The concept of inducible and heritable phenotypic modification was first proposed by Lamarck (11)in 1809 when he hypothesized that organisms undergo physiologic changes in response to environmental stimuli that persist after cell division. More recently, evidence to support this Lamarckian view of inheritance has emerged from studies of individuals experiencing intrauterine malnutrition (12). Follow-up of children born after the Dutch winter hunger famine of 1944 to 1945 confirmed they had a higher body mass index and increased risk of diabetes and cardiovascular events in adulthood compared with their unexposed siblings; these complex disease phenotypes have persisted in their descendants (13). Epigenetic modifications are an important mechanistic link between remote environmental stress and longer term changes to the program of gene expression.
RNA can reduce gene expression after transcription by repressing translation of messenger RNA (mRNA) or increasing mRNA degradation (25, 26). Advances in transcriptomic profiling have revealed relatively large numbers of noncoding RNA sequences transcribed from the human genome; micro-RNA (miRNA) form part of this group. These small, noncoding RNA molecules can regulate gene expression and epigenetic phenomena, resulting in changes in levels of thousands of proteins. Sequencing, microarrays, or quantitative real-time polymerase chain reaction may be used to analyze miRNA.
The discovery and continued characterization of miRNAs, RNA molecules composed of approximately 22 nucleotides (27), has revolutionized the understanding of gene regulation, cell differentiation, proliferation, and apoptosis. A complex epigenetic network exists whereby even miRNA expression is under epigenetic control (28). Several miRNAs have been associated with allograft rejection (29). Lorenzen et al. (30) recently reported alteration in miRNAs in the urine of renal transplant recipients with acute rejection, suggesting that miRNAs may prove to be useful noninvasive biomarkers in transplantation.
Altered epigenomes have been demonstrated in chronic diseases, including cardiovascular disease, chronic obstructive pulmonary disease, depression, schizophrenia, chronic kidney disease (CKD), and obesity (1, 34, 35, 42–44). Prospective epigenetic studies are required to establish the causal role of these epigenetic modifications in complex disease.
CKD is associated with accumulation of uremic toxins and enhanced oxidative stress, and these have the potential to modify the epigenetic signature. In patients with CKD, global hypermethylation is independently associated with cardiovascular mortality (44). Recently, epigenetic hypermethylation of RASAL1, encoding an inhibitor of the Ras oncoprotein, has been reported to be associated with persistent fibroblast activation and renal fibrogenesis (45). This kidney fibrosis is ameliorated in animal models that are heterozygous for the gene encoding the methyltransferase enzyme DNMT1 (45). Both epigenetic modifications occurring in the recipient’s “uremic” environment and those resulting from allograft ischemia-reperfusion injury could potentially change gene expression and affect renal allograft outcomes.
The cumulative injurious burden of nonimmunologic insults contributes to the development of chronic allograft dysfunction. Recipients who receive a human leukocyte antigen–identical transplant can develop interstitial fibrosis as a result of nonimmunologic injury (46).
Prolonged ischemia preoperatively is associated with delayed graft function, acute rejection, chronic allograft dysfunction, and reduced transplant survival (47). Reperfusion of the ischemic graft stimulates the release of oxygen and hydroxyl free radicals, which damage DNA, proteins, lipids, and plasma membranes, and these free radicals have the potential to alter the epigenome. In a rodent model of renal transplantation, it was demonstrated that prolonged cold ischemia of rat kidneys caused hypomethylation of the complement factor 3 gene (48, 49). Loss of transcriptional repression of this gene provides a plausible explanation for the accentuated immunologic injury, which often follows protracted ischemia of the allograft. Of interest, myocardial hypoxia induces HDAC enzymes, but the area of experimental cardiac ischemic injury can be substantially reduced by treatment with HDAC inhibitors. These acetylase antagonists inhibit cell death and reduce vascular permeability in the injured myocardium (50). H3 acetylation follows acute renal ischemia in mice, with resulting activation of inflammatory genes, enhanced cytokine expression, and fibrosis (51). If these epigenetic modifications contribute to allograft dysfunction, there may be an opportunity for therapeutic pharmacologic intervention.
