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Am J Transl Res. 2019 Oct 15;11(10):6422-6432. eCollection 2019.

Comparative study of human and cynomolgus T-cell depletion with rabbit anti-thymocyte globulin (rATG) treatment-for dose adjustment in a non-human primate kidney transplantation model.

Kwon Y1,2, Lee KW2,3,4, Park H2,4,5, Son JK2,5, Lee J2,4, Hong J2, Park JB1,2,3,4, Kim SJ2,4,5.

Author information

1
Department of Health Sciences & Technology, Samsung Advanced Institute for Health Sciences & Technology, Graduate School, Sungkyunkwan University Seoul, Korea.
2
Transplantation Research Center, Samsung Biomedical Research Institute, Samsung Medical Center Seoul, Korea.
3
Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine Seoul, Korea.
4
Department of Medicine, Sungkyunkwan University School of Medicine Suwon, Korea.
5
GenNbio Inc. Seoul, Korea.

Abstract

Rabbit-antithymocyte globulin (rATG) is commonly used in kidney transplantation (KT) as an induction agent and is also commonly used in non-human primate (NHP) KT models. However, the optimal dose has not been reported. In this study, we evaluated which cumulative dose of rATG was most appropriate for transplantation in NHPs. Cynomolgus monkeys were treated with intravenous 5 mg/kg rATG (Thymoglobulin®, Genzyme Ltd., UK) twice, on days 0 and 2 (a total of 10 mg/kg, n=2), or 4 times, on days 0, 1, 2, and 3 (a total of 20 mg/kg, n=6). In addition, we performed allo-KT in cynomolgus monkeys (n=4) with a cumulative 20 mg/kg dose of rATG with optimized dosing for induction therapy. We further compared immune cells, including naïve, central memory, and effector memory T cells, in reconstituted distributions in human KT patients (n=22). The kinetics of lymphocytes showed a rapid decrease at day 1 that was maintained for 2 weeks in the 20 mg/kg rATG group, while lymphocyte depletion was not maintained for more than 1 week in the 10 mg/kg rATG group. During the early period of rATG treatment in the NHP-KT model, the frequency of total T cells in the 20 mg/kg group showed a pattern of depletion similar with that of KT patients treated with rATG (1.5 mg/kg, 3 days). However, the pattern of reconstituted T cell subpopulations was different, as the number of effector memory cells rebounded in the NHP-KT model. These data indicate that lymphocyte-depletion induced by rATG was influenced by cumulative dose, and that an rATG dose of 20 mg/kg is suitable for induction therapy in renal transplantation in cynomolgus monkeys compared to human KT.

KEYWORDS:

Rabbit-antithymocyte globulin; cynomolgus monkey; immunosuppressants drug; induction therapy; kidney transplantation

PMID:
31737194
PMCID:
PMC6834489

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