Microbes and allogeneic transplantation

Abstract

Microbial products can be recognized by pattern recognition receptors expressed by immune and parenchymal cells and drive innate immunity that can in turn shape adaptive immune responses to microbial and transplant antigens. In transplanted patients, the signals and their downstream inflammatory cytokines elicited in response to infections can modulate ongoing alloimmune responses and modify the fate of transplanted organs. In recent years, it has become apparent that microbial signals can be generated not only by active pathogenic infections but also by commensal microbiota, thus opening a new field of research into the interplay between the microbiota and the immune system in homeostasis and disease. The wide use of antibiotics and immunosuppressive drugs in transplanted patients can have dramatic consequences on the microbiota that can in turn shape immune responses and perhaps alloresponses, whereas the ongoing immune responses can in turn affect the commensal or pathogenic microorganisms in a feed-forward circle. Here, we discuss known and hypothesized mechanisms for how infections or microbiota-derived signals may affect local or systemic alloimmunity and briefly review data on downstream effects of antibiotics and vaccinations.

Figure 1. Interplay between microbes and the alloimmune response

Infections prior to transplantation as well as inadvertent immunity to commensal microbiota may generate cross-reacting alloreactive memory T cells. Microbiota-derived microbial products transported systemically may also lower the activation threshold of APCs that may be presenting alloantigen. Infections at the time of or after transplantation may enhance the alloresponse directly by providing ligands to PRRs on APCs thus boosting alloantigen presentation, or indirectly via the cytokines produced during the anti-microbial response that can lower the activation threshold of an ongoing alloresponse or can dictate the phenotype of a differentiating alloreactive T cell. In addition to these effects that would be detrimental to an allograft, microbes may also help prevent alloimmunity. For instance, intestinal microbiota can generate iTregs and it is theoretically conceivable that these play a role in dampening the alloimmune response.