Circulation. 1999;100:II-229-II-235
(Circulation. 1999;100:II-229.)
© 1999 American Heart Association, Inc.
Thoracic Transplantation and Ventricular Assist Devices |
Intravenous Immunoglobulin Reduces Anti-HLA Alloreactivity and Shortens Waiting Time to Cardiac Transplantation in Highly Sensitized Left Ventricular Assist Device Recipients
Ranjit John, MD;
Katherine Lietz, MD, PhD;
Elizabeth Burke, RN;
Jan Ankersmit, MD;
Donna Mancini, MD;
Nicole Suciu-Foca, PhD;
Niloo Edwards, MD;
Eric Rose, MD;
Mehmet Oz, MD;
Silviu Itescu, MD
From the College of Physicians and Surgeons of Columbia University, New
York, NY.
Correspondence to Silviu Itescu, MD, Department of Surgery, College of Physicians and Surgeons of Columbia University, 622 W 168th St, PH 14 W, Room 1485, New York, NY 10032.
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Abstract
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Background—Recipients of left
ventricular assist devices
(LVADs) develop prominent B-cell
hyperreactivity. We investigated
the influence of anti-HLA antibodies
on waiting time to cardiac
transplantation in LVAD recipients and
compared the effects
of 2 immunomodulatory regimens on anti-HLA
serum reactivity.
Methods and Results—Fifty-five previously nonsensitized LVAD
recipients of a TCI device implanted between 1990 and 1996 were
studied. Patients with anti-HLA antibodies received monthly courses of
either intravenous immunoglobulin (IVIg) or plasmapheresis,
in conjunction with cyclophosphamide. The effects of these regimens on
anti-HLA alloreactivity and waiting time to transplantation were then
determined by Kaplan-Meier log-rank statistics,
nonparametric Wilcoxon rank-sum test, and
Student’s t test. Prolongation in transplant waiting
time was related to serum IgG anti–HLA class I alloreactivity.
Infusion of IVIg (2 g/kg) caused a mean reduction of 33% in anti–HLA
class I alloreactivity within 1 week. Waiting time to transplantation
was significantly reduced by IVIg therapy and subsequently approximated
that in nonsensitized patients. Side effects of IVIg (2 g/kg) were
minimal and related primarily to immune complex disease. Although
plasmapheresis caused a similar reduction in alloreactivity to IVIg,
this effect was achieved after longer treatment. Moreover,
plasmapheresis was associated with an unacceptably high frequency of
infectious complications. In patients resistant to low-dose (2
g/kg) IVIg therapy, high-dose (3 g/kg) IVIg was effective in reducing
alloreactivity but was associated with a high incidence of reversible
renal insufficiency.
Conclusions—These results indicate that IVIg is an effective and
safe modality for sensitized recipients awaiting cardiac
transplantation, reducing serum anti-HLA alloreactivity and shortening
the duration to transplantation. The therapeutic and safety profile of
IVIg would appear to be superior to plasmapheresis.
Key Words: antibodies • immune system • transplantation • ventricular assist devices
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Introduction
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Antibodies in the serum of a cardiac allograft recipient
that
are directed against donor HLA class I major histocompatibility
complex
(MHC) antigens constitutively expressed by allograft
endothelium
portend a significant risk for early graft
failure (ie, within
the first 24 to 48 hours) and poorer patient
survival as a result
of complement-mediated humoral
rejection.
1 2 3 Because T lymphocytes
constitutively
express MHC class I antigens, the presence of
preformed lymphocytotoxic
antibodies, particularly IgG isotype,
detected in a routine T-cell
cross-match is considered a contraindication
to solid organ
transplantation.
1 To identify patients at high
risk of
having a positive donor-specific cross-match, cardiac
transplantation
candidates are screened for anti-HLA antibodies
reactive with
lymphocytes from a panel of volunteers representative
of
the major HLA allotypes, collectively referred to as measurements
of
panel-reactive antibodies (PRAs). Patients with high PRA
levels are
considered to be "sensitized" to various alloantigens
and require
donor-specific cross-matches before transplantation.
