Tacrolimus (FK506): Safety and Applications in Reconstructive Surgery

Abstract

Tacrolimus (FK506) is a macrolide immunosuppressive drug that is approved for the prevention of allograft rejection. It is a standard component of immunosuppressive regimens currently in use for organ and reconstructive tissue transplants. The experimental literature has demonstrated potential efficacy in the management of other diseases for which transplantation does not play a role. The ability of tacrolimus to modulate the immune system and inhibit T cell activation provides a potential benefit for the treatment of disorders in which autoimmune phenomena are central to their pathogenesis such as rheumatoid arthritis and inflammatory bowel disease. Tacrolimus also has well-established neuroprotective and neuroregenerative properties through both similar and different mechanisms that have been extensively demonstrated in both small and large animal models. However, as a potent immunosuppressive agent, it can cause serious adverse effects, some of which are irreversible and potentially life threatening. This article reviews its safety under different therapeutic requirements and applications in both allogeneic and autogenous tissue reconstruction.

The Role of Pharmacological Agents in Nerve Regeneration after Peripheral Nerve Repair

“…The primary biological effect of calcineurin inhibition includes the decrease of the production of inflammatory cytokines such as tumour necrosis factor (TNF)-α, interleukin-2 and interferon-γ [28]. The drug's immunosuppressive effects are mediated largely through FKBP12, which is involved in intracellular calcium flux and cycle regulation [83].…”

“…Drugs commonly used for this purpose include tacrolimus [26][27][28][29], hyaluronic acid and its derivatives [30][31][32], melatonin [33][34][35], methylprednisolone [36][37][38][39], vitamin B complex and vitamin B12, [40][41][42], calcium and potassium channel blockers [43,44] and riluzole [45,46]. These substances have neuroprotective and neuroregenerative properties, though different mechanisms contribute markedly to nerve regeneration.…”

Tissue engineered constructs for peripheral nerve surgery

“…Their use, however, requires immunosuppression to avoid rejection and regeneration failure [54]. The use of pharmacological immunosuppression is associated with significant clinical morbidity [55] and limits the use of allografts in peripheral nerve repair to only the most severe cases of nerve injury [56]. To avoid the morbidity associated with immunosuppression, tissue preparation methods have been employed to remove the cellular component and diminish the immunogenicity of the allografts.…”

“…Certain immunosuppressive compounds have been shown to improve axonal regeneration following nerve injury and could be seen as a positive side effect of ES cell therapy [143–158]. However, the barrier for the use of immunosuppressive therapies for nonlife threatening diseases, such as peripheral nerve injury, is high and will likely seriously impede the translation of ES cell derived therapies for peripheral nerve injury [55]. …”

Rational design of a Kv1.3 channel-blocking antibody as a selective immunosuppressant

“…Current therapeutics for autoimmune diseases and other T-cell-mediated inflammatory disorders are based on the general inhibition or depletion of T cells and other leukocytes (10)(11)(12). Nonselective immunosuppression by such drugs as corticosteroids, FK506, and cyclosporine often leads to severe side effects, including opportunistic infections (11,13,14). Therapeutics designed to specifically inhibit the function of effector memory T (T EM ) cells without impairing the function of naive T cells or central memory T (T CM ) cells may offer an improved safety profile for the treatment of autoimmune diseases and organ transplantation.…”