title: Allospecific CD154+ T cells associate with rejection risk after pediatric liver transplantation.
abstract: Antigen-specific T cells, which express CD154 rapidly, but remain untested in alloimmunity, were measured with flow cytometry in 16-h MLR of 58 identically-immunosuppressed children with liver transplantation (LTx), to identify Rejectors (who had experienced biopsy-proven rejection within 60 days posttransplantation). Thirty-one children were sampled once, cross-sectionally. Twenty-seven children were sampled longitudinally, pre-LTx, and at 1-60 and 61-200 days after LTx. Results were correlated with proliferative alloresponses measured by CFSE-dye dilution (n = 23), and CTLA4, a negative T-cell costimulator, which antagonizes CD154-mediated effects (n = 31). In cross-sectional observations, logistic regression and leave-one-out cross-validation identified donor-specific, CD154 + T-cytotoxic (Tc)-memory cells as best associated with rejection outcomes. In the longitudinal cohort, (1) the association between CD154 + Tc-memory cells and rejection outcomes was replicated with sensitivity/specificity 92.3%/84.6% for observations at 1-60 days, and (2) elevated pre-LTx CD154 + Tc-memory cell responses were associated with significantly increased incidence (p = 0.02) and hazard (HR = 7.355) of rejection in survival/proportional hazard analysis. CD154 expression correlated with proliferative alloresponses (r = 0.835, p = 7.1e-07), and inversely with CTLA4 expression of allospecific CD154 + Tc-memory cells (r =-0.706, p = 3.0e-05). Allospecific CD154 + T-helper-memory cells, not CD154 + Tc-memory, were inhibited by increasing Tacrolimus concentrations (p = 0.026). Collectively, allospecific CD154 + T cells provide an estimate of rejection risk in children with LTx.
authors.affiliation: University of Pittsburgh and Children's Hospital of Pittsburgh, Department of Transplant Surgery, Pittsburgh, PA, USA.
authors.forename: C
authors.initials: C
authors.lastname: Ashokkumar
authors.forename: A
authors.initials: A
authors.lastname: Talukdar
authors.forename: Q
authors.initials: Q
authors.lastname: Sun
authors.forename: B W
authors.initials: BW
authors.lastname: Higgs
authors.forename: J
authors.initials: J
authors.lastname: Janosky
authors.forename: P
authors.initials: P
authors.lastname: Wilson
authors.forename: G
authors.initials: G
authors.lastname: Mazariegos
authors.forename: R
authors.initials: R
authors.lastname: Jaffe
authors.forename: A
authors.initials: A
authors.lastname: Demetris
authors.forename: J
authors.initials: J
authors.lastname: Dobberstein
authors.forename: K
authors.initials: K
authors.lastname: Soltys
authors.forename: G
authors.initials: G
authors.lastname: Bond
authors.forename: A W
authors.initials: AW
authors.lastname: Thomson
authors.forename: A
authors.initials: A
authors.lastname: Zeevi
authors.forename: R
authors.initials: R
authors.lastname: Sindhi
mesh_terms: D015703:Antigens, CD / Q000276:immunology; D023201:CD40 Ligand / Q000276:immunology*; D060908:CTLA-4 Antigen; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005260:Female; D006084:Graft Rejection / Q000276:immunology*; D006801:Humans; D007156:Immunologic Memory; D016031:Liver Transplantation / Q000276:immunology*; D008297:Male; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D015703:Antigens, CD; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D023201:CD40 Ligand