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Genetic predictors of acute renal transplant rejection.

While rates of acute rejection (AR) continue to decrease, it remains the strongest predictor of long-term allograft survival [1–5]. Better understanding of factors predicting AR may contribute to more individualized patient care. Environmental factors associated with AR have been evaluated in the past, specifically, ischaemia–reperfusion injury [6], and the degree of immunosuppression [7–9] has been associated with AR. Similarly, literature discussing genetic predictors of AR has emerged in recent years. Indirect evidence that AR might indeed be associated with genetic factors come from expression studies demonstrating that gene expression profiles between rejecting and non-rejecting kidneys are different [10,11]. Also, there are evidence from genealogy analysis demonstrating familial aggregation of recipients with AR and those with rejection-free course [12]. Existing studies of genetics of AR are based on candidate gene approach. Candidate genes are mostly selected based on biologic plausibility and known polymorphisms associated with functionality (e.g. level of cytokine secretion). At the same time, reports based on genome-wide association studies are lacking. Using this approach, many important cytokines involved in immune response have been evaluated. A brief summary of the action of important cytokines and their role in immune response is as follows. Interleukin (IL)-12 stimulates the differentiation of Th1 cells, which in turn secrete tumour necrosis factor (TNF), interferon (IFN), IL-12, IL-2 and IL-3. IL-2 causes further proliferation of Th1 cells, promotes cell-mediated immune response [13] and stimulates clonal proliferation of B cells and cytotoxic T cells. IL-12 also causes the activation of natural killer cells. On the other hand, IL-4 stimulates the Th2 phenotype, T cells that release IL-4, IL-6 and IL-7, essential for B cell maturation and antibody-mediated immunity. They also produce IL-10 that blocks the proliferation of Th1 and cytotoxic T cells. In this review, we discuss the role of specific genetic determinants other than major histocompatibility complex (MHC) in the development of acute allograft rejection (Table 1).