Introduction. Xenotransplantation may alleviate the organ shortage, yet experimental renal xenotransplant has met limited success. We have previously reported the longest surviving pig-to-nonhuman primate (NHP) renal xenotransplant with induction CD4/CD8 T cell depletion and maintenance costimulation blockade. We aimed to evaluate whether only CD4 or CD8 depletion was necessary or sufficient for long-term survival.

Methods. Macaques with low titers of antibodies against donor α-1,3-galactosyltransferase knockout, human decay-accelerating factor pigs underwent renal xenotransplant with antiCD154 (5c8) and only antiCD4(n=3), only antiCD8(n=3), or both(n=4). Xenograft-infiltrating cells (GICs) were analyzed by flow cytometry.

Results. CD4/CD8 T cell depletion offered a median survival time (MST) of 360d and a max survival time of 405d, which is the longest reported survival to date. Depletion of CD4 was sufficient to significantly prolong survival (MST>252d, p<.001), and it was necessary for survival benefit. CD4 cells infiltrated rejected grafts of animals that received CD8 depletion alone or CD4/CD8 depletion. Animals receiving CD4 depletion alone have not rejected their grafts despite reconstitution of CD4/CD8 cells confirmed by flow cytometry.

Conclusions. We report the longest survival of pig-to-NHP xenotransplants to date, exceeding previous reports by over 250d. CD4 depletion is necessary and sufficient to significantly prolong survival. There were more CD4 GICs at the time of rejection, and animals with only CD4 depletion enjoy continued graft function despite peripheral reconstitution of CD4/CD8 cells. These data reveal an important role of CD4s in xenograft rejection in a preclinical model.

CITATION INFORMATION: Kim S, Higginbotham L, Mathews D, Breeden C, Stephenson A, Larsen C, Ford M, Tector J, Adams A. CD4 Depletion Is Necessary and Sufficient for Long-Term Nonhuman Primate Xenotransplant Survival. Am J Transplant. 2017;17 (suppl 3).

« Back to 2017 American Transplant Congress