Humoral Theory of Transplantation:
Mechanism, Prevention, and Treatment
Junchao Cai and Paul I. Terasaki
ABSTRACT: We discuss the potential mechanisms of
antibody-induced primary endothelium injury, which in-
cludes complement-dependent pathway (membrane attack
complex formation, recruitment of inflammatory cells, and
complement-complement receptor-mediated phagocytosis)
and complement independent pathway antibody-dependent
cell cytotoxicity. Secondary to endothelium injury, the fol-
lowing pathological reactions are found to be responsible for
progressive tissue injury and final graft function loss: plate-
let activation and thrombosis, pathological smooth muscle
and endothelial cell proliferation, and humoral and/or cel-
lular infiltrate-mediated parenchyma damage after endothe-
lium injury. We also introduce three categories of thera-
peutic strategy in the prevention and treatment of antibody-
mediated rejection: (1) inhibition and depletion of antibody
producing cells (immunosuppressants, antilymphocyte an-
tibodies, splenectomy); (2) removal or blockage of preexist-
ABBREVIATIONS
HLA human leukocyte antigen
MIC major histocompatibility complex class Irelated
chain
INTRODUCTION
We have reviewed accumulated evidence regarding the
role of antibody in graft injury [1]. Antibodies are
associated with hyperacute, acute, and chronic rejection
[2]. In a prospective trial, it has already been found
that by using antibody screening tests with flow cy-
tometry or enzyme-linked immunosorbent assay, about
14%23% of transplant recipients with functioning
grafts have detectable human leukocyte antigen (HLA)
antibodies [3]. Within a 1-year follow-up period, 21
(8.6%) of 244 antibody-positive patients experienced
graft rejection, which is significantly higher than that
found in the HLA antibodynegative patient group
(43/1421 100% 3%, p 0.00003). These data
suggest that some transplants may still function well in
the presence of alloantibodies, which might be because
From the Terasaki Foundation Laboratory, Los Angeles, CA, USA.
Address reprint requests to: Dr. Paul I. Terasaki, Terasaki Foundation
Laboratory, 11570 W Olympic Blvd., Los Angeles, CA 90064; Tel: (310)
479-6101 ext 104; Fax: (310) 445-3381; E-mail: terasaki@
terasakilab.org.
Received October 19, 2004; accepted January 19, 2005.
Human Immunology 66, 334 342 (2005)
American Society for Histocompatibility and Immunogenetics, 2005
Published by Elsevier Inc.
ing or newly developed antibodies (immunoadsorption,
plasmapheresis/plasma exchange, intravenous immunoglob-
ulin); and (3) impediment or postponement of antibody-
mediated primary and secondary tissue injury (anticoagula-
tion, glucosteroids). In conclusion, because alloantibodies
have destructive effect on allografts, alloantibody monitor-
ing becomes extremely important. It will help clinicians to
determine a patients humoral responses against allograft
and will therefore direct clinicians to optimize and/or min-
imize immunosuppressive drug therapy. Human Immu-
nology 66, 334 342 (2005). American Society for His-
tocompatibility and Immunogenetics, 2005. Published by
Elsevier Inc.
KEYWORDS: HLA antibody; antibody monitoring; al-
lograft; antibody-mediated rejection; chronic rejection
PE plasma exchange
PPH plasmapheresis
of the compensational reactions of the transplanted
organ to tissue injury. However, the graft may finally
be rejected when the tissue repair system can not fully
compensate for the antibody-mediated injury. This
damage-repair-damage process could take years to re-
sult in irreversible graft loss. This hypothesis has been
supported by the study of Lee et al., who found that in
some patients, it took many years for antibody-positive
transplants to finally be rejected [4].
Why are some transplants rejected sooner and other
transplants rejected later, after the presence of alloanti-
bodies is found in the periphery blood? In this review, we
discuss how antibody causes graft rejection after it binds
to its target and how to prevent and treat antibody-
mediated rejection.