The proportion of highly sensitized patients on cardiac transplant
waiting lists has been progressively expanding as a result of both
widespread use of left ventricular assist devices (LVADs)
and increasing numbers of patients undergoing retransplantation. LVAD
recipients develop prominent B-cell activation, as evidenced by
heightened production of anti–HLA class I and II
antibodies.4 5 6 Although use of leukocyte-filtered
platelets can partially reduce anti–HLA class I antibody
production,6 B-cell hyperreactivity associated
with LVAD implantation results from a multifactorial immunological
dysregulatory process involving heightened T-cell apoptosis,
selective loss of Th1-type T cells, and unopposed production of
Th2-type cytokines.7 As a consequence of
circulating anti–HLA class I and II antibodies, LVAD recipients have
repeated positive cross-match reactions, increased waiting time to
cardiac transplantation, and heightened risk of cellular rejection
after transplantation.4 5 6
Recent studies have suggested that pooled human intravenous
immunoglobulin (IVIg) is an effective modality to reduce
allosensitization.8 9 10 11 12 Postulated mechanisms include the
presence in IVIg of anti-idiotypic antibodies,9 13 14 15
antibodies against membrane-associated immunological molecules such as
CD4 or CD5,16 17 or soluble forms of HLA
molecules.18 19 In this study, we initially investigated
the effects of IVIg on serum reactivity to HLA class I molecules in
LVAD recipients and compared these effects to plasmapheresis, an
alternative modality for reduction of alloreactive
antibodies.20 21 The results of our study demonstrate that
treatment with IVIg is an effective and safe modality to reduce serum
reactivity to HLA class I antigens, decreases the risk for positive
cross-match reactions, and consequently shortens the waiting time of
sensitized LVAD recipients to cardiac transplantation.
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Methods
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Patient Population and Study Design
The influence of anti-HLA antibodies on waiting time to cardiac
transplantation
was studied in 55 previously nonsensitized LVAD
recipients of
a TCI device implanted between 1990 and 1996. For each
analysis
examining the effects of anti-HLA antibodies directed
against
either HLA class I or II molecules on waiting time to
transplantation,
patients were divided into 2 groups on the basis of
the presence
or absence of antibody development. A treatment regimen
consisting
of 1 to 3 monthly courses of IVIg 2 g/kg administered in 4
divided
daily doses was then administered to 16 sensitized patients
with
anti-HLA antibodies awaiting cardiac transplantation. In addition,
4
sensitized patients received 1 to 2 monthly courses of plasmapheresis
administered
2 to 3 times per week. All treated patients additionally
received
cyclophosphamide monthly in a single infusion dose of 0.5 to
1.0
g/m
2 IV. The effects of these treatment
regimens on anti-HLA
alloreactivity and on waiting time to
transplantation were then
determined. The treatment protocols were
approved by the Institutional
Review Board, and patients were fully
aware of all potential
consequences of the regimens instituted.
Detection of Anti-HLA Antibodies
Sera were obtained from all patients at risk for sensitization
on the day of initial listing as United Network of Organ Sharing
status I for transplantation and then every 2 weeks until
transplantation. Sera were screened for the presence of lymphocytotoxic
antibodies against separated T and B lymphocytes obtained from a panel
of 70 control individuals representative of the most
frequently encountered HLA class I and II antigens in the general
population. Anti-HLA IgG antibodies were considered positive if serum,
in the presence of dithioerythritol (DTT), demonstrated
complement-mediated lytic activity against >10% of the T-cell
reference panel. Anti-HLA reactivity >20% was considered an absolute
indication for requirement of a donor-specific cross-match before
transplantation.
Determination of Anti-HLA Antibody Specificity for MHC Class I or
II Antigens
Working definitions for IgG antibodies against HLA class I or II
molecules were established in our laboratory by use of, as reference,
sera from 28 cardiac transplantation patients with PRA values >10%
and with anti–MHC class I and II specificities defined by standard
Tail analysis. Because MHC class I antigens are constitutively
expressed by both T and B cells, IgG antibodies against HLA class I
molecules were considered present in our working definition when
DTT-treated serum reacted against >10% of both the T-cell reference
panel and the B-cell panel. This working definition for IgG anti–HLA
class I molecules correlated in 100% of cases (20 of 20) with patient
sera having defined specificity for HLA class I antigens.
