title: Activation-induced T cell death, and aberrant T cell activation via TNFR1 and CD95-CD95 ligand pathway in stable cardiac transplant recipients.
abstract: Specific blockade by antibodies (Abs) utilized in induction therapy may cause activation-induced cell death (AICD) in lymphocytes of transplant recipients, preactivated via CD95 and tumour necrosis factor-alpha receptor type 1 (TNFR1), and reduce allograft rejection frequency. Amongst 618 heart transplant (HTX) patients receiving antithymocytes globulin (ATG) therapy, 14 recipients with IVUS-verified freedom of transplant vasculopathy were studied. The control group contained 14 patients awaiting transplantation, classified by the New York Hearth Association heart failure as class IV. From 618 HTX patients 89% were free of rejection grade ISHLT > or =2-3 within 3-month post transplantation and 86% after one year. The death inducing receptors (DIR) such as CD95, CD95L and soluble TNFR1 were significantly increased in HTX recipients versus controls, as demonstrated by FACS, immunoblotting or ELISA (P < 0.001). The presence of increased DIR and in vivo apoptosis in HTX recipients, indicated by annexin-V binding, was further confirmed by the presence of high concentration of histones in the sera of patients. ATG, anti-IL-2R and OKT-3 Abs inhibited cell proliferation in a dose-dependent manner. The induction of apoptosis and/or necrosis was demonstrated in cells cultured with these Abs by annexin-V and 7-aminoactinomycin staining, respectively. Our findings demonstrate that T cells from HTX recipients express high level of CD95, CD95L and soluble TNFR1, and undergo apoptosis and AICD. These cells recognizing donor alloantigens may be selectively eliminated in vivo, and should be responsible for the observed immunological unresponsiveness, indicated by low rejection rates in our patient cohort treated by conventional triple therapy.
authors: Department of Surgery, General Hospital of Vienna University, Vienna, Austria. hjankersmit@hotmail.com
authors: H J
authors: HJ
authors: Ankersmit
authors: B
authors: B
authors: Moser
authors: A
authors: A
authors: Zuckermann
authors: G
authors: G
authors: Roth
authors: S
authors: S
authors: Taghavi
authors: M
authors: M
authors: Brunner
authors: E
authors: E
authors: Wolner
authors: G
authors: G
authors: Boltz-Nitulescu
mesh_terms: D000328:Adult; D017304:Annexin A5 / Q000378:metabolism; D000906:Antibodies / Q000494:pharmacology; D015703:Antigens, CD / Q000378:metabolism; D000961:Antilymphocyte Serum / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis; D002478:Cells, Cultured; D053222:Fas Ligand Protein; D006084:Graft Rejection / Q000188:drug therapy; D016027:Heart Transplantation / Q000276:immunology* / Q000473:pathology; D006657:Histones / Q000097:blood; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000378:metabolism*; D016853:Muromonab-CD3 / Q000494:pharmacology; D015375:Receptors, Interleukin-2 / Q000037:antagonists & inhibitors / Q000276:immunology; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D047888:Receptors, Tumor Necrosis Factor, Type I; D012189:Retrospective Studies; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology*; D019014:fas Receptor / Q000378:metabolism
chemical_list: D017304:Annexin A5; D000906:Antibodies; D015703:Antigens, CD; D000961:Antilymphocyte Serum; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D006657:Histones; D007166:Immunosuppressive Agents; D008562:Membrane Glycoproteins; D016853:Muromonab-CD3; D015375:Receptors, Interleukin-2; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D019014:fas Receptor