Current Drug Targets - Cardiovascular & Haematological Disorders, Volume 5, Number 3, 2005
Contents
Fighting Antibody Mediated Rejection
Guest Editor: Robert Zhong
Editorial Pp.197-198
Robert Zhong
Pathological Features of
Antibody-Mediated Rejection Pp.199-214
Akira Shimizu
and Robert B. Colvin
Modulating Alloimmune
Responses with Plasmapheresis and IVIG Pp.215-222
Daniel S.
Warren, Christopher E. Simpkins, Matthew Cooper and Robert A. Montgomery
Targeting Antibody-Mediated
Rejection in the Setting of ABOIncompatible Infant Heart Transplantation: Graft
Accommodation vs. B Cell Tolerance Pp.223-232
Lori J. West
Antibody Mediated Rejection
in Pig-To-Nonhuman Primate Xenotransplantation Models Pp.233-253
Emanuele Cozzi,
Michela Severo, Erika Bosio, Federica Besenzon and Ermanno Ancona
Beyond Antibody-Mediated
Rejection: Hyperacute Lung Rejection as a Paradigm for Dysregulated
Inflammation Pp.255-269
Bao H. Nguyen,
Egon Zwets, Carsten Schroeder, Richard N. Pierson III and Agnes M. Azimzadeh
B Cell Tolerance: Lessons
from Transplantation Pp.271-275
Marilia
Cascalho
Abstracts
[Back to top] Editorial
Robert Zhong
Fighting Antibody Mediated
Rejection
The most difficult barrier to organ transplantation is humoral
rejection, a condition initiated by binding of antibodies to blood vessels in
the graft [1]. Although cellular rejection is common following transplantation,
this type of rejection can be effectively controlled by currently available
immunosuppressive agents [2]. In contrast, antibody mediated rejection is more
vigorous than cellular rejection and it is difficult to prevent by conventional
immunosuppression [3]. For example, antibody mediated rejection remains the
major problem in organ transplantation for highly sensitized patients and
recipients receiving ABO incompatible organs [4]. Antibody mediated rejection
has been also considered a major cause of chronic rejection [5]. Furthermore,
antibody mediated rejection has also been a major barrier for
xenotransplantation [6].
In this special issue, we have invited several experts in this field to
contribute a series of reviews on antibody mediated rejection. As a lead
article in this issue, Shimizu reviews pathological features of antibody
mediated rejection in both allotransplantation and xenotransplantation. He has
emphasized that microvascular injury is a characteristic feature of antibody
mediated rejection that develops in hyperacute, acute and chronic antibody
mediated rejection in both allografts and discordant xenografts. He also
reviews that endothelial cell activation and endothelial cell death in
microvasculature can contribute to ultimate graft loss by triggering capillary
destruction, interstitial hemorrhage, and platelet-rich microthrombi in
hyperacute and acute antibody mediated rejection as well with the formation and
progression of fibrotic scars in chronic antibody mediated rejection.
Next, Warren and his colleagues review two treatment strategies, which
have been developed to overcome antibody-mediated barriers to renal
transplantation, including donor specific anti-HLA and antiblood group
antibodies. These regimens rely on the immunomodulatory properties of
intravenous immunoglobulin (IVIG) administered alone at relatively high doses,
or at lower doses in combination with the non-selective depletion of antibodies
from plasmapheresis. They report that both protocols have been successfully
used for desensitization of patients with donor-specific anti-HLA antibody and
have allowed for renal transplantation with excellent outcomes. The combined
strategy of plasmapheresis/IVIG has also been successfully employed for renal
transplantation in recipients of ABO blood group incompatible kidneys.
Another important contribution in this issue has been made by West and
colleagues. They previously reported that the requirement for ABO compatibility
in heart transplantation is not applicable to infants. Here, they show that
ABO-incompatible heart transplantation during infancy results in the
development of B-cell tolerance to donor blood group A and B antigens. This
mimics animal models of neonatal tolerance and indicates that the human infant
is susceptible to intentional tolerance induction.
