(Circulation. 1999;100:II-211.)
© 1999 American Heart Association, Inc.
Thoracic Transplantation and Ventricular Assist Devices |
Quantitative Changes In T-Cell Populations After Left Ventricular Assist Device Implantation
Relationship to T-Cell Apoptosis and Soluble CD95
From the College of Physicians and Surgeons of Columbia University, New York, NY.
Correspondence to Silviu Itescu, MD, Transplantation Immunology Department of Surgery, College of Physicians & 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—Left ventricular assist devices (LVADs) are currently being evaluated as permanent therapy for end-stage heart failure. Because life-threatening infections limit successful long-term device implantation, we investigated the relationship between quantitative T-cell defects in LVAD recipients and CD95-mediated T-cell apoptosis.
Methods and Results—Immunological studies were performed in NYHA class IV patients awaiting cardiac transplantation who received either a TCI Heartmate left ventricular assist device (LVAD) or medical management. Fluorochrome-labeled Mabs were used in T-cell phenotypic analyses. T-cell apoptosis was measured by annexin V binding of T cells cultured in medium for 24 hours. Circulating serum levels of soluble CD95 were measured by ELISA. LVAD recipients had a relative lymphopenia and reduction in CD4 T-cell levels compared with NYHA class IV heart failure controls. These observations were confirmed in a longitudinal study in LVAD recipients, which showed that device implantation was accompanied by progressive and sustained reductions in circulating CD4 T-cell levels. These abnormalities in LVAD recipients were accompanied by increased levels of circulating soluble CD95 and by excessive CD4 and CD8 T-cell apoptosis. Susceptibility to induction of apoptosis was >2-fold greater for CD4 T cells than for CD8 T cells.
Conclusions—These results suggest that the reduction in CD4 T-cell levels accompanying LVAD implantation is a consequence of an augmented pathway of CD95-mediated apoptosis. The clinical consequences of these abnormalities may include increased prevalence of systemic infections.
Key Words: assist devices, left ventricular • heart failure • transplantation • apoptosis
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Introduction |
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Congestive heart failure remains a major public health problem.1 As a result of the encouraging medium-term results with implantation of left ventricular assist devices (LVADs),2 3 such devices are being evaluated as a permanent therapeutic modality for patients with end-stage heart failure. However, LVAD implantation has been complicated by a high incidence of systemic infections, irrespective of the type of device used.4 5 6 7 8 9 In fact, prophylactic use of antifungal therapy has been advocated in selected LVAD recipients to reduce the risk of fungal infection.4 The high prevalence of fungal infection in LVAD recipients raises the possibility that LVAD implantation may be associated with the development of defects in host immunity.
In addition to possible defects in T-cell immunity, LVAD recipients develop prominent B-cell activation, as evidenced by heightened production of anti-HLA and antiphospholipid antibodies.10 11 12 A similar discordance between defects in T-cell immunity and B-cell hyperreactivity characterizes 2 other immunological disorders, systemic lupus erythematosus13 14 15 and infection with the human immunodeficiency virus type-1 (HIV-1).16 17 A proposed mechanism to account for the coexistence of T-cell defects and autoimmunity in these disorders is inappropriate induction of apoptotic T-cell death18 19 20 21 22 due to heightened interactions between CD95 (Fas) and CD95L (FasL).23 24 25 26
In this study, we initially performed cross-sectional and longitudinal quantitative analyses of T-cell populations in LVAD recipients. We then investigated whether quantitative T-cell defects were related to induction of T-cell apoptosis in LVAD recipients and whether this involved a CD95-dependent activation pathway. Our studies demonstrate heightened susceptibility of CD4 T cells from LVAD recipients to apoptosis and suggest that these abnormalities may be related to the high prevalence of infectious complications that accompany LVAD implantation.
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Methods |
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Study Patients
40 NYHA class IV patients awaiting cardiac transplantation who received either a TCI Heartmate LVAD (n=20) or medical management (n=20) were available for immunological evaluation. No patients had any infection at the time of study, and none received immunosuppression therapy. All immunological studies were performed at least 1 month after implantation to limit the confounding effects of surgery.
Immunophenotypic Analysis of Circulating T Cells
Cross-sectional immunophenotypic analyses were performed
in 12 LVAD recipients and 20 controls, and serial studies were
performed in 6 LVAD recipients. Cell counts from LVAD recipients and
controls were acquired by Coulter counter analysis.
Fluorochrome-labeled monoclonal antibodies (Mabs) against CD4 and CD8
(Becton Dickinson Systems) were used in 2-color
immunofluorescence analyses. Log
fluorescence was measured using a FACScan 500 flow cytometer
(Becton Dickinson).
Assay for Quantification of T-cell Apoptosis
Peripheral blood mononuclear cells from LVAD
recipients or heart failure controls were isolated from heparinized
whole blood by Ficoll reagent, cultured in RPMI medium for 24 hours,
and analyzed for apoptosis with a flow cytometric
apoptosis detection kit (Becton Dickinson Systems). Briefly,
after 24 hours of culture, 3x105
peripheral blood mononuclear cells were stained with
fluorochrome-conjugated anti-CD3, anti-CD4, and anti-CD8 and then
costained with 10 µL of FITC-conjugated annexin V (R&D systems) to
detect phosphatidylserine expression on cells
during early apoptotic phases.22 23 The samples
were then analyzed by FACStar 500.
