title: Alternative immunomodulatory strategies for xenotransplantation: CD40/154 pathway-sparing regimens promote xenograft survival.
abstract: Immunosuppressive therapies that block the CD40/CD154 costimulatory pathway have proven to be uniquely effective in preclinical xenotransplant models. Given the challenges facing clinical translation of CD40/CD154 pathway blockade, we examined the efficacy and tolerability of CD40/CD154 pathway-sparing immunomodulatory strategies in a pig-to-nonhuman primate islet xenotransplant model. Rhesus macaques were rendered diabetic with streptozocin and given an intraportal infusion of ≈ 50 000 islet equivalents/kg wild-type neonatal porcine islets. Base immunosuppression for all recipients included maintenance therapy with belatacept and mycophenolate mofetil plus induction with basiliximab and LFA-1 blockade. Cohort 1 recipients (n = 3) were treated with the base regimen alone; cohort 2 recipients (n = 5) were additionally treated with tacrolimus induction and cohort 3 recipients (n = 5) were treated with alefacept in place of basiliximab, and more intense LFA-1 blockade. Three of five recipients in both cohorts 2 and 3 achieved sustained insulin-independent normoglycemia (median rejection-free survivals 60 and 111 days, respectively), compared to zero of three recipients in cohort 1. These data show that CD40/CD154 pathway-sparing regimens can promote xenoislet survival. Further optimization of these strategies is warranted to aid the clinical translation of islet xenotransplantation.
authors.affiliation: Emory Transplant Center, Emory University, Atlanta, GA, USA.
authors.forename: P
authors.initials: P
authors.lastname: Thompson
authors.forename: I R
authors.initials: IR
authors.lastname: Badell
authors.forename: M
authors.initials: M
authors.lastname: Lowe
authors.forename: A
authors.initials: A
authors.lastname: Turner
authors.forename: J
authors.initials: J
authors.lastname: Cano
authors.forename: J
authors.initials: J
authors.lastname: Avila
authors.forename: A
authors.initials: A
authors.lastname: Azimzadeh
authors.forename: X
authors.initials: X
authors.lastname: Cheng
authors.forename: R N
authors.initials: RN
authors.lastname: Pierson
authors.forename: B
authors.initials: B
authors.lastname: Johnson
authors.forename: J
authors.initials: J
authors.lastname: Robertson
authors.forename: M
authors.initials: M
authors.lastname: Song
authors.forename: F
authors.initials: F
authors.lastname: Leopardi
authors.forename: E
authors.initials: E
authors.lastname: Strobert
authors.forename: G
authors.initials: G
authors.lastname: Korbutt
authors.forename: G
authors.initials: G
authors.lastname: Rayat
authors.forename: R
authors.initials: R
authors.lastname: Rajotte
authors.forename: C P
authors.initials: CP
authors.lastname: Larsen
authors.forename: A D
authors.initials: AD
authors.lastname: Kirk
mesh_terms: D000818:Animals; D019013:CD40 Antigens / Q000276:immunology*; D023201:CD40 Ligand / Q000276:immunology*; D015331:Cohort Studies; D003921:Diabetes Mellitus, Experimental / Q000601:surgery; D006085:Graft Survival / Q000276:immunology*; D064593:Heterografts; D007156:Immunologic Memory; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D016381:Islets of Langerhans Transplantation; D008253:Macaca mulatta; D013552:Swine; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D019013:CD40 Antigens; D007166:Immunosuppressive Agents; D023201:CD40 Ligand