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

JOURNAL OF HEART AND LUNG TRANSPLANTATION

卷:31

Article

Millington, Timothy¹  Koulmanda, Maria²  Ng, Choo¹  Boskovic, Svjetlan¹  Nadazdin, Ognjenka M.¹  Benichou, Gilles¹  Zheng, Xin Xiao²  Strom, Terry B.²  Madsen, Joren C.^1,3 

[1] Massachusetts Gen Hosp, Transplant Ctr, Boston, MA 02114 USA

[2] Beth Israel Deaconess Med Ctr, Transplant Inst, Boston, MA 02215 USA

[3] Harvard Univ, Sch Med, Dept Surg, Div Cardiac Surg,Massachusetts Gen Hosp, Boston, MA 02115 USA

关键词: heart;    transplantation;    interleukin-15;    primates;    rejection;   

DOI  :  10.1016/j.healun.2012.01.864

来源: Elsevier

【 摘 要 】

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 naive 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. J Heart Lung Transplant 2012;31:427-35 (C) 2012 International Society for Heart and Lung Transplantation. All rights reserved.

【 授权许可】

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