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(American Journal of Pathology. 1998;153:1813-1824.)
© 1998 American Society for Investigative Pathology

Regular Articles

T Cell Apoptosis in Human Heart Allografts

Association with Lack of Co-Stimulation?

Els Van Hoffen* , Dick F. Van Wichen* , Jaklien C. Leemans* , Richard A.J.F. Broekhuizen* , Annette H. Bruggink* , Mark De Boer{dagger} , Nicolaas De Jonge{ddagger} , Hans Kirkels{ddagger} , Piet J. Slootweg* , Frits H.J. Gmelig-Meyling§ and Roel A. De Weger*

From the Department of Pathology,* the Heart Lung Institute,{ddagger} and Department of Immunology,§ University Hospital, Utrecht, and PanGenetics B.V.,{dagger} Amsterdam, The Netherlands

It is unclear whether the intracardial immune reactivity after heart transplantation influences the peripheral immunological status (activation or nonresponsiveness) of the patient. Co-stimulation and activation-induced cell death (AICD) or apoptosis play an important role in determining the balance between lymphocyte reactivity and nonreactivity. Therefore, we studied the expression of co-stimulatory molecules and the process of apoptosis in biopsies of human heart allografts, using immunohistochemistry. Although a normal expression of co-stimulatory molecules on antigen-presenting cells was observed, the expression of their counter-structures on T cells was absent. This may be due to chronic T cell activation, which can lead to the induction of apoptosis via the Fas/Fas ligand pathway. In the infiltrates, a considerable percentage of the lymphocytes, but not the macrophages, were apoptotic. Apoptosis was confirmed by DNA fragmentation analysis. Increased numbers of Bax-expressing versus decreased numbers of Bcl2-expressing lymphocytes in comparison with normal lymphoid tissue confirmed a imbalance in favor of apoptosis. Apoptosis was biased towards CD4+ T cells (65.7% versus 26.6% in CD8+ T cells). Fas was expressed on most of the infiltrating cells. Fas ligand expression was also observed, not only on most of the T cells but also on all macrophages. Because macrophages were often detected in close contact with T cells, they may play a role in T cell regulation via the Fas/Fas ligand pathway. This study indicates that, during rejection, not only is tissue damage induced by infiltrating T cells, but also the infiltrating lymphocytes themselves are actively down-regulated (eg, AICD) by one another and by macrophages in the infiltrate. This regulatory process may affect the immunological status of the patient after heart transplantation.




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