title: Processing-dependent and -independent pathways for recognition of iodinated contrast media by specific human T cells.
abstract: BACKGROUND
  One to three percent of patients exposed to intravenously injected iodinated contrast media (CM) develop delayed hypersensitivity reactions. Positive patch test reactions, immunohistological findings, and CM-specific proliferation of T cells in vitro suggest a pathogenetic role for T cells. We have previously demonstrated that CM-specific T cell clones (TCCs) show a broad range of cross-reactivity to different CM. However, the mechanism of specific CM recognition by T cell receptors (TCRs) has not been analysed so far.
  
  
  OBJECTIVE
  To determine how T cells specifically recognize CM.
  
  
  METHODS
  CM-specific TCCs were generated from human blood of three CM-allergic patients and a specific TCR was transfected into a mouse T cell hybridoma. Functional analysis such as proliferation assays, IL-2 secretion assays, and calcium influx experiments were performed using irradiated, glutaraldehyde-fixed, CM-pre-incubated, human leucocyte antigen (HLA)-DR-matched or -mismatched antigen-presenting cells (APCs), and HLA-blocking antibodies.
  
  
  RESULTS
  We identified two mechanisms of T cell stimulation: some TCCs and the transfectant reacted to CM independent of uptake by APCs because proliferation/IL-2 secretion occurred in the presence of glutaraldehyde-fixed APCs, and intracellular calcium increased within seconds after drug addition. Other TCCs required functional APCs, compatible with uptake and presentation of CM on MHC-class II molecules, as implied by three findings: (1) glutaraldehyde fixation of APCs abrogated presentation; (2) CM could not be washed away from CM-pre-incubated APCs; and (3) the optimal pulsing time was 10-20 h. Because allogeneic, MHC-matched, CM-pulsed APCs could induce proliferative responses as well, the ability of CM uptake and presentation is not unique to APCs from patients with CM-induced delayed hypersensitivity.
  
  
  CONCLUSIONS
  Our data suggest that CM may be stimulatory for T cells either by direct binding to the MHC-TCR complex or by binding after uptake and processing by APCs. This questions the assumed inert nature of CM.
authors.affiliation: Adverse Drug Reactions - Analysis and Consulting (ADR-AC) GmbH, Bern, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Keller
authors.forename: M
authors.initials: M
authors.lastname: Lerch
authors.forename: M
authors.initials: M
authors.lastname: Britschgi
authors.forename: V
authors.initials: V
authors.lastname: Tâche
authors.forename: B O
authors.initials: BO
authors.lastname: Gerber
authors.forename: M
authors.initials: M
authors.lastname: Lüthi
authors.forename: P
authors.initials: P
authors.lastname: Lochmatter
authors.forename: G
authors.initials: G
authors.lastname: Kanny
authors.forename: A J
authors.initials: AJ
authors.lastname: Bircher
authors.forename: C
authors.initials: C
authors.lastname: Christiansen
authors.forename: W J
authors.initials: WJ
authors.lastname: Pichler
mesh_terms: D000368:Aged; D000818:Animals; D002118:Calcium / Q000276:immunology; D049109:Cell Proliferation; D003287:Contrast Media / Q000009:adverse effects*; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000139:chemically induced* / Q000276:immunology*; D007376:Interleukin-2 / Q000378:metabolism; D008297:Male; D051379:Mice; D008875:Middle Aged; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*
chemical_list: D003287:Contrast Media; D000949:Histocompatibility Antigens Class II; D007376:Interleukin-2; D011948:Receptors, Antigen, T-Cell; D002118:Calcium