MECHANISM OF HUMORAL REJECTION
Endothelial CellThe Primary Target of Antibody
Among cellular and humoral immunologists, there is
limited debate that the endothelium of transplanted
0198-8859/05/$see front matter
doi:10.1016/j.humimm.2005.01.021
Humoral Theory of Transplantation
organs serve as the primary target of patient immune
responses. In the humoral theory of organ transplanta-
tion, the endothelium of a donor organ is primarily
targeted by alloantibody, either preexisting or developed
de novo after transplant [515].
Primary Effects of Antibody-Antigen Interaction
As proposed here and shown in Figure 1.1 4, binding of
antibodies to antigens on endothelial cells can finally
cause endothelium damage via four distinct pathways.
Damage of endothelium can be mediated directly by
complement via forming membrane attack complex [16]
(Figure 1.2) or inflammatory cells recruited by soluble
complement fragments [17, 18] (Figure 1.1), or by
phagocytes that recognize complement fragments depos-
ited on endothelial cells via a complement receptor [19]
(Figure 1.3). These three pathways are complement de-
pendent. The finding of complement C4d in graft cap-
illaries provided strong evidence to support this comple-
ment-dependent hypothesis [20]. However, it is also
possible that after antibody binds to its target antigen on
the surface of the endothelial cell, antibody-dependent
cell cytotoxicity may play a role in mediating endothe-
lium damage without the involvement of complement
[2124] (Figure 1.4).
Secondary Effects After Endothelium Injury
Secondary pathological changes after endothelium damage
include platelet activation and thrombosis, endothelial and
smooth muscle cell proliferation, and humoral and/or cel-
lular infiltrates mediated direct organ/tissue damage (Fig-
ure 1AD). Hyperacute rejection, the best documented
example of antibody-mediated rejection, is mediated by
preexisting antibodies (e.g., anti blood group antigen A or
B antibodies, or anti-HLA antibodies) that bind to endo-
FIGURE 1 Mechanisms of antibody-mediated transplant
rejection.
335
thelium and activate complement. Antibody binding and
complement activation induce a series of pathological
changes in the graft endothelium that promote intravas-
cular thrombosis. Endothelial cells are stimulated to se-
crete von Willebrand factor that mediates platelet adhe-
sion and aggregation. Complement activation leads to
endothelial cell injury and exposure of subendothelial base-
ment membrane proteins that activate platelets. These
series processes contribute to thrombosis and vascular oc-
clusion; therefore, the organ suffers irreversible ischemic
damage (Figure 1A).
We know that the rapid progress of antibody-mediated
hyperacute rejection is related to a large amount of preex-
isting alloantibodies and it usually happens in ABO-in-
compatible or presensitized patients. However, in current
transplant clinics, transplantation is performed primarily
in ABO-compatible, low-sensitized patients; moreover,
highly effective immunosuppressive drug therapies are
widely used in transplant recipients. Therefore, unlike
hyperacute rejection, acute or chronic graft function loss
might not result mainly from thrombosis-related rapid
vascular occlusion. Instead, they are most likely due to a
progressive damage-repair-damage pathological process.
As found in chronic rejection, which is manifested as
atherosclerosis of the vessels of the transplanted organ, the
intimal thickening is the result of the proliferative effects
of anti-HLA antibodies (Figure 1B,C) [25]. It is also a
possibility that after endothelium injury, humoral and/or
cellular infiltrates can directly cause organ parenchyma
damage (Figure 1D). This direct parenchyma injury also
follows the law of quantitative change to qualitative
change. The process speed of any potential pathological
changes after endothelium injury depends on the following
three major factors: the level of alloantibodies; the capa-
bility of transplanted organ tissue repair; and immunosup-
pressive and other supportive therapy.
The first factor is the level of alloantibodies. In ABO-
compatible transplantation, there was considerable vari-
ation in antibody titers against blood group antigens
[26]. Recipients with higher antibody titers against
blood group antigens had a much higher incidence of
early graft failure [27, 28]. In ABO-compatible trans-
plantation, there was a significant stepwise decrease in
graft outcome with increasing levels of sensitization.
