title: Anti-CD25 therapy reveals the redundancy of the intragraft cytokine network after clinical heart transplantation.
abstract: BACKGROUND
  Despite blockade of the interleukin-2/interleukin 2 receptor (IL-2/IL-2R) pathway by the murine anti-CD25 (i.e., IL-2R alpha chain) monoclonal antibody BT563, cardiac rejection can still occur. In these cases, growth factors other than IL-2 may contribute to allograft rejection. We studied the expression of IL-15, a macrophage-derived cytokine associated with T-cell activation, which interacts with the beta and gamma chains of the IL-2R during rejection episodes under anti-CD25 therapy.
  
  
  METHODS
  We measured intragraft IL-15 mRNA expression and the number of IL-15- and CD68-positive cells in posttransplantation endomyocardial biopsies (EMBs; n=45) and in nontransplanted, donor-heart specimens (n=11) by competitive template reverse transcription-polymerase chain reaction and immunohistochemistry, respectively.
  
  
  RESULTS
  IL-15 mRNA expression was present in the majority of posttransplantation EMB specimens (91%, 41/45) and in nontransplanted donor-heart specimens (91%, 10/11). Relative IL-15 mRNA levels were neither associated with transplantation nor with rejection status. After transplantation, the number of IL-15- and CD68-positive cells significantly increased (P<0.001), but IL-15-positive cell counts did not reflect the histological rejection grade. Anti-CD25 treatment, in contrast to its effects on the IL-2/IL-2R complex, had no influence on intragraft IL-15 mRNA and protein production. In rejection EMB specimens, during (n=5) and after (n=8) anti-CD25 therapy, no differences in relative IL-15 mRNA levels, or in IL-15- and CD68-positive cell counts, were measured.
  
  
  CONCLUSIONS
  After heart transplantation, high numbers of IL-15- and CD68-positive cells infiltrate the graft. This phenomenon is independent of the rejection status. IL-15 remains present during blockade of the IL-2/IL-2R pathway by anti-CD25 monoclonal antibodies, and it may participate in T cell-dependent donor-directed immune responses, thereby explaining the occurrence of rejection in the absence of IL-2.
authors: Department of Internal Medicine I, University Hospital Rotterdam-Dijkzigt, The Netherlands. baan@inw1.azr.nl
authors: C C
authors: CC
authors: Baan
authors: C J
authors: CJ
authors: Knoop
authors: T
authors: T
authors: van Gelder
authors: C T
authors: CT
authors: Holweg
authors: H G
authors: HG
authors: Niesters
authors: T J
authors: TJ
authors: Smeets
authors: F
authors: F
authors: van der Ham
authors: P E
authors: PE
authors: Zondervan
authors: L P
authors: LP
authors: Maat
authors: A H
authors: AH
authors: Balk
authors: W
authors: W
authors: Weimar
mesh_terms: D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D015703:Antigens, CD / Q000032:analysis; D015214:Antigens, Differentiation, Myelomonocytic / Q000032:analysis; D016207:Cytokines / Q000096:biosynthesis*; D006084:Graft Rejection; D016027:Heart Transplantation / Q000276:immunology*; D006801:Humans; D019409:Interleukin-15 / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis; D015375:Receptors, Interleukin-2 / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000097382:CD68 Molecule
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D016207:Cytokines; D019409:Interleukin-15; D007376:Interleukin-2; D015375:Receptors, Interleukin-2; C067980:CD68 antigen, human; D000097382:CD68 Molecule