Xenotransplantation has been an increasingly important issue over the
decade as the organ shortage has continued to expand. Antibody mediated
mechanisms are central to the rejection that occurs when pig organs are
transplanted into primates. In this issue, Cozzi and colleagues review the
histopathological features of the humoral rejection process in a
pig-to-non-human primate model. They demonstrate that antibodies against
Gala1-3a (Gal) antigen or non-Gal antigens play an essential role in initiation
of hyperacute rejection as well as acute vascular rejection in this model. They
also report the recent progress in the development of transgenic pigs with
human complement regulatory molecules as well as Gal knock-out pigs.
Nguyen and colleagues further review hyperacute rejection following
lung xenotransplantation. They believe that hyperacute rejection (HAR)
following lung xenotransplantation is beyond antibody mediated rejection. They
further review recent progress in the development of specific strategies to
overcome lung HAR through production of genetically engineered pig organs,
modification of host innate immunity, control of antibody and complements, as
well as targeting coagulation cascade in HAR.
The final contribution from Cascalho reviews the fundamental mechanisms
of B cell tolerance that operate in development and direct the reader for
possible mechanisms explaining how B cell tolerance fails to develop following
transplantation. The answers to these questions would be counted among the
important contributions of transplantation to the field of immunology.
In summary, fully understanding the mechanisms of antibody mediated
rejection and B cell tolerance are essential to develop novel strategies to
overcome antibody mediated rejection and induce tolerance. I hope the readers
will enjoy this issue.
[Back to top] Pathological Features of
Antibody-Mediated Rejection
Akira Shimizu
and Robert B. Colvin
Although cell-mediated rejection has remained the most common form of
graft rejection after organ transplantation, antibody-mediated rejection has
recently gained much significance in clinical transplantation. New evidence
points to an antibody-mediated rejection contributing not only to hyperacute
and acute but also to chronic allograft rejection. In addition, in discordant
xenotransplantation, severe forms of antibody-mediated rejection, including
hyperacute rejection and acute humoral xenograft rejection, represent major
immunological barriers to successful xenotransplantation. Antibody-mediated
rejection in both allotransplantation and xenotransplantation typically does
not respond to conventional anti-rejection therapy, so it has recently been
recognized as a major cause of graft loss. Histopathology remains the most
definitive and reliable tool for the diagnosis of graft rejection in both
allografts and xenografts. In this review, we discuss the concept that
microvascular injury is a characteristic feature of antibodymediated rejection
that develops in hyperacute, acute and chronic antibody-mediated rejection in
both allografts and discordant xenografts as well as in kidney and heart
grafts. We also review work indicating that endothelial cell activation and
endothelial cell death in the microvasculature can contribute to ultimate graft
loss by triggering capillary destruction, interstitial hemorrhage, and
platelet-rich microthrombi in hyperacute and acute antibody-mediated rejection
as well as with the formation and progression of fibrotic scars in chronic
antibody-mediated rejection.
[Back to top] Modulating Alloimmune Responses
with Plasmapheresis and IVIG
Daniel S.
Warren, Christopher E. Simpkins, Matthew Cooper and Robert A. Montgomery
Antibody-mediated barriers to renal transplantation, including donor
specific anti-HLA and anti-blood group antibodies, have become an increasingly
important issue over the last forty years as the organ shortage has continued
to expand. The inevitable result of the unmet demand for compatible organs has
been a continuous increase in recipient waiting times. Over the last decade,
two treatment strategies have been developed to address this problem. These
regimens rely on the immunomodulatory properties of intravenous immunoglobulin
(IVIG) administered alone at relatively high doses, or at lower doses in
combination with the non-selective depletion of antibodies from plasmapheresis.
Both protocols have been successfully used for desensitization of patients with
donor-specific anti-HLA antibody and have allowed for renal transplantation
with excellent outcomes. The combined strategy of plasmapheresis/IVIG has also
been successfully employed for renal transplantation in recipients of ABO blood
group incompatible kidneys. This review will provide an overview of these
therapies and their application to incompatible renal transplantation.