Patients with less than 10% panel-reactive antibodies
had a significantly longer half-life than patients with
higher levels of sensitization [29]. These data suggested
that graft outcome is strongly associated with the alloan-
tibody level. High levels of antibodies result in more
irreversible rejection. These data also implied that in
lower sensitized patients, because of the lower levels of
preexisting antibodies, the rejection process is slower,
but the transplanted graft may finally be rejected when
336 J. Cai and P.I. Terasaki

TABLE 1 Prevention and treatment of antibody-mediated rejection

No. Categorya Treatment Major mechanism

1 I Cyclosporin A Indirectly inhibit B cell proliferation secondary to reduced cytokine

production by T cells
2 I Tacrolimus (FK506) Indirectly inhibit B cell proliferation secondary to reduced cytokine
production by T cells
3 I Rapamycin (sirolimus) Indirectly inhibit B cell proliferation secondary to reduced cytokine
production by T cells
4 I Azathioprine Inhibit DNA synthesis in dividing cells (T,B and other dividing cells)
5 I Cyclophosphamide Inhibit DNA synthesis in dividing cells (T,B and other dividing cells)
6 I Mycophenolate mofetil (MMF) Inhibit DNA synthesis in dividing cells (mainly T and B cells)
7 I Rituximab AntiCD-20 (B cell surface marker) mAb, deplete B cells
8 I OKT3 Anti-CD3 (T-cell surface marker) antibody, indirectly inhibit B-cell
proliferation
9 I Anti-thymocyte globulin (ATG) and anti- Directly deplete or indirectly inhibit B cells
lymphocyte globulin (ALG)
10 I Campath-1H Anti-CD52 (surface marker of thymocytes, T, B cells, etc.), direct
deplete B cells
11 I Splenectomy Surgically remove lymphocyte-producing organ (both B and T)
12 II Immunoadsorption Remove antibody from periphery (blood group antigen-, protein A- or
anti-human Ig antibody-coated columns)
13 II Plasmapheresis (PPH) or plasma exchange (PE) Remove antibodies and other humoral factors (complements,
cytokines, etc.) from periphery
14 II Intravenous immunoglobulin (IVIG) Anti-idiotypic effects (blocking of the antigen-binding cites of anti-
donor antibodies) and others
15 III Anticoagulation therapy Inhibit the formation of clot (Figure 1A)
16 III and I Glucocorticoid Anti-inflammatory effects (Figure 1.1 and D), B-cell apoptosis
a
I inhibition and depletion of antibody-producing cells; II removal or blocking of preexisting or newly developed antibodies; III impediment or
postponement of antibody-mediated primary and secondary tissue injury.

a majority of parenchyma are affected and cannot be
compensated by tissue repair.
The second factor is the capability of transplanted
organ tissue repair. This is the major mechanism to
impede or postpone the development of rejection; but
this regeneration capability is tissue dependent. Some
tissue cells have the capacity to regenerate after injury
(e.g., endothelial cells, renal tubular cells, hepatocytes),
but other cells, such as myocardial cells, cannot regen-
erate and are usually replaced by scar tissue (typically
fibrosis) after irreversible injury and cell loss. Also, there
should be an awareness that uncontrolled tissue repair
sometimes becomes a risk factor that accelerates the
rejection process (Figure 1B,C) [25].
The third factor is immunosuppressive and other sup-
portive therapy. Different immunosuppressants many have
different effects on inhibition of antibody development [3];
therefore, they affect graft survival [30, 31]. For example,
as previously discussed, the major characteristics of anti-
body-mediated hyperacute rejection are antibody/comple-
ment-mediated endothelium injury and activated platelet-
mediated thrombosis and vascular occlusion. On the basis
of the hypothesis that preventing clot formation may post-
pone graft rejection, anticoagulation therapy was used in
transplant clinics [3235]. Recently, in combination with
other antibody depletion or suppression treatments, anti-
coagulation therapy successfully reduced hyperacute/acute
rejection episodes and enabled ABO-incompatible trans-
plantation to become feasible and reach satisfying long-
term graft survivals [36].
