Melatonin--a pleiotropic molecule involved in pathophysiological processes following organ transplantation

Abstract

Mammals adjust their physiology in response to seasonal changes to environment (i.e. photoperiod, temperature, food availability). These changes are thought to predominantly occur for the conservation of energy during winter, by pervasive changes such as the inhibition of reproduction. Previous reports have suggested that circannual changes also occur to the immune system. In mammals, this chronological effect may be dependent on photoperiod, and evidence exists to suggest that there is a great deal of immune variation in response to light, or circadian rhythm. This is a clinically relevant, yet under-reported area of human transplantation. The aim of this review is to discuss immune variation, with specific emphasis on melatonin secretion, in the context of organ rejection, infection, neoplasia formation, and immunosuppression.

Figure 1

The inflammatory effects of melatonin on graft rejection. Melatonin increases CD4⁺ T-cell activity, inducing cell proliferation and the synthesis of pro-inflammatory cytokines. Monocyte generation and recruitment occurs, allowing monocyte differentiation to macrophages and dendritic cells (DC). Melatonin augments major histocompatibility complex (MHC) class II expression and induces the production of tumour necrosis factor-α (TNF-α), interleukin-1 (IL-1) and IL-12 by DC, increasing CD4⁺ T-cell activation. B-cell maturation occurs via direct CD4⁺ T-cell responses, and melatonin induces the production of antibody. Antibody binds to allograft, inducing direct effects, and also binds Fc receptor⁺ cells such as natural killer (NK) cells. Melatonin also increases NK cell populations, which infiltrate the allograft, secrete inflammatory cytokines and respond directly.

Figure 2

The anti-inflammatory effects of melatonin on graft rejection; melatonin commits naïve CD4⁺ cells to T helper type 2 (Th2) cells, which then secrete anti-inflammatory cytokines, including interleukin-10 (IL-10). This induces the generation of IL-10-producing TREG cells, which directly prevent inflammatory processes. The IL-10 inhibits the production of inflammatory cytokines from macrophages, and prevents the normal maturation of dendritic cells (DC). Major histocompatibility complex (MHC) class II expression is also down-regulated on DC, preventing antigen presentation. Melatonin directly reduces graft immunogenicity and damage by preventing mitochondrion-dependent apoptosis. This occurs via the removal of superoxide anions generated during ATP production. Melatonin activates other cell-protective molecules, including glutathione, preventing graft cell apoptosis.