Anti-CD25 therapy reveals the redundancy of the intragraft cytokine network after clinical heart transplantation.
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.
Baan
C C
CC
Department of Internal Medicine I, University Hospital Rotterdam-Dijkzigt, The Netherlands. baan@inw1.azr.nl
Knoop
C J
CJ
van Gelder
T
T
Holweg
C T
CT
Niesters
H G
HG
Smeets
T J
TJ
van der Ham
F
F
Zondervan
P E
PE
Maat
L P
LP
Balk
A H
AH
Weimar
W
W
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
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