PREVENTION AND TREATMENT OF
HUMORAL REJECTION
Therapeutic strategies to prevent and treat antibody-
mediated rejection include: (1) inhibition and depletion
of antibody producing cells; (2) removal or blockage of
preexisting or newly developed antibodies; and (3) im-
pediment or postponement of antibody-mediated pri-
mary and secondary tissue injury.
Inhibition or Depletion of
Antibody-Producing Cells
This strategy is etiotropic. B cells, or more precisely,
plasma cells, are the main antibody-secreting cells of the
body. Therefore, to prevent and/or treat antibody-medi-
ated humoral rejection, inhibition or depletion of anti-
body producing cells becomes extremely important (Ta-
ble 1.111).
Primary immunosuppressants. Generally speaking, almost
all currently used immunosuppressive drugs have direct
Humoral Theory of Transplantation
or indirect effects in inhibiting/depleting B cells. The
most commonly used primary agents of maintenance
immunosuppression, such as cyclosporine A, FK506 (ta-
crolimus), and rapamycin (sirolimus), are powerful im-
munosuppressants that interfere with T-cell signaling.
The successful prolongation of graft survival by using
these agents has misled many clinicians and some im-
munologists into thinking that T cell is the only player
that causes graft rejection. However, because many al-
loantigens eliciting antibody responses are proteins (e.g.,
HLA, major histocompatibility complex class Irelated
chain [MIC]) and antibody responses to protein antigens
require antigen-specific T-cell help, T-cell targeting
agents not only prevent T-cell but also antibody (B
cell)-mediated immune responses. This mechanism ex-
plains why these primary agents can be used alone or in
combination with other therapies to treat antibody-me-
diated humoral rejection [3739] (Table 1.13).
Adjunct immunosuppressants. Unlike primary immunosup-
pressive agents, which block T-cell signaling and indi-
rectly inhibit proliferation of B cell secondary to reduced
cytokine production by T cell, adjunctive immunosup-
pressants interfere with DNA synthesis and have their
major pharmacological action on dividing tissues [40
42]. Hence, these agents, including azathioprine, cyclo-
phosphamide, mycophenolate mofetil (MMF), have di-
rect inhibitory effects on B cell, an active dividing tissue
cell. It is notable that because of its role in targeting the
de novo purine biosynthesis pathway, mycophenolates can
inhibit human lymphocytes (B and T cells) more specif-
ically and efficiently than other cell types [40, 43].
Clinical observations demonstrated that immunosup-
pressive protocols with MMF-inhibited antibody produc-
tion therefore reduces allograft rejection episodes [3, 44,
45]. UNOS data analysis also indicated its superiority
over azathioprine [30, 31] (Table 1.4 6).
Antilymphocyte antibodies. Antibodies against lymphocyte
surface molecules act by removing specific lymphocyte
subsets or inhibiting cell function [46 55]. Among
these antilymphocyte monoclonal or polyclonal antibod-
ies listed in Table 1.710, rituximab is the only antibody
specifically targeting B-cell surface marker CD20.
Garrett and colleagues reported the first case of humoral
rejection successfully treated with rituximab [46]. Re-
cently, using a single dose of rituximab in addition to
other therapies, a Wisconsin group successfully treated
27 patients who were diagnosed with biopsy-confirmed
rejection manifested by thrombotic microangiopathy
and/or endothelialitis between February 1999 and Feb-
ruary 2002. Twenty-four received additional steroids,
and 22 of 27 patients were also treated with plasma-
pheresis (PPH) and antithymocyte globulin. Only three
337
patients experienced graft loss not associated with pa-
tient death during the follow-up period (605 335.3
days). In the 24 successfully treated patients, serum
creatinine at the time of initiating rituximab therapy was
5.6 1.0 mg/dl and was decreased to 0.95 0.7 mg/dl
at discharge. Authors predicted that the addition of
rituximab may improve outcomes in severe, steroid-re-
sistant or antibody-mediated rejection episodes after kid-
ney transplantation [47] (Table 1.710).
