Anti-CD25 therapy reveals the redundancy of the intragraft cytokine network after clinical heart transplantation

C C Baan, C J Knoop, T van Gelder, C T Holweg, H G Niesters, T J Smeets, F van der Ham, P E Zondervan, L P Maat, A H Balk, W Weimar

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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.

Original languageEnglish
Pages (from-to)870-6
Number of pages7
JournalTransplantation
Volume67
Issue number6
Publication statusPublished - 27-Mar-1999
Externally publishedYes

Keywords

  • Antibodies, Monoclonal
  • Antigens, CD
  • Antigens, Differentiation, Myelomonocytic
  • Cytokines
  • Graft Rejection
  • Heart Transplantation
  • Humans
  • Interleukin-15
  • Interleukin-2
  • Receptors, Interleukin-2
  • Reverse Transcriptase Polymerase Chain Reaction

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