To concomitantly identify and discriminate IgG antibodies against HLA
class II molecules in the presence of IgG anti–HLA class I molecules,
we established an algorithm that used the ratio of serum reactivity to
B versus T cells, because MHC class II antigens are constitutively
expressed by B but not T cells. To confirm this working definition
using sera with defined IgG anti-MHC class II specificities, a logistic
regression analysis was performed by a maximum-likelihood
procedure with Biological Management Database Program statistical
software to calculate the predictive values of the IgG anti–HLA class
II molecules for the ratios of B-cell serum reactivity to T-cell
reactivity of 1.25, 1.50, 1.75, 2.00, and 3.00. Maximal sensitivity
(91%) for identifying sera with reactivity against MHC class II
antigens was obtained by use of a ratio of B-cell to T-cell serum
reactivity of 2.00 (model coefficient, -3.481; SE, 1.19;
P=0.0002). Therefore, IgG antibodies against both MHC class
I and II molecules were considered present if DTT-treated serum
reacted against >10% of both the T- and B-cell reference panels and
B-cell reactivity exceeded T-cell reactivity by 
2-fold. IgG anti–HLA
class II molecules were also considered present if DTT-treated
serum reacted against >10% of the B- but not T-cell reference panel.
Testing the validity of this approach with sera analyzed by
Tail analysis confirmed that 100% of samples reactive only
with B cells (n=11) actually had anti–MHC class II specificity.
Overall, using these combined criteria for identifying IgG anti–HLA
class II reactivity (ie, reactivity with only B cells or 2-fold
higher reactivity with B than T cells) correctly identified patients
with MHC class II serum reactivity with 94% sensitivity and
specificity.
Statistical Analyses
Kaplan-Meier log-rank statistics were used to study the effects
of anti-HLA antibodies with specificities against HLA class I or II
molecules on waiting time to cardiac transplantation. Similarly,
Kaplan-Meier log-rank statistics were used to assess the effect of
reduction in alloreactivity by IVIg on waiting time to cardiac
transplantation. The Cox proportional-hazard model was used for
multivariable analysis. A nonparametric
Wilcoxon rank-sum test and Student’s t test were
used to evaluate the effects of individual treatment courses and of
repeated courses of either IVIg or plasmapheresis on reduction of serum
alloreactivity. All data were analyzed with SAS system software
(SAS Institute Inc).
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Results
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Circulating IgG Antibodies Against Class I But Not Class II
Molecules Increase Waiting Time to Cardiac Transplantation in LVAD
Recipients
The first series of studies aimed to investigate the relationship
between
anti-HLA antibodies and waiting time to cardiac transplantation
in
55 LVAD recipients. At our institution, a positive
donor-specific
cross-match, performed by screening recipient serum for
complement-mediated
lytic activity against donor T cells, is considered
a contraindication
to transplantation. Therefore, waiting time is a
direct reflection
of repeated instances of positive
cross-matches between recipient
serum and
donor T cells.
Because resting T cells express HLA class I but not class II molecules,
we investigated whether the presence of circulating alloreactive IgG
antibodies directed against HLA class I antigens might be better
predictors of positive donor-specific reactions and consequently of
prolongation in waiting time to transplantation than IgG antibodies
against HLA class II antigens. As shown in Figure 1
, the waiting time of LVAD recipients to
transplantation was prolonged in the presence of IgG antibodies against
HLA class I molecules compared with patients without these antibodies.