Splenectomy. The spleen is an organ that produces lym-
phocytes, filters the blood, stores blood cells, and de-
stroys those that are aging. The rationale to perform
splenectomy in transplant recipients is to remove a major
source of lymphocytes, including antibody-secreting B
cells. The benefits of splenectomy in prolonging graft
and patient survival remain controversial. It has been
reported that splenectomized patients had reduced inci-
dences and intensity of rejection episodes and better graft
and patient survival rates [56]; however, this beneficial
effect was short-termed [57]. The long-term benefit from
splenectomy was mainly compromised by increased
chances of fatal infection and sepsis [56 58]. Recently,
in combination with other treatment, splenectomy seems
to play an important role in preventing humoral rejec-
tion and prolonging graft survival in ABO-incompatible
transplantation [36] (Table 1.11).
Removal or Blockage of Preexisting or Newly
Developed Antibodies
This strategy is also etiotropic. It mainly focuses on
reducing existing antibodies or blocking their detrimen-
tal effects (Table 1.1214).
Immunoadsorption. This is an in vitro approach that spe-
cifically removes immunoglobulins from patient periph-
ery by using blood group antigen A or B, protein A, or
antihuman Ig-coated columns. Originally, it was primar-
ily used as a preemptive therapy for ABO-incompatible
or presensitized patients [59 67]. But successful reversal
of antibody-mediated rejection were also reported [68
71]. An ABO antigen-coated column was used to spe-
cifically remove anti-ABO antibodies [72]; however,
HLA antigen column, specialized to remove HLA anti-
bodies, is not yet commercially available (Table 1.12).
PPH/plasma exchange (PE). Removal of antibodies and
other plasma factors by PPH and PE is an effective
antihumoral rejection treatments. They have been used
as a preemptive strategy to prevent potential rejection
episodes [36, 7375]. They have also been used to reverse
established antibody-mediated rejection [76 83]. Un-
like immunoadsorption, PPH and PE remove not only
antibodies but also many other humoral factors, such as
338
complements and cytokine. Therefore, PPH and PE
might theoretically be more efficient in preventing
and/or reversing humoral rejection. However, the cur-
rently available, uncontrolled studies seemed to end in
controversy [84], suggesting that further controlled clin-
ical investigations are imperative (Table 1.13).
Intravenous immunoglobulin. Given the fact that intrave-
nous immunoglobulin preparations are isolated from
plasma pools of several thousand healthy blood donors, it is
assumed that an almost unlimited spectrum of antibody
specificities is present therein. It is reported that the mech-
anism of suppression of panel-reactive antibodies in pa-
tients awaiting transplantation appear to be related to
antiidiotypic antibodies presented [85]. However, many
other potential mechanisms have already been proposed
that include inhibition of complement activation [86, 87],
blockade and downregulation of Fc receptors [88, 89], and
modulation of T- and B-cell activation and differentiation
[88]. Detailed discussion of its mechanisms is available in
other reviews in this issue (Table 1.14).
Impediment or Postponement of
Antibody-Mediated Primary and Secondary
Tissue Injury
Unlike the two strategies discussed above, this strategy is
an absolute allopathy. It is used to impede or postpone
antibody-caused tissue damages in order to prolong graft
survival (Table 1.15 and 1.16).
Anticoagulation therapy. As we discussed in the mecha-
nism section, antibody-mediated transplant rejection is
characterized by primary endothelium injury, followed
by some harmful secondary effects after endothelium
damage. Posttransplant thrombosis is a major patholog-
ical characteristic of hyperacute or acute rejection (Figure
1A) [90 96]. Depending on the level of antidonor an-
tibodies, antibody-mediated posttransplant thrombosis
may result in vascular narrowing or occlusion. On the
basis of the hypothesis that preventing clot formation
may postpone graft rejection, anticoagulation therapy
was used in transplant clinics [3235]. Recently, in
combination with other antibody depletion or suppres-
sion treatment, anticoagulation therapy successfully re-
duced hyperacute/acute rejection episodes and enabled
ABO-incompatible transplantation to become feasible
and reach satisfying long-term graft survivals [36] (Table
1.15).
