The microbiota, the immune system and the allograft

Abstract

The microbiota represents the complex collections of microbial communities that colonize a host. In health, the microbiota is essential for metabolism, protection against pathogens and maturation of the immune system. In return, the immune system determines the composition of the microbiota. Altered microbial composition (dysbiosis) has been correlated with a number of diseases in humans. The tight reciprocal immune/microbial interactions complicate determining whether dysbiosis is a cause and/or a consequence of immune dysregulation and disease initiation or progression. However, a number of studies in germ-free and antibiotic-treated animal models support causal roles for intestinal bacteria in disease susceptibility. The role of the microbiota in transplant recipients is only starting to be investigated and its study is further complicated by putative contributions of both recipient and donor microbiota. Moreover, both flora may be affected directly or indirectly by immunosuppressive drugs and antimicrobial prophylaxis taken by transplant patients, as well as by inflammatory processes secondary to ischemia/reperfusion and allorecognition, and the underlying cause of end-organ failure. Whether the ensuing dysbiosis affects alloresponses and whether therapies aimed at correcting dysbiosis should be considered in transplant patients constitutes an exciting new field of research.

Keywords: Acute rejection; alloimmunity; chronic rejection; microbiota; pattern-recognition receptor.

Figure 1. The intestinal epithelium and immune system control the local microbiota

The immune system, whose maturation is helped by the microbiota, in turn contains it and prevents outgrowth of pathogenic species via production of mucus that physically separates the microbiota from the host, antimicrobial peptides (AMP) that create a sterility gradient and secretory IgA that neutralizes biologically active antigens. In peripheral lymph nodes, innate lymphoid cells (ILC) help contain translocated bacteria. IEL, intra-epithelial lymphocyte; IEC, intestinal epithelial cell; GALT, gut-associated lymphoid tissue.

Figure 2. The microbiota promotes maturation and differentiation of the immune system

The microbiota carries many essential functions to ensure that optimal immune responses can be generated, including helping development and maturation of lymphoid structures, differentiation of T cell subsets and potentiation of the function of innate immune cells. GALT, gut-associated lymphoid tissue; PP, Peyer’s patches; mLN, mesenteric lymph node; IEL, intestinal epithelial cell; iTreg, induced T regulatory cell; DC, dendritic cell.

Figure 3. Speculative model for how the microbiota may affect alloresponses

Although it is not known if the microbiota can affect alloresponses, parallels drawn from other fields suggest mechanisms by which the microbiota could both inhibit and promote anti-transplant immunity. For instance, intestinal bacteria and microbial products can promote the differentiation of local and possibly distal regulatory and effector T cells. These T cells may cross-react with alloantigen and therefore inhibit or promote alloresponses, respectively. The microbiota has also been reported to prime antigen-presenting cells (APC) such that alloantigen could potentially be presented more efficiently to alloreactive T cells. In addition, when transplanting colonized organs such as composite grafts, intestine or lung (airways contain resident microbiota although bacterial density decreases with diminishing size of the airways), the microbiota from the donor organ may control the organ’s own local immunity and perhaps also distal immunity and thus further influence regulatory and/or effector alloresponses. Dashed lines represent speculative effects that need to be investigated.