The mean duration to transplantation in patients without IgG antibodies
against HLA class I molecules (n=18) was 3.1 months (range, 0.3 to 10.7
months), whereas in patients with IgG antibodies against HLA class I
molecules (n=37), it was increased to 7.1 months (range, 0.2 to 17.9
months; P=0.001). In contrast, the presence of IgG
antibodies against HLA class II molecules did not significantly
increase the waiting time to cardiac transplantation (Figure 2). The mean duration to transplantation
in patients without IgG antibodies against HLA class II molecules
(n=24) was 4.8 months (range, 0.5 to 17.9 months), which was not
significantly different from the 5.2 months (range, 0.3 to 14.5 months)
in patients with IgG antibodies against HLA class II molecules (n=30;
P=0.21). These results indicated that prolongation of
waiting time to cardiac transplantation in sensitized LVAD recipients
was directly related to the presence of circulating alloreactive IgG
antibodies against HLA class I molecules.
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Figure 1. Effect of IgG antibodies against HLA class I
antigen on waiting time to cardiac transplantation. In 37 sensitized
LVAD recipients, presence of IgG antibodies against HLA class I antigen
increased waiting time to cardiac transplantation compared with 18
nonsensitized LVAD recipients (P<0.001).
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Figure 2. Effect of IgG antibodies against HLA class II
antigen on waiting time to cardiac transplantation. In 30 sensitized
LVAD recipients, presence of IgG antibodies against HLA class II
antigen did not increase waiting time to cardiac transplantation
compared with 24 nonsensitized LVAD recipients
(P=NS).
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IVIg (2 g/kg) Reduces Reactivity of Circulating IgG Antibodies
Against Allogeneic HLA Class I Molecules: Early Effect Sustained by
Repeated Courses
We next evaluated the efficacy of monthly IVIg courses, at 2 g/kg,
on reduction of reactivity of circulating IgG antibodies for allogeneic
HLA class I molecules. Data were obtained from 16 patients who received
1 to 3 monthly courses of IVIg (total, 28 courses). Each course of IVIg
was evaluated as an independent event, and the effects of each IVIg
course on IgG anti–HLA class I antibodies during the ensuing 4 weeks
were analyzed. Within 1 week of infusion of IVIg in 4 divided
daily doses, the reactivity of circulating IgG antibodies for
allogeneic HLA class I molecules was reduced by a mean of 33% (range,
14% to 52%; P=<0.01; Figure 3). This was the maximal level of
reduction in alloreactivity during the 4 weeks after IVIg infusion,
with IVIg efficacy progressively decreasing by the end of week 4 to a
mean reduction in alloreactivity of 8±7%.
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Figure 3. Effect of IVIg therapy on reduction of serum
anti–HLA class I IgG alloreactivity. Maximal reduction in serum
alloreactivity occurs within 1 week of IVIg therapy.
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Because IVIg has been shown to reduce circulating immunoglobulins by a
variety of immunomodulatory mechanisms, we next sought to determine
whether sequential courses of IVIg therapy demonstrated progressive
augmentation in the effect on circulating anti-HLA antibodies. For this
analysis, the maximal mean reduction in reactivity of
circulating IgG antibodies with allogeneic HLA class I molecules was
determined for each IVIg course, and the data for corresponding courses
in each patient were then pooled. As shown in Figure 5, sequential courses of IVIg did not
have an additive effect on reduction of reactivity of circulating IgG
antibodies with allogeneic HLA class I molecules. Each course resulted
in a similar level of reduction in alloreactivity compared with
baseline, with mean decreases of 38±11%, 36±17%, and 35±24%
accompanying first, second, and third courses of IVIg,
respectively.
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Figure 5. Effect of high-dose (3 g/kg) IVIg therapy in
highly sensitized patients resistant to low-dose (2 g/kg)
therapy. High-dose IVIg therapy in highly sensitized patients causes a
significant reduction in serum IgG anti–HLA class I
alloreactivity.