Allograft rejection is a complex process involving interaction between the donor cells of the transplanted organ and the recipient immune system. It remains a persistent challenge in transplantation. Although the incidence of acute rejection could be reduced by increasing the immunosuppressive load, this is at the expense of a predisposition to serious infection and malignancy. All of the major immune cells involved in allograft rejection are influenced by epigenetic factors (Table 1).
The major histocompatibility complex (MHC) encodes glycoproteins, which present antigens to the immune system. MHC class I antigens are present on almost all nucleated cells, whereas class II are selectively expressed by antigen-presenting cells. The initial phase of rejection is the recognition of an alloantigen by T cells (61, 62). Direct allorecognition relies on T-cell detection of an alloantigen presented by a donor cell. Donor dendritic cells have a key role; they reside in the allograft but migrate when activated by inflammatory cytokines to allow T-cell activation (63). The indirect pathway involves the presentation of alloantigens by self MHC molecules (64). Concurrent T-cell receptor and costimulatory signaling propagate proliferation and differentiation of the T-cell lineage, cytokine production, and T-cell migration to the inflammatory site (61, 65).
MHC expression is fundamental to alloantigen recognition. Downregulation of MHC expression is a characteristic of gametes, embryonic cells, and neoplastic cells and confers them a degree of protection from the immune system (21). DNA methylation controls MHC class I and II expression; MHC class II expression is also affected by histone modifications. The histone methyltransferase CARM1 is critical to the constitutive expression of MHC II in B cells, and acetylation of the MHC II promoter enhances gene expression (66). In acute rejection, there is an increase in MHC II glycoproteins within the allograft (67).
B lymphocytes also play a significant role in rejection because of the high affinity of the B-cell receptor for foreign antigens. After interaction with a complementary epitope, the B cell communicates with its cognate T cell. Direct signaling and T-cell cytokine production stimulate the maturation, activation, and differentiation of B cells into plasma cells and memory cells (71). Alloantibodies cause severe graft rejection by binding to the transplanted organ and initiating the inflammatory cascade (72). A role for epigenetic regulation of B cells has recently been discovered. DNA methylation, histone modification, and chromatin remodeling determine B-cell receptor commitment, phenotypic stability, and cell signaling, whereas miRNAs have been implicated in differentiation (73).
T regulatory cells (Tregs) are of fundamental importance in immune modulation and the maintenance of self-tolerance. Their main role is to suppress self-reactive T cells that have escaped negative selection in the thymus, but Tregs also attenuate allograft rejection (74, 75). Several studies have identified an association between chronic rejection and low Treg populations (76, 77).
Genetic variation may have a significant effect on the action of immunosuppressants. Thiopurine methyltransferase genotyping can be used in clinical practice to assess the risk of myelosuppression with azathioprine treatment (86), and mutations in the multidrug resistance 1 gene can also affect clinical response to azathioprine (87). Calcineurin inhibitors are metabolized by cytochrome P450 enzymes, and an association has been identified between the CYP3A5 genotype and tacrolimus dosing requirements (88). Mycophenolate mofetil action and the incidence of adverse events are affected by single-nucleotide polymorphisms in the inosine monophosphate dehydrogenase type I and II genes (89, 90), the solute carrier organic anion transporter family member 1B1 gene (91), the IL-12A gene, complement factor H gene, and the cytochrome P450 2C8 gene (92). It is likely that immunosuppressive regimens induce clinically significant epigenetic modification. Glucocorticoids inhibit natural killer cell activity in vitro by altering histone deacetylation, but their global effect on the epigenome is unknown (93). The epigenetic effects of other immunosuppressive agents still remain to be elucidated. A greater understanding of the epigenetic modifications involved in allograft rejection could lead to the development of pharmacologic agents that act selectively on epigenetic targets.
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