J Thorac Cardiovasc Surg 1998;116:532-533
© 1998 Mosby, Inc.
Letters To The Editor
Reply to the Editor
We read with interest the letter written by Kawauchi and associates 1 in response to our article concerning the pathology of explanted cryopreserved allograft heart valves versus aortic valves from orthotopic heart transplants. 2 In a primate heterotopic heart transplant model, Kawauchi and colleagues have observed mononuclear inflammatory cells in association with the allograft aortic valve and have interpreted this to represent cell-mediated "rejection." Since they observe that the extent of inflammatory infiltrate in the valves is lower than that seen within the myocardium proper, the authors also infer that the rejection of valves is weaker than that of the myocardium. As in the recent paper by Rajani and colleagues, 3 the criteria that permit the presence of mononuclear cell infiltrates in valves to be interpreted as immunologically specific rejection are not stated. Moreover, there is no evidence that valve degeneration or dysfunction can be attributed to the inflammatory cells. Nevertheless, on the basis of these findings, as well as those reported previously in rat allograft valve experiments, 4,5 Kawauchi and associates 1 suggest that "small-dose immunosuppression may arrest homograft degeneration."
We believe that it is extremely important to respond to the letter and to clearly reiterate two points that we made in our original article: (1) Tissue immunogenicity is not equivalent to immunologically mediated dysfunction. (2) Although inflammatory cell infiltrates are characteristically associated with rejection, the presence of such cells does not necessarily denote a rejection pathogenesis.
As regards the first point, allograft valves clearly may induce a detectable humoral and/or cellular allogeneic response. 4,8 Indeed, it would be unusual if tissue expressing foreign histocompatibility antigens did not elicit a detectable response. However, there is not evidence that the observed loss of cellularity and architectural degeneration of cryopreserved allograft valves can be attributed to such immunologic responses. Indeed, some sort of immunologic variant of Koch's postulates* should be satisfied before one concludes that immune destruction is the basis for valve failure. Essentially, it is first necessary to demonstrate that immunologically specific elements (antibodies or cells) are associated with failing valves; by the judicious use of isografts, an important corollary is that antibodies and cells found on valves are not nonspecifically present because of surgical manipulation or aberrant flow conditions. The second step would be to use antibodies or cells from animals that have dysfunctional transplanted valves and cause valve degeneration by transfer into an appropriate second host (i.e., haplotype-matched to the original valve donor). Finally, the adoptively transferred cells or antibodies should be recoverable from the failed valve in the second host.
Animal models, such as that described by Kawauchi and colleagues, provide an excellent way to satisfy such postulates. However, the appropriate experiments have thus far not been done. In fact, in the animal and human studies cited, 1,4 8 workers have only demonstrated that allograft valves are immunogenic and that immunosuppressants (e.g., cyclosporine [INN: ciclosporin]) may modulate the ability to generate an immunologic response. 4 In our opinion there exists no evidence that valve destruction or loss of function is mediated by immune elements, or even that blockage of immune mechanisms by immunosuppression prevents that outcome.
The results of our examination of explanted cryopreserved allografts days to years after implantation 2 suggest that factors related to harvesting, handling, ischemic time, freezing, and thawing are most responsible for the loss of cellular viability. The absence of neutrophilic and/or increased mononuclear cell infiltrates (above the resident population in valves) in explanted cryopreserved valves, even at time points where clear-cut architectural changes and loss of cellular staining are occurring, leads to the conclusion that immunologic phenomena cannot be causally implicated in most allograft degeneration. Moreover, even in heart transplant patients where immunologic phenomena caused allograft failure, or where patients had multiple episodes of parenchymal rejection, evidence of immunologic injury to the valves is not seen (i.e., no valvular scarring or loss of cellularity). These results in orthotopic heart transplants suggest that allogeneic valves may be relatively resistant to immune injury, perhaps owing to a combination of high flow, the normal lack of valvular microvasculature, low alloantigen expression, and/or lower expression of relevant adhesion or co-stimulator molecules. 2 In this regard, the observation by Kawauchi and associates 1 concerning lower apparent antigenicity of valves versus myocardium is intriguing, although a controlled comparison of the relative alloresponse (e.g., mixed lymphocyte culture) to valves versus myocardium was not done.
The second point above, that mononuclear cells do not equate to rejection, is particularly germane in regard to the conclusions reached by Kawauchi and colleagues. 1 First, it is not possible to unequivocally conclude that the subendothelial valvular infiltrate is above background levels. No indication is given for the number of intrinsic resident mononuclear cells in the macaque monkey valves; our study found that normal human valves have a low level, diffuse population of macrophages and T cells present as normal cellular constituents. 2 Second, the composition of the mononuclear cells present has not been characterized; they may well be predominantly macrophages and not lymphocytes. Indeed, the single illustration provided appears most like an organizing thrombus, which would be expected to have a large population of macrophages even in the absence of a specific immune response. Third, the fact that the model used by Kawauchi's group involves heterotopic cardiac allografts (with recipient abdominal aortic anastomosis to donor ascending aorta) means the vascular stasis and thrombosis both above and below the valve may be significant confounding factors. Obviously, in orthotopic transplantation, normal high flow across the valve will minimize the ability of cells and/or antibodies to adhere; in heterotopic transplantation, substantial stasis, as well as the presence of organizing thrombus, may allow an artifactually high accumulation of these immune elements. In this regard, analyzing the pulmonic valves from these orthotopic transplants (which will have more normal flow) may minimize the confounding variable of thrombosis. Finally, even in this heterotopic model, no evidence is presented to suggest that the mononuclear inflammatory cells are causing functional valve degeneration or that immunosuppression might be efficacious in modulating the inflammatory response.
Consequently, although the findings of Kawauchi and coworkers are interesting, the model is incompletely characterized. Moreover, we believe that it is extremely premature to advocate the use of immunosuppression (itself associated with widely known and substantial morbidity) to prevent valvular degeneration in cryopreserved allografts, a process that appears to be a consequence of ischemia, freezing, and thawing, and for which we find no substantive evidence implicating an immune pathogenesis.
Department of PathologyBrigham and Women's Hospital,
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