Innate immunity in solid organ transplantation: an update and therapeutic opportunities

Abstract

Innate immunity is increasingly recognized as a major player in transplantation. In addition to its role in inflammation in the early post-transplant period, innate immunity shapes the differentiation of cells of adaptive immunity, with a capacity to promote either rejection or tolerance. Emerging data indicate that innate allorecognition, a characteristic previously limited to lymphocytes, is involved in allograft rejection. This review briefly summarizes the physiology of each component of the innate immune system in the context of transplantation and presents the current or promising therapeutic applications, such as cellular, anticomplement and anticytokine therapies.

Keywords:

• complement
• cytokines
• dendritic cells
• innate immunity
• monocytes
• Toll-like receptors
• transplantation

Financial & competing interests disclosure

SA De Serres participated in a scientific advisory board of Alexion Pharmaceuticals in March 2014. SA De Serres is the recipient of a Kidney Research Scientist Core Education and National Training (KRESCENT) Program New Investigator Award from Kidney Foundation of Canada KRES12002 and Canadian Institutes of Health Research KRI123890. SA De Serres holds a scholarship from the FQRS (26726). Stéphanie Béland is the recipient of a Grant from the Department of Medicine from Laval University. This work was supported by the Canadian Institutes of Health Research through the Grant PCL134068. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Key issues

• Innate immunity shapes the activation of adaptive immunity.

• Experimental studies reveal that every component of the innate immunity is involved in transplant rejection; however, some of them seem to have a dispensable role, notably NK cells and neutrophils.

• Pilot clinical trials show that manipulating macrophages ex vivo to produce regulatory macrophages and reinjecting the cells into patients is feasible and potentially prevents rejection.

• Recognition of allogeneic non-self by monocytes has been demonstrated in mice, challenging the concept that innate immunity only activates upon the release of non-specific danger molecules.

• Proteins of the complement are the target of intense investigation to determine their role in rejection. Preliminary data using anti-C5 monoclonal antibodies suggest that they may prevent humoral rejection, but more robust data are needed.

• Anticytokine therapeutics are used in islet transplant with success; however, such therapies have found little use in other organs to date. Experimental and observational mechanistic data in patients suggest that they may be potential targets for new immunosuppressive strategies.

• Agents targeting cell adhesion molecules or their ligands have been tested in the transplant and in the autoimmune setting, with some success. However, their ubiquitous nature in the cells increases the risk of serious adverse effects, such as progressive multifocal leukoencephalopathy, that occurred with anti-lymphocyte function-associated antigen 1 agent.

• Similarly, TLRs are an interesting therapeutic target. Genotyping studies revealed associations between specific polymorphisms of TLR4 in patients and decreased rates of acute rejection. However, TLR therapeutics raises big challenges in terms of specificity of action and potential side effects as well.