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High-Dose (3 g/kg) IVIg Is Effective in Reducing Alloreactivity in
Patients Resistant to Low-Dose (2 g/kg) IVIg
Therapy
Of the 16 highly sensitized patients, 6 were found to be
resistant to treatment with IVIg at 2 g/kg, with a mean
reduction of only 4% (range, 2% to 4%) in reactivity of circulating
IgG antibodies with allogeneic HLA class I molecules per treatment
course in this group. These patients were subsequently treated with 1
to 2 courses of high-dose IVIg therapy, 3 g/kg in 4 divided daily
doses. In each patient treated, high-dose IVIg therapy reduced
reactivity of circulating IgG antibodies with allogeneic HLA class I
molecules. As shown in Figure 5
, alloreactivity in this group was reduced by a mean of 20% (range, 16%
to 24%) per treatment course (P<0.05).
IVIg (2 g/kg) Has Faster Onset and Greater Efficacy in Reducing IgG
Anti-HLA Class I Alloreactivity Than Plasmapheresis
We next compared the effects of IVIg (2 g/kg) with plasmapheresis
on the reduction of reactivity of circulating IgG antibodies with
allogeneic HLA class I molecules in LVAD recipients. Four sensitized
patients received 1 to 2 monthly courses of plasmapheresis,
administered 2 to 3 times per week (total, 6 courses). Each monthly
course of plasmapheresis was evaluated as an independent event, and the
effects of each course on IgG anti–HLA class I antibodies during the
ensuing 4 weeks were analyzed. As shown in Figure 6, reactivity of circulating IgG
antibodies with allogeneic HLA class I molecules was not significantly
reduced within the first 2 weeks of initiation of plasmapheresis.
Maximal reduction in alloreactivity, 38±11%, occurred by week 4 of
plasmapheresis. These results show that IVIg has earlier onset of
action and greater efficacy in reducing IgG anti-HLA alloreactivity
compared with plasmapheresis.
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Figure 6. Effect of plasmapheresis therapy on reduction of
anti–HLA class I IgG alloreactivity. Maximal reduction in
alloreactivity occurs at 4 weeks.
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IVIg Therapy Shortens the Waiting Time to Cardiac Transplantation
in Sensitized Patients
We next investigated whether treatment with IVIg (2 g/kg) to
reduce alloreactivity in sensitized recipients affected waiting time to
transplantation. The first 3 highly sensitized LVAD recipients to
receive IVIg therapy had unsuccessfully been waiting for cardiac
transplantation for a mean of 303±25 days before the onset of therapy
as a result of repeated positive donor-specific cross-matches (mean,
33; range, 24 to 43). After initiation of IVIg therapy with or without
additional immunodepletion with plasmapheresis, all patients obtained
negative donor-specific cross-matches and were successfully
transplanted in a mean duration of 99±8 days (Figure 7). On the basis of these results, a
formal protocol was established to initiate monthly courses of IVIg
therapy (2 g/kg) after initial detection of allosensitization. The
duration from listing to cardiac transplantation was then compared
between 28 sensitized patients who did not receive IVIg treatment and
16 sensitized patients who received 1 to 2 courses of IVIg (2 g/kg)
after detection of anti–HLA class I IgG antibodies. None of these
patients received additional plasmapheresis. Whereas the mean duration
to cardiac transplantation was 7.1 months (range, 0.2 to 17.9 months)
in patients with IgG antibodies against HLA class I molecules, this
time was significantly reduced to 3.3 months (range, 0.3 to 6.2 months)
in sensitized recipients receiving 1 to 2 courses of IVIg (2 g/kg)
(P<0.05). No patient in either group was transplanted
across a positive donor-specific IgG T-cell cross-match. This duration
was similar to the waiting time to transplantation in 27 nonsensitized
patients (3.1 months; range, 0.3 to 10.7 months).
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Figure 7. Effect of IVIg and/or plasmapheresis on waiting
time to transplantation in highly sensitized patients.
