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LITERATURE Watch Implications for transplantation

A primary focus for the role of microorganisms has been on their potential to induce infection in the immunosuppressed recipient and how infection may compromise graft acceptance (Fishman and Ruben; Caineli and Vento). However, new considerations may belie this perspective. The viewpoint of microorganisms as invaders is incomplete in light of new discoveries about the vast expanse of microorganisms known as the commensal microbiota (Lozupone et al.; Weinstock). Many transplanted organs are in direct contact with a commensal microbiota (eg, lung, intestine), while all other organs are exposed to commensal-derived microbial products in the circulation. Prevention of transplant rejection is a process of facilitating acceptance of the graft as self, and manipulation of the microbiota may be a mechanism to promote tolerance. The commensal microbiota exhibit a reciprocal, symbiotic relationship with host immunity; thus many immune responses previously considered to be driven by distinctions of self and non-self are actually influenced by the microbiota to the extent that the microbiota may be an additional component in the definition of self (Eberl). This notion has recently been illustrated by studies demonstrating the generation of microbiota-specific regulatory T cells (Josefowicz et al.; Lathrop et al.). Regulatory T cells (Tregs) develop at lower frequencies in the colon of mice devoid of commensal bacteria (Geuking et al.). Furthermore, sequencing of the T cell receptor (TCR) repertoire reveals that colonic Tregs maintain a unique set of TCRs that are reactive to specific members of the commensal microbiota. In the absence of FoxP3 induction, such TCRs induce autoimmune colitis, suggesting that Tregs respond to microbial antigens and prevent autoimmunity (Lathrop et al.). This idea has been bolstered by the demonstration that extrathymic development of peripheral Tregs at body surfaces prevent autoimmunity (Samstein et al.). The ability of the microbiota to induce suppressive T cell populations may be a mechanism by which such microbes prevent autoimmune disease. Such a possibility in humans is suggested by the observation that a lower abundance of Faecalibacterium prausnitzii increases the risk of postoperative recurrence of ileal Crohn’s disease (Sokol et al.). In a separate study, bone marrow transplant recipients with graft-versus-host disease (GVHD) maintained higher levels of Lactobacillus species compared with non-GVHD patients. Mouse experiments reveal that Lactobacillus species mitigate the severity of GVHD, and argue against the use of antibiotics that deplete species (Jenq et al.). While the concept of microbes as foreign invaders has been essential in preventing illness in transplantation, it is intriguing to consider the possibility that probiotics or targeted antibiotic therapies might serve helpful roles in promoting graft acceptance (Fishman and Rubin). It is immediately evident that the microbiota may play a role in tolerance in the lung, skin, small intestine, or colon, but it is also important to remember that the liver is exposed to a high concentration of microbial products; as a result, liver transplant tolerance may be amenable to manipulation via the microbiota. This concept may even be extended to heart or kidney transplant, although their exposure to microbial products is less obvious than that of the liver. Given the important realization in the field of immunity—that the concept of self may have to be revised to additionally include the commensal microbiota— it is exciting to consider the vast potential for manipulation of the microbiota to facilitate graft tolerance.