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

P. Thompson, I. R. Badell, M. Lowe, A. Turner, J. Cano, J. Avila, A. Azimzadeh, X. Cheng, R. N. Pierson, B. Johnson, J. Robertson, M. Song, F. Leopardi, E. Strobert, G. Korbutt, G. Rayat, R. Rajotte, C. P. Larsen, A. D. Kirk*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

66 Scopus citations

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 insulinindependent 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.

Original languageEnglish
Pages (from-to)1765-1775
Number of pages11
JournalAmerican Journal of Transplantation
Volume12
Issue number7
DOIs
StatePublished - Jul 2012
Externally publishedYes

Keywords

  • Costimulation blockade
  • Islets
  • LFA-1
  • LFA-3
  • T-cell memory
  • Tacrolimus
  • Type 1 diabetes
  • Xenotransplantation

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