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Complication of Therapy for Reduction of Allosensitization in
Patients Awaiting Cardiac Transplantation
The Table summarizes the complications
associated with IVIg and plasmapheresis therapies in sensitized
patients awaiting cardiac transplantation. IVIg therapy (2 g/kg) was
associated with clinical manifestations of immune complex disease in 4
of 27 monthly courses (15%), as evidenced by fevers, arthralgias, and
maculopapular rashes. Only 1 of 27 courses was associated with systemic
infection, Staphylococcus aureus sepsis. High-dose IVIg
therapy (3 g/kg) was associated with reversible renal insufficiency
(defined as >50% increase in serum creatinine level) in 4
of 6 courses. All cases resolved spontaneously over the ensuing 3 weeks
after infusion. Renal insufficiency was not observed in any courses of
low-dose IVIg. Systemic infection accompanied 3 of 6 courses (50%) of
plasmapheresis (2 cases of Staphylococcal aureus sepsis, 1
case of Acinetobacter sepsis). In addition, 2 of 6 courses
of plasmapheresis were associated with systemic anaphylaxis, as defined
by hypotension requiring pressor support. Together, these results
suggest that low-dose (2 g/kg) IVIg has a better safety profile than
plasmapheresis in this group of patients.
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Discussion
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Preexisting recipient serum reactivity against donor HLA class
I
antigens constitutively expressed by cardiac allograft
endothelium
can cause complement-mediated humoral
rejection and early graft
failure.
1 2 3 To identify
patients whose sera contain antibodies
against allogeneic HLA class I
molecules, cardiac transplantation
candidates are screened for anti-HLA
antibodies reactive with
lymphocytes from a panel of volunteers
representative of the
major HLA allotypes, collectively
referred to as measurements
of PRA. At our institution and many other
cardiac transplant
centers, sera from patients with high PRA levels are
subsequently
screened for donor-specific T-cell alloreactivity before
donor
allograft selection, because T lymphocytes constitutively express
HLA
class I antigens.
1 Individuals whose sera repeatedly
test positive
in donor-specific cross-match assays will obviously have
longer
waiting times to transplantation. Moreover, the requirement
for
a cross-match precludes distant organ procurement for sensitized
patients
because of the requirement for short ischemic times in
cardiac
transplantation. The complications of long-term LVAD use,
together
with the effects of the underlying disease state, make such
prolongation
of the waiting time to transplantation a significant risk
factor
for morbidity and mortality of patients on cardiac transplant
waiting
lists.
In this study, we initially showed that prolongation in the waiting
time to cardiac transplantation in LVAD recipients was directly related
to the presence of circulating IgG antibodies against allogeneic HLA
class I molecules. Infusion of IVIg (2 g/kg) in 4 divided daily doses
caused within 1 week a mean reduction of 33% in the reactivity of
circulating IgG antibodies for allogeneic HLA class I molecules. More
importantly, the waiting time to transplantation in sensitized LVAD
recipients was significantly reduced by IVIg therapy and subsequently
approximated that in nonsensitized patients. Side effects of IVIg (2
g/kg) were minimal and related primarily to immune complex disease.
Although plasmapheresis caused a similar reduction in alloreactivity to
IVIg, this effect was achieved after a longer duration of treatment,
presumably because of IgG equilibration between the intravascular and
extravascular spaces. Because plasmapheresis removes only intravascular
IgG, replenishment of the removed IgG occurs rapidly as a result of
diffusion from the extravascular to the intravascular space. Thus, to
achieve a prolonged steady state of low circulating IgG levels,
multiple courses of plasmapheresis are necessary. Moreover,
plasmapheresis was associated with an unacceptably high frequency of
infectious complications. Together, these results indicate that IVIg is
an efficacious and safe modality for sensitized recipients awaiting
cardiac transplantation, reducing serum anti-HLA alloreactivity and
shortening the duration to transplantation. The therapeutic and safety
profiles of IVIg would appear to be superior to those of
plasmapheresis.
In patients resistant to low-dose (2 g/kg) IVIg therapy,
high-dose (3 g/kg) IVIg was effective in reducing alloreactivity.
