tn) and CD95(+) cells (Tmem), one day, one month and up to three months after Alemtuzumab infusion. CD52 expression, susceptibility to Alemtuzumab cytotoxicity and pro-apoptotic caspase-3 were evaluated in Tn and Tmem. In vivo, Alemtuzumab induction profoundly depleted lymphocytes in PB (99% reduction) but exerted a lesser effect in LN (70% reduction), with similar depletion of Tn and Tmem subsets. After transplantation, Tmem comprised the majority of lymphocytes in PB and LN. In vitro, LN T cells were more resistant to Alemtuzumab-mediated cytotoxicity than PB lymphocytes. CD4(+) Tn and Tmem were equally susceptible to Alemtuzumab-mediated cytotoxicity, whereas CD8(+) Tn were more resistant than CD8(+) Tmem. However, no significant differences in CD52 expression between lymphocyte subsets in PB and LN were observed. Caspase-3 expression was higher in PB than LN T cells. CD4(+) and CD8(+) Tn expressed lower levels of Caspase-3 than Tmem, in both PB and LN. Thus, after Alemtuzumab infusion, residual Tn in secondary lymphoid tissue may predispose to rapid recovery of Tmem in allograft recipients.
authors.affiliation: Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: M R L
authors.initials: MR
authors.lastname: Marco
authors.forename: E M
authors.initials: EM
authors.lastname: Dons
authors.forename: D J
authors.initials: DJ
authors.lastname: van der Windt
authors.forename: J K
authors.initials: JK
authors.lastname: Bhama
authors.forename: L T
authors.initials: LT
authors.lastname: Lu
authors.forename: A F
authors.initials: AF
authors.lastname: Zahorchak
authors.forename: F G
authors.initials: FG
authors.lastname: Lakkis
authors.forename: D K C
authors.initials: DK
authors.lastname: Cooper
authors.forename: M B
authors.initials: MB
authors.lastname: Ezzelarab
authors.forename: A W
authors.initials: AW
authors.lastname: Thomson
mesh_terms: D000074323:Alemtuzumab; D064591:Allografts; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D053148:Caspase 3 / Q000276:immunology; D016027:Heart Transplantation; D008212:Lymphocyte Depletion; D008221:Lymphoid Tissue / Q000276:immunology* / Q000473:pathology; D008252:Macaca fascicularis; D008570:Memory, Short-Term / Q000187:drug effects*; D019014:fas Receptor / Q000276:immunology
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D019014:fas Receptor; D000074323:Alemtuzumab; D053148:Caspase 3
keywords: ATG; Alemtuzumab; LN; Lymph node; MFI; Memory T cell; NHP; Naïve T cell; Non-human primate; PBMC; Tmem; Tn; Transplantation; anti-thymocyte globulin; lymph node(s); mean fluorescence intensity; memory T cell(s); naïve T cell(s); non-human primate; peripheral blood mononuclear cells