title: 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.
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, 28-76 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 naïve 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.
authors.affiliation: Massachusetts General Hospital Transplant Center, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Timothy
authors.initials: T
authors.lastname: Millington
authors.forename: Maria
authors.initials: M
authors.lastname: Koulmanda
authors.forename: Choo
authors.initials: C
authors.lastname: Ng
authors.forename: Svjetlan
authors.initials: S
authors.lastname: Boskovic
authors.forename: Ognjenka M
authors.initials: OM
authors.lastname: Nadazdin
authors.forename: Gilles
authors.initials: G
authors.lastname: Benichou
authors.forename: Xin Xiao
authors.initials: XX
authors.lastname: Zheng
authors.forename: Terry B
authors.initials: TB
authors.lastname: Strom
authors.forename: Joren C
authors.initials: JC
authors.lastname: Madsen
mesh_terms: D000818:Animals; D001706:Biopsy; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D006085:Graft Survival / Q000187:drug effects*; D016027:Heart Transplantation / Q000276:immunology*; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000494:pharmacology; D019409:Interleukin-15 / Q000494:pharmacology*; D007376:Interleukin-2 / Q000494:pharmacology*; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D008252:Macaca fascicularis / Q000276:immunology*; D023421:Models, Animal; D009206:Myocardium / Q000276:immunology / Q000473:pathology; D010641:Phenotype; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D020123:Sirolimus / Q000494:pharmacology*; D014184:Transplantation, Homologous
chemical_list: D007141:Immunoglobulin Fc Fragments; D007166:Immunosuppressive Agents; D019409:Interleukin-15; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D011993:Recombinant Fusion Proteins; D020123:Sirolimus