[Back to top] Targeting Antibody-Mediated
Rejection in the Setting of ABOIncompatible Infant Heart Transplantation: Graft
Accommodation vs. B Cell Tolerance
Lori J. West
In order for ABO-incompatible organ transplantation to be performed
successfully, the antibody response must be targeted. Aggressive strategies are
usually required both to remove pre-existing antibodies directed at donor A/B
antigens and to suppress further production of antibodies. If this can be
accomplished in the short-term, graft accommodation of ABO-incompatible
transplants may develop upon eventual re-accumulation of antibodies as the
graft acquires resistance to antibody-mediated damage. In contrast to mature
individuals, very young infants lack isohemagglutinins due to a natural lag in
development of immunity to T cell-independent polysaccharide antigens. This
delay in maturation permits a window of safety during which infants can receive
ABO-incompatible grafts without the requirement for aggressive
immunosuppressive strategies. We have recently demonstrated that
ABO-incompatible heart transplantation performed during this stage of
immaturity is followed by the spontaneous development of donor-specific B cell
tolerance rather than graft accommodation, and that tolerance in this setting
occurs by a cellular mechanism of antigen-specific B cell elimination. This
finding is strikingly similar to the original descriptions of neonatal T cell
tolerance in mice. Our data provide compelling justification that every effort
should be made to include juvenile recipients routinely as subjects in
tolerance research. Through understanding the mechanisms underlying tolerance
in this setting, as with murine models of neonatal tolerance originally
described by Medawar and colleagues, it may be possible to expand the potential
applications of tolerance strategies to older patient populations.
[Back to top] Antibody Mediated Rejection in Pig-To-Nonhuman
Primate Xenotransplantation Models
Emanuele Cozzi,
Michela Severo, Erika Bosio, Federica Besenzon and Ermanno Ancona
Antibody-mediated mechanisms are central to the rejection that occurs
when pig organs are transplanted into primates. In this article, the
histopathological features of the humoral rejection process in these species
combinations, namely hyperacute rejection and acute humoral xenograft
rejection, will be illustrated. The profile of the natural and elicited
antibodies involved will also be discussed. It has now been demonstrated that
the natural immune response to a porcine xenograft is primarily directed to Gala1-3Gal (aGal)
specificities, whilst the elicited immune response is directed to both aGal and non-aGal
antigens. The principal characteristics of anti-aGal,
anti-non-aGal and polyreactive antibodies will be
described, together with the identification of the molecules recognised by
natural and elicited xenoreactive antibodies. The role of the humoral immune
response in the rejection of porcine islets in the primate is still uncertain
and the current views on the subject will be discussed. Finally, a concise but
comprehensive review of the different strategies that have been attempted to
prevent the onset of antibody-mediated rejection is presented. These strategies
encompass approaches aimed at interfering with the binding of xenoreactive
antibodies with their targets, the use of conventional or novel
immunosuppressants and splenectomy. It is undeniable that significant progress
has been recently achieved in understanding the humoral rejection process of
pig organs transplanted into primates. It is expected that a more comprehensive
elucidation of the mechanisms underlying accommodation and tolerance may, in
the not too distant future, further extend survival of pig organs transplanted
into primates.
[Back to top] Beyond Antibody-Mediated
Rejection: Hyperacute Lung Rejection as a Paradigm for Dysregulated
Inflammation
Bao H. Nguyen, Egon Zwets, Carsten Schroeder, Richard N. Pierson III and Agnes M. Azimzadeh
The use of animal organs for transplantation in humans is seen as a
potential solution to the short supply of human donor organs available for
clinical transplantation. However, to develop this therapeutic option as
clinical reality will require surmounting formidable obstacles. The primary
immunologic barrier to pig-to-human xenotransplantation is hyperacute rejection
(HAR), a phenomenon previously characterized as resulting from antibody binding
and complement activation. This article will first review recent progress in
the development of specific strategies to overcome hyperacute lung rejection
(HALR), through production of genetically engineered pig organs, modification
of the host innate immunity and control of antibody and complement. Additional
therapeutic targets identified in HALR are reviewed, with particular emphasis
on recent studies describing a critical role for the coagulation cascade in
HAR.
[Back to top] B Cell Tolerance: Lessons
from Transplantation
Marilia Cascalho
Given the ability of the B cell compartment to acquire tolerance to
self we cannot explain why spontaneous humoral tolerance does not arise
following transplantation. Here we review the fundamental mechanisms of B cell
tolerance that operate in development and direct the reader to possible
mechanisms that may explain how B cell tolerance fails to develop following
transplantation.