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Xenotransplantation. 2019 Feb 16:e12502. doi: 10.1111/xen.12502. [Epub ahead of print]

Potential pathological role of pro-inflammatory cytokines (IL-6, TNF-α, and IL-17) in xenotransplantation.

Author information

1
Department of Nephrology, Shenzhen Longhua District Central Hospital, Guangdong Medical University Affiliated Longhua District Central Hospital, Shenzhen, China.
2
Shenzhen Xenotransplantation Medical Engineering Research and Development Center, Shenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University, Shenzhen University School of Medicine, Shenzhen, China.
3
Department of Medical Laboratory, Shenzhen Longhua District Central Hospital, Guangdong Medical University Affiliated Longhua District Central Hospital, Shenzhen, China.
4
Xenotransplantation Program, Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama.

Abstract

The major limitation of organ transplantation is the shortage of available organs from deceased human donors which leads to the deaths of thousands of patients each year. Xenotransplantation is considered to be an effective way to resolve the problem. Immune rejection and coagulation dysfunction are two major hurdles for the successful survival of pig xenografts in primate recipients. Pro-inflammatory cytokines, such as IL-6, TNF-α, and IL-17, play important roles in many diseases and in allotransplantation. However, the pathological roles of these pro-inflammatory cytokines in xenotransplantation remain unclear. Here, we briefly review the signaling transduction and expression regulation of IL-6, TNF-α, and IL-17 and evaluate their potential pathological roles in in vitro and in vivo models of xenotransplantation. We found that IL-6, TNF-α, and IL-17 were induced in most in vitro or in vivo xenotransplantation model. Blockade of these cytokines using gene modification, antibody, or inhibitor had different effects in xenotransplantation. Inhibition of IL-6 signaling with tocilizumab decreased CRP but did not increase xenograft survival. The one possible reason is that tocilizumab can not suppress IL-6 signaling in porcine cells or organs. Other drugs which inhibit IL-6 signaling need to be investigated in xenotransplantation model. Inhibition of TNF-α was beneficial for the survival of xenografts in pig-to-mouse, rat, or NHP models. Blockade of IL-17 using a neutralizing antibody also increased xenograft survival in several animal models. However, the role of IL-17 in the pig-to-NHP xenotransplantation model remains unclear and needs to be further investigated. Moreover, blockade of TNF-α and IL-6 together has got a better effect in pig-to-baboon kidney xenotransplantation. Blockade two or even more cytokines together might get better effect in suppressing xenograft rejection. Better understanding the role of these cytokines in xenotransplantation will be beneficial for choosing better immunosuppressive strategy or producing genetic modification pig.

KEYWORDS:

IL-17; IL-6; TNF-α; Xenotransplantation

PMID:
30770591
DOI:
10.1111/xen.12502

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