title: Allospecific CD154 + T-cytotoxic memory cells as potential surrogate for rejection risk in pediatric intestine transplantation.
abstract: Clinical end-points dictate large trial enrollments and exclude children with the rare intestine transplant procedure (ITx), who experience higher drug-related morbidity. We evaluate the novel rejection-risk parameter, allo-(antigen)-specific CD154 + TcMs (i) as surrogates for ACR using Prentice's criteria, (ii) for association with immunosuppression targets to determine Fleming's surrogate end-point designation, and (iii) as time-to-event end-point in a simulated comparison of alemtuzumab (NCT#01208337, n = 14) and rabbit anti-human thymocyte globulin (rATG, n = 16) among 30 children with ITx. CD154 + TcM were measured in MLR before, and at 1-60 and 61-200 days after ITx (NCT#01163578). CD154 + TcM correlate significantly with rejection severity (Spearman r = 0.685, p = 2.03E-5) and associate with biopsy-proven ITx rejection with sensitivity/specificity of 94%/84% [corrected] independent of immunosuppressant. Previously stated sensitivity of 90% is incorrect. [corrected]. The rejection-risk threshold of CD154 + TcM resolves rapidly in 200-day follow-up (46 ± 20 vs. 158 ± 59 days, p = 0.009, K-M) with alemtuzumab, which demonstrates lower 90-day ACR incidence (50% vs. 69%, p=NS, Fisher's exact), and is associated with accelerated prednisone minimization to ≤2.5 mg/day, compared with rATG (120 ± 28 vs. 180 ± 30 days, p = 0.027, K-M). As a surrogate end-point, time-to-rejection-risk resolution measured with CD154 + TcM portends 50% reduction in sample sizes in a simulated trial of alemtuzumab vs. rATG. Rejection-risk assessment with CD154 + TcM may enable informed immunosuppression minimization, and preliminary efficacy comparisons in pediatric ITx.
authors: Hillman Center for Pediatric Transplantation, Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center, Pittsburgh, PA 15224, USA. rakesh.sindhi@chp.edu
authors: Rakesh
authors: R
authors: Sindhi
authors: Chethan
authors: C
authors: Ashokkumar
authors: Brandon W
authors: BW
authors: Higgs
authors: P B
authors: PB
authors: Gilbert
authors: Qing
authors: Q
authors: Sun
authors: Sarangarajan
authors: S
authors: Ranganathan
authors: Ron
authors: R
authors: Jaffe
authors: Sara
authors: S
authors: Snyder
authors: Mylarappa
authors: M
authors: Ningappa
authors: Kyle A
authors: KA
authors: Soltys
authors: Geoffrey J
authors: GJ
authors: Bond
authors: George V
authors: GV
authors: Mazariegos
authors: Kareem
authors: K
authors: Abu-Elmagd
authors: Adriana
authors: A
authors: Zeevi
mesh_terms: D000293:Adolescent; D000961:Antilymphocyte Serum / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D023201:CD40 Ligand / Q000096:biosynthesis*; D002648:Child; D002675:Child, Preschool; D006084:Graft Rejection; D006801:Humans; D007156:Immunologic Memory; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007223:Infant; D007422:Intestines / Q000637:transplantation*; D010372:Pediatrics / Q000379:methods; D012306:Risk; D012680:Sensitivity and Specificity; D013601:T-Lymphocytes / Q000378:metabolism*; D014180:Transplantation / Q000379:methods*; D014184:Transplantation, Homologous / Q000379:methods
chemical_list: D000961:Antilymphocyte Serum; D015415:Biomarkers; D007166:Immunosuppressive Agents; D023201:CD40 Ligand