CD200:CD200R interaction in organ transplantation

CD200:CD200R interaction in organ transplantation

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Reg Gorczynski, BA, PhD, MD
Senior Scientist, University Health Network
Professor, Department of Medicine, University of Toronto

Organ transplantation remains the treatment of choice for end organ failure associated with a number of clinical disease entities. The development of artificial organs—or the promise of stem cell technology to render transplantation an obsolete methodology—remains a still-distant objective. While limitation of organ supply has encouraged the development of techniques for live donor transplantation, the fact that a foreign graft will be recognized by the recipient immune system and will generate a potent rejection response, is still a key obstacle to long-term graft acceptance. Currently, the only suitable option to counter rejection is the ongoing use of immunosuppressive drugs, which, in turn, is associated with three major unwanted side effects, namely: drug toxicity, opportunistic infection, and malignancy. It has been the immunologist’s “dream” that uncovering mechanism(s) that could induce specific tolerance to foreign grafts, presumably through processes akin to those by which we are naturally tolerant of our own self tissues, would overcome the need for non-specific immunosuppressive drugs and provide the long-sought after breakthrough for transplantologists.

Basic immunology research over the past decades has established a framework by which we can understand how T cells (thought to be the main “culprit” in initiating rejection responses) are activated, and in turn regulated. From this body of knowledge, new efforts have been developed to combat rejection which have built upon the ideas about attenuation of signals leading to T cell priming (i.e. blockade of effective antigen presentation; suppression of costimulatory signals; neutralization of cytokine growth signals; and/or fostering the activation and expansion regulatory T cells). Many of these approaches are in the throes of clinical trial, or indeed are already incorporated into more novel regimens for patient treatment post engraftment.

Our own laboratory’s efforts have centered around improving our understanding of the actions of a novel molecule, CD200, increased expression of which we showed many years ago could suppress immune inflammation and foster enhanced organ allograft survival following interaction with the inhibitory receptor, CD200R1. Using genetically constructed mice over-expressing CD200 (CD200tg), or lacking either CD200 or its receptor (CD200-/-, CD200R1-/-), along with gene expression profiling of accepted grafts in CD200tg animals and immunohistology, we concluded that important mechanism(s) implicated in CD200-mediated increased graft survival involved increased infiltration of Foxp3+ regulatory T cells (Treg) and non-degranulating myeloid cells (MCs) in the graft. Despite this, however, indefinite allograft survival of the most vigorously rejected grafts was not seen for all recipients, and tolerance was not being achieved.

In models based on studies of natural neonatal tolerance in mice, an embryonic (immature) immune system encountering (allo)antigen develops “true tolerance”. In these scenarios we and others showed several decades ago that grafts expressing the same antigens applied to adults treated as neonates are permanently accepted, without the concomitant non-specific immune hyporesponsiveness, which often accompanies adult allogeneic bone marrow transplantation. Again, Treg are implicated in graft survival in such neonatal tolerance models. In our most recent studies we examined whether mice receiving transplants under cover of rapamycin as immunosuppressant, and subsequently receiving autologous marrow transplants after drug-induced myeloablation (using busulphan and cyclophosphamide), would become tolerant to allografts such that following marrow regeneration, long-term graft survival would be possible in the absence of exogenous immunosuppression.

Using this protocol in CD200tg animals, a state of true tolerance develops in mice, and is associated with marked graft infiltration with Foxp3+ Tregs. We anticipate a similar regimen could be of use in clinical transplantation.