However, a high incidence of reversible renal insufficiency accompanied
high-dose IVIg. Reversible renal insufficiency is a well-recognized
complication of IVIg and appears to result from osmotic damage to the
renal tubules and interstitium by carbohydrates in the IVIg
preparation.22 23 24 25 The histopathology shows severe tubular
vacuolization with cellular swelling and preservation of the brush
border. There is no evidence of inflammatory cell or immune
complex–mediated injury in this process, and renal insufficiency is
reversible after cessation of treatment. Although this was also the
case in our patients, 1 required temporary hemodialysis. Because
preexisting renal insufficiency is a risk factor for renal
complications associated with IVIg use, LVAD recipients receiving IVIg
should be carefully monitored for this complication, particularly when
receiving high-dose therapy.
The effect of each IVIg infusion on anti-HLA antibodies was transient,
and serial IVIg infusions were required for maintenance of
reduction in alloreactivity. These results argue against an
immunomodulatory mechanism of action, such as reduction in helper CD4
T-cell activity16 17 26 or suppression of T-cell
alloreactivity by inhibition of cytokine
production,27 both of which would cause sustained
alterations in immune function. More likely, the mechanism may involve
a direct effect of IVIg on circulating IgG anti-HLA immunoglobulins.
Because naturally occurring anti-idiotypic antibodies to HLA improve
graft survival in sensitized renal allograft
recipients,28 29 a similar effect may occur after exposure
of serum from sensitized LVAD recipients to anti-idiotypic antibodies
in pooled human IVIg.13 14 15 Moreover, IVIg appears to
stimulate the production of anti-idiotypic IgM blocking
antibodies in recipient serum.9 Alternatively, transient
reduction in anti-HLA serum reactivity may be related to the presence
in the IVIg preparation of soluble HLA class I molecules, which may
bind circulating anti-HLA antibodies,18 19 or of
non–complement-fixing antibodies against HLA class I molecules, which
may compete with recipient alloreactive antibodies for HLA
binding.30 Such antibodies have been demonstrated in IVIg
preparations to react with nonpolymorphic determinants in the
alpha-helical region of HLA class I molecules.
We emphasize the need to carefully screen all patients at risk for
sensitization before transplantation and to identify the presence,
isotype, and specificity of anti-HLA antibodies that portend heightened
risk for adverse posttransplant outcomes. We advocate that before
transplantation all patients should be specifically screened for the
presence of antibodies against both MHC class I and II antigens and
that immunosuppressive strategies be instituted in these patients
before transplantation. In addition to using IVIg, our
immunosuppressive protocol included monthly infusions of
cyclophosphamide 0.5 to 1.0 g/m2 IV. Because
cyclophosphamide has selective suppressive effects on discrete stages
of the B-cell cycle, including proliferation and
differentiation,31 the rationale for its use was to
prevent the possible rebound in B-cell immunoglobulin synthesis after
therapy with IVIg or plasmapheresis. The intravenous
regimen used in our study was adapted from regimens used in the
treatment of systemic lupus
erythematosus and systemic vasculitides, in
which intermittent low-dose pulse therapy has been shown to
significantly reduce the incidence of leukopenia, infections,
hemorrhagic cystitis, and neoplastic complications compared with oral
cyclophosphamide.32 33 The immunosuppressive protocol
outlined in this article, combining IVIg therapy with
intravenous cyclophosphamide, appears to be safe and
effective in reducing IgG anti–HLA class I serum alloreactivity.
Consequently, this regimen increases the likelihood of obtaining a
cross-match–negative allograft in sensitized patients on LVAD support.
Moreover, the posttransplant clinical outcome in these patients appears
to be significantly improved by this regimen, with longer
rejection-free intervals and reduced cumulative annual high-grade
rejection frequency.34 We also have observed similar
results using this regimen in cardiac transplant recipients sensitized
by means other than LVAD implantation and currently treat all
sensitized patients in a similar manner. The long-term efficacy and
safety of IV cyclophosphamide used before and after transplantation in
sensitized LVAD recipients remain to be fully evaluated.
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Figure 4. Effect of sequential courses of IVIg therapy on
serum IgG anti–HLA class I alloreactivity. Sequential courses of IVIg
do not cause additive effect on reduction in serum IgG anti–HLA class
I alloreactivity.
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Abstract
Introduction