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

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

Research output: Contribution to journal › Article › Academic › peer-review

41 Citations (Scopus)

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 language	English
Pages (from-to)	870-6
Number of pages	7
Journal	Transplantation
Volume	67
Issue number	6
Publication status	Published - 27-Mar-1999
Externally published	Yes

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

Cite this

@article{9144068a8fe54050a8a73852bfe85600,

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.",

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",

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

year = "1999",

month = mar,

day = "27",

language = "English",

volume = "67",

pages = "870--6",

journal = "Transplantation",

issn = "0041-1337",

publisher = "LIPPINCOTT WILLIAMS & WILKINS",

number = "6",

}

Anti-CD25 therapy reveals the redundancy of the intragraft cytokine network after clinical heart transplantation. / Baan, C C; Knoop, C J; van Gelder, T; Holweg, C T; Niesters, H G; Smeets, T J; van der Ham, F; Zondervan, P E; Maat, L P; Balk, A H; Weimar, W.

In: Transplantation, Vol. 67, No. 6, 27.03.1999, p. 870-6.

Research output: Contribution to journal › Article › Academic › peer-review

TY - JOUR

T1 - Anti-CD25 therapy reveals the redundancy of the intragraft cytokine network after clinical heart transplantation

AU - Baan, C C

AU - Knoop, C J

AU - van Gelder, T

AU - Holweg, C T

AU - Niesters, H G

AU - Smeets, T J

AU - van der Ham, F

AU - Zondervan, P E

AU - Maat, L P

AU - Balk, A H

AU - Weimar, W

PY - 1999/3/27

Y1 - 1999/3/27

N2 - 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.

AB - 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.

KW - Antibodies, Monoclonal

KW - Antigens, CD

KW - Antigens, Differentiation, Myelomonocytic

KW - Cytokines

KW - Graft Rejection

KW - Heart Transplantation

KW - Humans

KW - Interleukin-15

KW - Interleukin-2

KW - Receptors, Interleukin-2

KW - Reverse Transcriptase Polymerase Chain Reaction

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M3 - Article

C2 - 10199736

VL - 67

SP - 870

EP - 876

JO - Transplantation

JF - Transplantation

SN - 0041-1337

IS - 6

ER -