Redundancy of the cytokine network in the development of rejection after clinical heart transplantation.
We used reverse transcriptase-polymerase chain reaction analysis to study the effects of anti-rejection prophylaxis with an anti-interleukin (IL)-2 receptor (IL-2R) monoclonal antibody (BT563) on the allogeneic process by analyzing intragraft IL-2, IL-4, and IL-15 mRNA expression. Analysis showed an association between rejection and intragraft IL-2 mRNA and IL-4 mRNA transcription, whereas IL-15 was constitutively expressed: IL-2, 62% (8/13) during rejection versus 23% (8/35) during immunological quiescence (P < 0.01); IL-4, 69% versus 23% (P < 0.01). BT563 therapy influenced the intragraft mRNA expression of IL-2 and IL-4 but not of IL-15. In endomyocardial biopsies (EMB) showing rejection, mRNA expression of IL-2 was detectable in 40% (2/5) during BT563 treatment versus 75% (6/8) in the absence of BT563; for IL-4, 23% versus 88%, respectively. In contrast, IL-15 mRNA transcription was not affected. Quantitative analysis in rejection EMB showed comparable IL-15 mRNA levels during and after BT563 treatment. This study demonstrates that therapeutic intervention within the IL-2-dependent T-cell activation cascade does not completely prevent rejection. Other cytokines, such as IL-15, may participate in IL-2-independent rejections.
Baan
C C
CC
Department of Internal Medicine, University Hospital Rotterdam-Dijkzigt, The Netherlands. baan@inw1.azr.nl
Holweg
C H
CH
van Gelder
T
T
Knoop
C J
CJ
Niesters
H G
HG
Zondervan
P
P
Mochtar
B
B
Balk
A H
AH
Weimar
W
W
D001706:Biopsy; D015870:Gene Expression; D006084:Graft Rejection / Q000276:immunology* / Q000473:pathology; D016027:Heart Transplantation / Q000276:immunology*; D006801:Humans; D019409:Interleukin-15 / Q000096:biosynthesis* / Q000235:genetics; D007376:Interleukin-2 / Q000096:biosynthesis* / Q000235:genetics; D015847:Interleukin-4 / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis
D019409:Interleukin-15; D007376:Interleukin-2; D012333:RNA, Messenger; D015847:Interleukin-4