J Korean Assoc Oral Maxillofac Surg.  2023 Dec;49(6):311-323. 10.5125/jkaoms.2023.49.6.311.

Review of two immunosuppressants: tacrolimus and cyclosporine

• Lee H
• Myoung H
• Kim SM

• KMID: 2550294
• DOI: http://doi.org/10.5125/jkaoms.2023.49.6.311

Abstract

Immunosuppressants are vital in organ transplantation including facial transplantation (FT) but are associated with persistent side effects. This review article was prepared to compare the two most used immunosuppressants, cyclosporine and tacrolimus, in terms of mechanism of action, efficacy, and safety and to assess recent trials to mitigate their side effects. PubMed and Google Scholar queries were conducted using combinations of the following search terms: “transplantation immunosuppressant,” “cyclosporine,” “tacrolimus,” “calcineurin inhibitor (CNI),” “efficacy,” “safety,” “induction therapy,” “maintenance therapy,” and “conversion therapy.” Both immunosuppressants inhibit calcineurin and effectively down-regulate cytokines. Tacrolimus may be more advantageous since it lowers the likelihood of acute rejection, has the ability to reverse allograft rejection following cyclosporine treatment, and has the potential to reinnervate nerves. Meanwhile, graft survival rates seem to be comparable for the CNIs. To avoid nephrotoxicity, various immunosuppressants other than CNIs have been studied. Despite averting nephrotoxicity, these medications show increases in acute rejection or other types of adverse effects compared to CNIs. FT has been a topic of interest for oral and maxillofacial surgeons, and the postoperative usage of immunosuppressants is crucial for the long-term prognosis of FT. As contemporary transplantation regimens incorporate novel medications along with CNIs, further research is required.

Keyword

Calcineurin inhibitors; Tacrolimus; Cyclosporine; Facial transplantation; Immunosuppressant

Figure

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  Fig. 1 Diagram of data selection flow showing the number of articles included and excluded in a stepwise process. A total of 84 articles was included in this general review.

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  Fig. 2 Chemical structures of cyclosporine with a cyclic undecapeptide, neutral, lipophilic molecule with low water solubility (A) and of tacrolimus with a macrolide lactam with a 23-membered lactone ring with poor water solubility (B).

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  Fig. 3 Schematic drawings of calcineurin inhibitor pathways in which a phosphatase dephosphorylates NFAT family members that then are transported into the nucleus and bind to the nuclear promotor of the IL-2 gene. Production of IL-2 will lead to full T-cell activation. Cyclosporine and tacrolimus show immunosuppression by directly interacting with calcineurin to inhibit its phosphatase action. While tacrolimus (FK506) binds to FK-binding protein (FKBP) to form an FK506-FKBP complex, cyclosporine (CsA) binds with cyclophilin to form a cyclophilin-cyclosporine complex. Both complexes directly inhibit calcineurin activity, leading to immunosuppression. Cyclosporine immunosuppression can be achieved by inhibition of MAPK. When MAPKs are activated by signal cascades, they translocate into the nucleus and phosphorylate activator protein 1 (AP-1), which is crucial for transcription of IL-2. Thus, blocking upstream of the MAPKKK cascade by cyclosporine leads to inhibition of MAPK activation and to immunosuppression. (NFAT: nuclear factor of activated T cell, IL-2: interleukin-2, JNK: Jun N-terminal kinase, MAPK: mitogen-activated protein kinase, MAPKK: MAPK kinase, MAPKKK: MAPK kinase kinase)

Reference

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