Effects of an agonist interleukin-2/Fc fusion protein, a mutant antagonist interleukin-15/Fc fusion protein, and sirolimus on cardiac allograft survival in non-human primates

Timothy Millington, Maria Koulmanda, Choo Ng, Svjetlan Boskovic, Ognjenka M. Nadazdin, Gilles Benichou, Xin Xiao Zheng, Terry B. Strom, Joren C. Madsen

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9 Scopus citations

Abstract

Background: To tilt the immunologic balance toward tolerance and away from rejection, non-human primate recipients of cardiac allografts were treated with interleukin (IL)-2/Fc, mutant (m) antagonist type mIL-15/Fc, and sirolimus. Methods: Heterotopic heart transplants were performed on 8 fully mismatched cynomolgus macaques. An untreated control recipient rejected its graft by post-operative Day 6. The remaining 7 animals received oral or intramuscular immunosuppression with sirolimus. A recipient treated with sirolimus alone rejected at the end of 28 days of immunosuppression. The remaining 6 monkeys also received IL-2/Fc and mIL-15/Fc intramuscularly until 28 days after transplant. One animal received a second 28-day course of fusion protein starting at Day 50. In these 6 animals, sirolimus was continued for 28 days (n = 4) or until protein levels were low (n = 2). Results: In the 4 monkeys treated with a 28-day course of sirolimus and fusion proteins, mean graft survival was 51.5 days (range, 2876 days). The animal receiving a second course of fusion protein rejected its graft on Day 177, despite detectable levels of the fusion proteins and sirolimus. The central memory, effector memory, and nave CD4 + and CD8 + T-cell populations in the peripheral blood did not change significantly during fusion protein administration. A 2.5-fold expansion in CD4 +CD25 + lymphocytes occurred in recipients treated with fusion proteins and sirolimus that was not observed in the recipient treated with sirolimus alone. Conclusions: Although IL-2/Fc, mIL-15/Fc, and sirolimus administered in this manner permitted modest prolongation of graft survival and expansion of CD4 +CD25 + T cells, tolerance was not achieved.

Original languageEnglish
Pages (from-to)427-435
Number of pages9
JournalJournal of Heart and Lung Transplantation
Volume31
Issue number4
DOIs
StatePublished - Apr 2012
Externally publishedYes

Keywords

  • heart
  • interleukin-15
  • primates
  • rejection
  • transplantation

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