title: Mechanisms of rejection during OKT3 therapy: propagation and characterization of CD3 resistant allospecific cytotoxic T cells from a rejecting liver allograft.
abstract: Allograft rejection remains the single largest impediment to success in the field of transplantation. While OKT3 therapy has proven to be a significant advancement, many grafts are still lost. Late treatment, subtherapeutic OKT3 levels, anti-OKT3 antibodies, and OKT3-induced class II antigen expression are possible explanations. To determine the mechanism of OKT3 resistant rejection we propagated and characterized infiltrating T cells from the biopsy of a liver transplant patient who was rejecting while on prophylactic OKT3. The T lymphocytes demonstrated allospecific proliferation and interleukin 2 (IL2) production and showed a high degree of cytolysis of donor splenocytes. CD3 epsilon monoclonal antibodies (Mab) in concentrations up to 100 micrograms/ml did not inhibit lysis. In contrast, T lymphocytes derived from rejecting allografts of patients receiving cyclosporine and prednisone were readily inhibited from killing by CD3 epsilon Mab at doses of 1 microgram/ml. Furthermore, allospecific proliferation and IL2 production were not inhibited in the OKT3-treated patient by the addition of CD3 epsilon MaB. Incomplete modulation of the CD3-TCR complex was noted after a 72-hr incubation with CD3 epsilon Mab. The T cells did demonstrate other intact CD3-mediated functions such as a rise in intracellular calcium and CD3-dependent cytotoxicity. These results should alert clinicians that CD3 resistant cytotoxic T cells can emerge during OKT3 therapy and may cause rejection. Immunotherapy that targets additional cell surface structures may be of benefit.
authors.affiliation: John P. Robarts Research Institute, Department of Surgery, University Hospital, London, Ontario, Canada.
authors.forename: F R
authors.initials: FR
authors.lastname: Sutherland
authors.forename: M
authors.initials: M
authors.lastname: Aboujaoude
authors.forename: M J
authors.initials: MJ
authors.lastname: White
authors.forename: J
authors.initials: J
authors.lastname: Yamada
authors.forename: C
authors.initials: C
authors.lastname: Ghent
authors.forename: D
authors.initials: D
authors.lastname: Grant
authors.forename: W
authors.initials: W
authors.lastname: Wall
authors.forename: B
authors.initials: B
authors.lastname: Garcia
authors.forename: R
authors.initials: R
authors.lastname: Mazaheri
authors.forename: A I
authors.initials: AI
authors.lastname: Lazarovits
mesh_terms: D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D015703:Antigens, CD / Q000276:immunology*; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology*; D017252:CD3 Complex; D003602:Cytotoxicity, Immunologic; D006084:Graft Rejection; D006801:Humans; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014184:Transplantation, Homologous
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D017252:CD3 Complex; D011948:Receptors, Antigen, T-Cell