Glucocorticoids. Glucocorticoid drugs are by far the most
powerful agents used widely in transplantation to inhibit
detrimental effects of immune responses induced by graft
rejection. Although glucocorticoids can directly induce
the apoptosis of B cells [9799] and inhibit the produc-
J. Cai and P.I. Terasaki
tion of alloantibodies, the major purpose of using glu-
cocorticoid to treat antibody-mediated rejection is its
strong antiinflammatory effects. As shown in Figure 1,
recruited inflammatory cells can directly cause endothe-
lial cell damage (Figure 1.1). In addition, after endothe-
lium injury, inflammatory cells can infiltrate into paren-
chyma and therefore affect its physiological function
(Figure 1D). The pharmacological effects of corticoste-
roid drugs on rejection result mainly from inhibition of
cytokine production [100, 101]. Because of its strong
immunosuppressive and antiinflammatory effects, glu-
costeroid is currently the first-line therapeutic drug for
transplant rejection. It is also a major component of
maintenance immunosuppressive regimens. However,
steroid therapy has many side effects, including fluid
retention, weight gain, diabetes, and bone mineral loss.
The benefits of continued rejection therapy with steroids
must be balanced against the potential for serious, some-
times fatal, adverse effects (Table 1.16).
PREVENTION IS BETTER THAN
CUREIMPORTANCE OF
ANTIBODY MONITORING
In current transplant clinics, the principal universal
method of monitoring is periodical laboratory examina-
tion and/or protocol biopsy. However, in light of the
recent evidence in renal transplantation that HLA anti-
bodies appear before rise in serum creatinine [3, 4, 102],
we can now suggest that testing for HLA antibodies is
added to the routine monitoring of patients. At any
given time after transplantation, approximately 20% of
patients can be expected to have HLA antibodies [3].
Evidence from the prospective study [3] suggests that it
is these patients with HLA antibodies who will eventu-
ally have grafts that fail as a result of humoral rejection.
Ongoing humoral rejection is not apparent by laboratory
indexes until the organ parenchyma is injured to some
critical level, after which no amount of immunosuppres-
sion can reverse the changes.
If this concept of antibody caused humoral injury is
correct, then antibody testing will be the key to monitor-
ing before irreversible damage has occurred. Various strat-
egies for eliminating antibody have already been used,
although in most instances, for acute humoral rejection.
Whether PPH is practicalfor example, for treatment of
chronic rejectionremains to be seen. How effective treat-
ment with monoclonal antibodies, such as rituximab
would be, requires testing. A drug treatment regimen that
reduces antibodies would be the method of choice. An
example is the use of FK and MMF, as described by
Theruvath et al. [103]. Drugs specifically aimed at reduc-
tion of antibodies will require development.
An important consequence of the humoral theory of
Humoral Theory of Transplantation
chronic rejection is that if antibodies are not found, then
immunosuppression might be reduced until production
of antibodies begins. That is, many patients may be
currently overimmunosuppressed, but we have no way of
knowing which patients can be safely weaned from their
current levels. If we can depend on circulating HLA
antibodies to be a good test of responsiveness, decisions
on drug levels can be based on it.
It should be mentioned, however, that monitoring for
HLA antibodies is likely not to be comprehensive be-
cause other antibodies, such as the MIC system, may also
be involved. Assays for MIC antibodies are just now
being developed and becoming widely available. Inter-
estingly, the blood group A and B antigens seem to be
different from HLAs because ABO-incompatible patients
have slightly, but not significantly, lower long-term
graft survival compared with those with ABO-compati-
ble grafts [36].
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