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J Thorac Cardiovasc Surg 1995;110:1773
© 1995 Mosby, Inc.

LETTERS TO THE EDITOR

Modulation of alloreactivity in transplant recipients by phenotypic manipulation of donor endothelium

Assistant Professor of Surgery
Washington University School of Medicine
St. Louis, MO 63110

To the Editor:

I read with interest the report by Quigley and associates (J THORAC CARDIOVASC SURG 1995;109:905-9) of their observations concerning rat cardiac allograft prolongation by pretreatment of the donor with intravascular injection of recipient type endothelial cells. Clearly such a simple approach could have direct clinical application. What is less clear is the interpretation of this interesting phenomenon. The title of the report suggests two things: (1) that the alloreactivity of the recipient has been altered and (2) that phenotypic manipulation of the donor endothelium itself has occurred. Unfortunately, there seems to be little evidence of the latter, and because of the lack of appropriate controls the article offers inadequate information with respect to the former.

Evidence is presented that recipient-type endothelial cells have "seeded the graft." An argument is presented in the discussion segment that these endothelial cells "proliferate in the allograft vascular tree"; however, there is no direct evidence of such proliferation provided. Furthermore, although the authors suggest that immunomodulation is occurring by "either masking the expression of the class II MHC [major histocompatibility complex] molecules or causing up-regulation or down-regulation of MHC or cell adhesion genes (or both) in the donor endothelium," they offer no immunohistochemical evidence of any of these potential mechanisms. The breadth of this hypothetical mechanism is such that it is of limited usefulness in the interpretation of the data. Furthermore, no direct evidence is provided that the donorendothelium is an any way phenotypically modified. Again, an immunohistochemical study demonstrating staining of endothelial cells with markers identifying the cells as donor in origin counterstained to demonstrate the hypothesized phenotypic modification would be more helpful. This is not to say that phenotypic modification did not occur. We simply do not know.

The studies presented leave us equally uninformed regarding the effect of this donor graft pretreatment on alloreactivity. Skin graft data are presented demonstrating (remarkably) neither prolongation nor accelerated rejection of donor-specific skin grafts in animals bearing treated grafts. That is, there is no effect on these grafts as compared with those of animals treated with subtherapeutic cyclosporine. Unfortunately, inasmuch as the hypothesis of this study is stated to be the effect of manipulation of allograft endothelium by means of recipient-type endothelial seeding, an additional crucial control would be an animal given an unmodified heart graft. Rejection of the skin graft does not cause rejection of the heart graft. It is as if the recipient is immunologically blind to the modified graft, a very intriguing observation! Unfortunately, this does not quite square with the mixed lymphocyte culture data presented, which actually demonstrate some evidence of sensitization to donor-type cells. Although the stimulation index is globally reduced (most likely as a result of cyclosporine immunosuppression, as acknowledged by the authors), the peak in the point of maximal proliferation is advanced from day 8 to day 6 as compared with proliferation in untreated animals. Again, a crucial control would be comparison with an animal receiving an unmodified graft. This control would address the question of whether the alloreactivity of the recipients has been modified by pretreatment of the donor graft.

The studies described by Quigley and associates are an exciting inverse of the classic enhancement experiments also performed with vascularized grafts in rats. In these, injection of donor-type cells into the host produced graft prolongation that appeared to be due to a local phenomenon that was transferrable with the graft itself on retransplantation. Retransplantation of these heart grafts into naive recipients might help to answer the question of whether some sort of local suppression is active. If so, would the authors consider this a form of local tolerance?

12/8/68742

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