The impact of infection and tissue damage in solid-organ transplantation

Abstract

Investigations over the past two decades are revealing complexities in the regulation of the innate immune response, and how this response, in turn, controls adaptive immunity. Microbial exposure, infections and tissue damage that accompany solid-organ transplantation result in the release of pathogen- and damage-associated molecular patterns, as well as pathogen- or allograft-derived antigens. Here, we review these triggers of innate and adaptive immunity, and discuss emerging paradigms of the many ways in which infections and tissue damage might directly or indirectly affect alloreactivity and the outcome of transplanted allografts.

Figure 1. Possible effects of infections before, at and after transplantation

Some T cells specific for microbial peptides presented by self-MHC molecules can cross-react with allogeneic MHC while bacterial superantigens can directly activate large populations of T cells. Therefore, infections experienced before transplantation can give rise to memory alloreactive T cells that may be more resistant to immunosuppression than naïve T cells ^, . Signals and cytokines elicited upon engagement of PRRs on APCs, T cells or parenchymal cells at the time of or after transplantation can result in enhanced priming, survival and expansion of alloreactive T cells, as well as dictate the phenotype of differentiating alloreactive T cells. Infections occurring late after transplantation may, in theory, elicit pro-inflammatory signals that activate tolerant T cells by enabling their escape from immunosuppression and/or peripheral mechanisms of tolerance, thereby precipitating rejection.

Figure 2. Anti-microbial immune responses can augment and shape alloimmunity

PRR-dependent signals can enhance alloreactivity by at least 3 mechanisms. a, T cells specific for microbial antigens and fully activated by APCs matured by infection-derived PAMPs and presenting microbial antigens in response to an infection may cross-react on donor MHC and therefore recognize allogeneic graft cells directly. b, The alloantigen can be presented to alloreactive T cells by an APC that is simultaneously receiving PRR signals either from its own infection, or from sensing PAMPs on or released by the microbe. This PRR-mediated stimulation can result in increased processing and presentation of the alloantigen, expression of co-stimulatory molecules, secretion of cytokines and priming of alloreactive T cells. c, inflammatory cytokines elicited by PAMPs during an infection may enhance and divert differentiating alloreactive T cells into specific phenotypes that elicit different graft pathologies. DAMPs may play similar roles to PAMPs.

Figure 3. Potential causes of graft damage during microbial infections

Graft destruction during an infection can occur by multiple mechanisms. a, microbes with a tropism for the graft organ may have direct cytopathic effects that cause the release of microbial or donor antigens as well as DAMPs. b, recipient APCs or endothelial cells (not shown) in the graft may take up and cross-present exogenous microbial antigens to recipient T cells. Activated APCs or T cells may secrete cytokines that are damaging to the graft or injure endothelial cells thereby reducing vascular supply to the graft. Of note, when HLA alleles are shared between the recipient and donor, recipient-restricted anti-microbial T cells may directly engage infected donor cells (not shown in the figure). c, infections may augment activation of direct alloreactive T cells by enhancing maturation of donor APCs (not shown) or parenchymal cells resulting in graft damage. d, similarly, infections may mature recipient APCs or endothelial cells (not shown) that have taken up donor antigen, resulting in activation of indirect alloreactive T cells and graft injury by toxic soluble factors that injure blood vessels. e, cellular graft damage may release cryptic antigens and DAMPs that then activate autoreactive T cells. Upon re-encounter with these antigens on cross-presenting recipient APCs or endothelial cells, these autoreactive T cells may contribute to graft damage in a phenomenon analogous to epitope spreading.