title: T cell apoptosis in human heart allografts: association with lack of co-stimulation?
abstract: 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.
authors.affiliation: Department of Pathology, University Hospital, Utrecht, The Netherlands.
authors.forename: E
authors.initials: E
authors.lastname: Van Hoffen
authors.forename: D F
authors.initials: DF
authors.lastname: Van Wichen
authors.forename: J C
authors.initials: JC
authors.lastname: Leemans
authors.forename: R A
authors.initials: RA
authors.lastname: Broekhuizen
authors.forename: A H
authors.initials: AH
authors.lastname: Bruggink
authors.forename: M
authors.initials: M
authors.lastname: De Boer
authors.forename: N
authors.initials: N
authors.lastname: De Jonge
authors.forename: H
authors.initials: H
authors.lastname: Kirkels
authors.forename: P J
authors.initials: PJ
authors.lastname: Slootweg
authors.forename: F H
authors.initials: FH
authors.lastname: Gmelig-Meyling
authors.forename: R A
authors.initials: RA
authors.lastname: De Weger
mesh_terms: D015703:Antigens, CD / Q000378:metabolism; D017209:Apoptosis; D001706:Biopsy; D016516:CD4-CD8 Ratio; D019084:Fluorescent Antibody Technique, Indirect; D006084:Graft Rejection / Q000276:immunology* / Q000473:pathology; D016027:Heart Transplantation / Q000276:immunology / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D009206:Myocardium / Q000276:immunology / Q000473:pathology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D013997:Time Factors; D051028:bcl-2-Associated X Protein
chemical_list: D015703:Antigens, CD; C494826:BAX protein, human; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein