The Ferret Era of Experimental Lung Transplantation Is Upon Us.

Abstract

It has become a commonly accepted dogma among transplant immunologists that laboratory mice can be used as defacto “tiny humans” for all investigations of alloimmunity. This belief is propped up by the 80% similarity in the protein-coding regions of the genome between the 2 species as well as the flexibility in transgenic technology that allows for easy modifications of inbred strains of mice. The low cost and rapid availability from commercial vendors also facilitate the utility of the murine model; however, to an outsider, the problem of relying exclusively on the mouse model for basic discovery and drug development is apparent. Since the description of orthotopic mouse lung transplantation over a decade ago, numerous studies from multiple groups have used this powerful tool to decipher mechanisms contributing to graft rejection and tolerance. The model successfully mirrors the spectrum of ischemia-reperfusion injury as well as T cell–mediated and antibody-mediated acute rejection.1 The mouse has also served as a reliable model of long-term tolerance induced by costimulatory blockade of the CD40-CD40 ligand and CD80/86-CD28 pathways2 as well as a traditional graft acceptance model induced by conventional immunosuppression with cyclosporine and methylprednisolone.3 Thus, the mouse has utility for investigations focusing on short-term outcomes, which have already improved dramatically in the modern era of perioperative patient care; however, with improvement in short-term outcomes, chronic lung allograft dysfunction (CLAD) has emerged as the major barrier to the long-term survival of lung transplant recipients. Thus, a major focus on CLAD is required to advance our field.