The role of anti Interleukin-2Receptor monoclonal antibody - RePub

120 Pages·2010·2.17 MB·English

The role of anti Interleukin-2Receptor monoclonal
antibody (BT563) in the prevention of acute
rejection after organ transplantation.
Gelder, Teunis van
The role of anti Interleukin-2Receptor monoclonal antibody (BT563) in the prevention of
acute rejection after organ transplantation. / Teunis van Gelder - Rotterdam : Erasmus
Universiteit, afdeling Inwendige Geneeskunde I.
Thesis Erasmus University Rotterdam - With ref. - With summary in Dutch.
ISBN 90-9009361-3.
Subject headings: transplantation / inununosuppression / interleukin-2receptol'
Printed by Haveka B. V., Alblasserdam.
Copyright: T. van Gelder, Rotterdam, NL.
The role of anti Interleukin-2 Receptor
monoclonal antibody (8T563) in the
prevention of acute rejection after organ
transplantation.
De rol van monoclonale antilichamen gericht tegen de
Interleukine-2 Receptor (BT563) ter voorkoming van acute
afstoting na orgaantransplantatie.
Proefschrift
Ter verkrijging van de graad van doctor
aan de Erasmus Universiteit Rotterdam
op gezag van de Rector Magnificus Prof. Dr. P.W.C. Akkermans, M.A.
en volgens besluit van het college voor promoties.
De openbare verdediging zal plaatsvinden op
woensdag 15 mei 1996 om 15:45 uur.
door
Teunis van Gelder
geboren te Vlaardingen.
Promotiecommissie
Promotor : Prof. Dr. W. Weimar
Overige leden : Pro!. Dr. M.L. Simoons
: Prof. Dr. Th.H. van der Kwast
: Dr. A.J. Hoitsma
Gast referent : Prof. Dr. P. Neuhaus
Financial support for the publication of this thesis by Biotest Pharma, Astra Pharmaceutic a,
GlaxoWellcome Bayer Nycomed-Christiaens Pfizer, Zenee8, Roche, Janssen-Cilag and
t t l
Sandoz is gratefully acknowledged.
CONTENTS
List of abbreviations
Chapter 1 Anti Interleukin-2 Receptor monoclonal antibodies in organ
transplantation.
/Ilfrodllctioll
Chapter 2 In vitro effects of BT563, an anti Interleukin-2 Receptor monoclonal
antibody.
Trallsplant /lItematiollaIJ994;7(Sllppl J):S556-S558
Chapter 3 In vivo effects and pharmacodynamics of prophylactic antirejection
therapy with an anti Interleukin-2 Receptor monoclonal antibody
(BT563) after heart and kidney transplantation.
Transplallfatioll Proceedings 1995;27:856-868
/lIIl11l1nOphanllacol 1995;30:237-246
Chapter 4 A randomized trial comparing safety and efficacy of OKT3 and a
monoclonal anti Interleukin-2 Receptor antibody (BT563) in the
prevention of acute rejection after heart transplantation.
Trallsplallfatioll (in press)
Chapter 5 Intragraft monitoring of rejection following prophylactic treatment with
monoclonal anti Interleukin-2 Receptor antibody (BT563) in heart
transplant recipients.
Journal of Heart and Lung Transplantation 1995;14:346-350
Chapter 6 A double-blind, placebo-controlled study of monoclonal anti
Interleukin-2 Receptor antibody (BT563) administration to prevent acute
rejction after kidney transplantation.
Transplantation 1995;60:248-252
Chapter 7 Reversal of heart allograft rejection with monoclonal anti Interleukin-2
Receptor antibody.
Lancet 1992;339:873 (Lellet)
Chapter 8 Summary and conclusions
Chapter 9 Samenvatting en conclusies
Dankwoord
Curriculum vitae
List of abbreviations:
AP Alkaline Phosphatase
ATN acute tubular necrosis
CD Cluster of Differentiation
BSA bovine serum albumin
CIT Cold Ischemia Time
CMP cardiomyopathy
CMV cytomegalovirus
CsA cyclosporin-A
EBV Epstein-Barr Virus
EMB endomyocardial biopsy
FITC fluorescein isothiocyanate
GAM Goat anti Mouse
GVHD Graft-versus-Host-Disease
HAMA human antiwmouse antibodies
HTX heart transplantation
Ig Immunoglobuline
IL-2R Interleukin-2Receptor
ISHLT International Society for Heart and Lung Transplantation
kDa kiloDalton
MoAb Monoclonal Antibody
MLR Mixed Lymphocyte Reaction
PBS Phosphate Buffered Saline
PCR Polymerase Chain Reaction
PE phycoerythrin
PRA Panel Reactive Antibodies
r-ATG rabbit-AntiThymocyteGlobuline
RIA radioimmunoassay
RTX renal transplantation
SEM standard error of the mean
sIL-2R soluble Interleukin-2Receptor
TBS Tris Buffered Saline
TCR T-cell receptor

Chapter 1
Anti-IL2 Receptor monoclonal antibodies in organ transplantation
This chapter is a modified versioll of a revielV all this subject, published as "Anti
IL2Receptor mOlloc/ollal antibodies ill orgall trallsplalltatioll." ill Developments ill
Nephrology -Leidell; Boer/wave course 1995.
1.0 Introduction
Results of solid organ transplantation have improved steadily over the last
decades. However, both acute and chronic rejections are still frequently found.
Detailed single center studies have shown that the presence or absence of acute
rejection episodes is one of the most powerful predictors of chronic rejection
and late graft failure' 23. In order to reduce the incidence of acute rejection in
the immediate postoperative period and to promote long·term
hyporesponsiveness to donor allo-antigens, the use of induction therapy with
anti T-Iymphocyte antibodies has been widely promoted'. Especially OKT3, a
murine monoclonal anti-CD3 antibody, has been used for this reason in some
regimens with the additional advantage of delaying the requirement for
cyclosporin, thereby reducing the risk of nephrotoxicity' '. The use of OKT3,
however, has several limitations7: first dose reactions may be life-threatening'
(cytokine release syndrome' '0), the procoagulant-effect may lead to early
graft loss ", and infections 12 '3 and neoplasms 14 may complicate the
clinical course as a result of excessive immunosuppression. Polyclonal anti T
lymphocyte antibody preparations additionally have the problem of batch-to
batch variability and the risk of serum sickness 16.
To avoid the drawbacks of aselective immunosuppression of anti-pan T-cell
preparations, monoclonal antibodies against specific T-cell activation
determinants have been developed". Using monoclonal antibodies T-cell
responsiveness might be manipulated in an attempt to achieve donor-specific
tolerance17• Antibodies directed against specific molecules that are only
expressed after antigenic stimulation and involved in the early steps toward
clonal expansion of alia reactive precursors will only interfere with the resulting
antigen-committed cells. An example are the anti Interleukin-2Receptor
monoclonal antibodies".
1.1 Interleukin-2 and the Interleukin-2Receptor
In the seventies it was established that T-cells are the source of a substance
with mitogenic activity, sustaining long term T-cell growth19• The term "T-cell
growth factor,,20 was changed into interleukin-2, according to the international
10