Alternative immunomodulatory strategies for xenotransplantation: CD40/154 pathway-sparing regimens promote xenograft survival.

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Thompson, P; Badell, IR; Lowe, M; Turner, A; Cano, J; Avila, J; Azimzadeh, A; Cheng, X; Pierson, RN; Johnson, B; Robertson, J; Song, M; Leopardi, F; Strobert, E; Korbutt, G; Rayat, G; Rajotte, R; Larsen, CP; Kirk, AD

Published Date

  • July 2012

Published In

Volume / Issue

  • 12 / 7

Start / End Page

  • 1765 - 1775

PubMed ID

  • 22458586

Pubmed Central ID

  • 22458586

Electronic International Standard Serial Number (EISSN)

  • 1600-6143

Digital Object Identifier (DOI)

  • 10.1111/j.1600-6143.2012.04031.x

Language

  • eng

Conference Location

  • United States