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Ann Thorac Surg 1997;64:1025
© 1997 The Society of Thoracic Surgeons
DR JAMES K. KIRKLIN (Birmingham, AL):
Perhaps you could educate us for a moment about two points. I was intrigued with the rapidity of the development of this vasculitis lesion, which seems to be much more rapid than you would find in a human model of cardiac transplantation. First, do you believe that this is the same lesion, and, if so, how do you explain the very accelerated nature of it in these inbred swine? Second, I thought that perhaps an anti-CD4 antibody, which is necessary for induction of B cells might play some role in blocking this response, but instead it was an anti-CD8. Could you comment on what you believe the mechanism is?
DR ALLAN:
Doctor Kirklin's first question raises a commonly asked point concerning the validity of animal models in which cardiac allograft vasculopathy develops over several weeks to several months' time, whereas in patients we tend to think of this disease as a manifestation of chronic rejection, occurring several years after transplantation. First, I would like to remind the audience that autopsy studies of cardiac transplant recipients have shown the presence of intimal lesions within the first year after transplantation. Thus, although patients may not be presenting with overt clinical manifestations of coronary vasculopathy for several years, intimal lesions may be developing soon after transplantation. I would also like to point out that small animal models of cardiac allograft vasculopathy using mice and rats are also examining lesions that occur over a similar time course. Thus, our model does not differ significantly from other models in this regard. Nonetheless, we are beginning several studies using a sustained triple-drug immunosuppression regimen to determine whether the vasculopathy progresses with a similar pattern in long-term survivors.
In support of our porcine model, I would like to make the following points. First, nontransplant arteriosclerosis naturally develops in swine, whereas it does not in most rodents. Also, lipid deposition, which is not seen in murine models of cardiac allograft vasculopathy, is a common finding in the lesions observed in our model. Furthermore, like humans, swine constitutively express class II antigens on their coronary endothelium, whereas rodents do not. Finally, lesions in our swine progress through the same histologic stages as do human lesions, beginning with an endotheliitis, moving on to intimal proliferation with the deposition of extracellular matrix and smooth muscle cells, and ultimately progressing to a more mature fibrotic lesion.
As to your second question, Dr Kirklin, we unfortunately do not have a depleting anti-porcine CD4 antibody with which to do similar experiments. As you have suggested, CD4+ lymphocyte depletion in murine models has resulted in prolonged graft survival. In contrast, with CD8+ lymphocyte depletion in our model, we have seen a trend, although not statistically significant, to a shortening of graft survival. It appears that the CD8+ cell and the CD4+ cell are working through two different pathways in mediating allograft vasculopathy on one hand, and interstitial rejection on the other. Further studies are needed to elucidate the humoral and cellular mechanisms involved in both of these processes.
DR J. KENT TRINKLE (San Antonio, TX):
Can you tell me the precise timing of the monoclonal antibody administration relative to revascularization of the graft? Specifically, did you give it before or after the graft was reperfused? If you administer it before reperfusion you do not have time for antigen presentation with an increase in the memory T and B cells. Theoretically, this ought to be more effective. If you give it after reperfusion, perhaps less so.
DR ALLAN:
Our protocol is to begin the administration of the antibody after a central venous catheter is placed in the recipient animal before transplantation. We therefore may be completing the antibody dose during the time when the graft is being sewn in place, before reperfusion of the donor heart.
DR TRINKLE:
Did you measure adhesion molecule changes? Is this just a nonspecific endothelial cell injury with neutrophil and platelet adherence and a mitogenic subintimal fibroproliferative response, or is it specific, due to the CD8 lymphocyte?
DR ALLAN:
We have an extensive immunohistochemical project underway to examine some of those issues, although I do not have those data for you at this time. The lack of intimal lesions in our antibody-treated animals as compared with control animals leads us to believe that CD8+ lymphocyte depletion is preventing a CD8+ cell-mediated injury to the endothelium.
DR BRUCE R. ROSENGARD (Philadelphia, PA):
If one uses the same NIH miniature swine strain combination and 12 days of cyclosporine, long-term tolerance of kidney transplants is uniformly induced with no reported incidence of graft vasculopathy. Can you speculate on the difference between heart and kidney grafts?
DR ALLAN:
We have seen a difference in the acceptance of class I mismatched kidney allografts and class I mismatched heart allografts, as Dr Rosengard has described. I think that these two organs may be immunologically different, resulting perhaps in the transfer of different donor antigen loads or passenger leukocytes. Our group is very interested in understanding this difference, and is currently studying the mechanism of organ-specific tolerance induction in studies involving thymectomy and cotransplantation of the heart and kidney.
Related Article
Ann. Thorac. Surg. 1997 64: 1019-1025.
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