Assay for Quantification of Soluble Circulating CD95
Levels
Serum samples were obtained from 20 LVAD recipients (at a
uniform time point of 1 month after LVAD implantation), 20 NYHA class
IV controls, and 13 normal individuals. Circulating serum levels of
soluble CD95 were measured in a commercial ELISA using polyclonal
antibodies against human CD95 (Cytoscreen, BioSource International,
Inc). The sensitivity of the ELISA is 20 pg/mL. The amount of protein
in each serum sample was calculated according to a standard curve of
optical density values constructed for known levels of soluble CD95
protein.
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Results |
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LVAD Recipients Have Relative Lymphopenia and Reduction in CD4 T-Cell Levels Compared With Heart Failure Controls
As shown in the Table
, in a
cross-sectional analysis of circulating leukocytes, LVAD
recipients had reduced proportions of lymphocytes compared with NYHA
class IV controls awaiting cardiac transplantation (mean lymphocyte
proportion 10±2% versus 17±2%, P<0.05). This relative
lymphopenia in LVAD recipients was accompanied by significant
reductions in both the mean CD4/CD8 T-cell ratios (2.0±0.3 versus
4.1±0.4, P<0.001) and in the mean number of circulating
CD4 T cells (374±6 versus 624±59 per cubic millimeter,
P<0.01). In contrast, mean CD8 T-cell counts were not
different between the 2 groups (230±1 versus 194±32 per cubic
millimeter, P=NS).
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LVAD Recipients Develop Progressive Reduction in CD4 T-Cell Levels
After Device Implantation
To investigate these observations sequentially, in 6 LVAD
recipients, serial measurements of T-cell subsets were performed at 1
and 2 months after implantation and compared with preimplantation
levels. As shown in Figure 1, the mean
CD4/CD8 T-cell ratio was reduced from 4±0.5 at baseline
preimplantation to 1.2±0.2 by 2 months after implantation. As shown in
Figure 2, this was a result of a progressive
reduction in mean percentage of CD4 T-cell levels, from 55±3% at
baseline preimplantation to 42±2% by 2 months after implantation, a
mean reduction of 24%. In contrast, mean percentage of CD8 T-cell
levels were not reduced during this period.
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CD4 T Cells in LVAD Recipients Have Heightened Susceptibility
to Apoptosis
We next investigated whether this progressive reduction in
circulating CD4 T cells in LVAD recipients could be explained on the
basis of differential susceptibility to induction of apoptosis.
T-cell apoptosis after 24 hours of culture was measured in NYHA
class IV controls and LVAD recipients by surface expression of
phosphatidylserine, which is translocated from the
internal leaflet to the external leaflet of the plasma membrane after
initiation of a death-inducing activation
process.27 28 As shown in Figure 3, CD4 T cells from heart failure controls
demonstrated a relative resistance to apoptosis after 24 hours
of culture versus CD8 T cells. Surface expression of
phosphatidylserine, as defined by annexin V
binding, was 26±3% for CD8 T cells, compared with only 10±2% for
CD4 T cells (P<0.01). In contrast, both CD8 and CD4 T cells
from LVAD recipients expressed high levels of
phosphatidylserine after 24 hours of culture
(71±1% and 67±2%, respectively). Figure 4
shows the relative increase in apoptosis of CD8 and CD4 T cells
between LVAD recipients and heart failure controls. Whereas
apoptosis of CD8 T cells increased by a mean of 2.7-fold in
LVAD recipients, apoptosis of CD4 T cells increased by a mean
of 6.9-fold (P<0.05). These results indicate that LVAD
recipients have greater susceptibility to apoptosis of CD4 T
cells than CD8 T cells.
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High Circulating Levels of Soluble CD95 in the Serum of LVAD
Recipients Compared With Heart Failure Controls
Translocation of phosphatidylserine as
an early component of T-cell apoptosis occurs after ligation of
CD95 (Fas). To investigate whether the heightened susceptibility of T
cells from LVAD recipients to apoptosis was a consequence of
CD95-mediated T-cell activation, we measured circulating levels of
soluble CD95 in sera of LVAD recipients and NYHA class IV heart failure
controls. As shown in Figure 5, mean serum
levels of soluble CD95 were significantly higher in LVAD recipients
than in heart failure controls (14±2 versus 7±1 ng/mL;
P<0.01). These results are consistent with a
heightened state of T-cell activation via a CD95-dependent pathway
accompanying LVAD implantation relative to heart failure.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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In this study, we have shown in a cross-sectional analysis that LVAD recipients demonstrate a relative lymphopenia and reduction in CD4 T-cell levels in comparison to NYHA class IV heart failure controls who were treated medically. These observations were confirmed in a longitudinal study in LVAD recipients, which showed that device implantation was accompanied by progressive and sustained reductions in circulating CD4 T-cell levels. These abnormalities were accompanied by excessive T-cell apoptosis and increased levels of circulating soluble CD95. Because high circulating serum levels of soluble CD95 are detected in other diseases associated with increased T-cell apoptosis, such as systemic lupus erythematosus,29 30 31 these results suggest that reduction in CD4 T-cell levels accompanying LVAD implantation may be a consequence of an augmented pathway of CD95-mediated apoptosis. The clinical consequences of these abnormalities appear to reflect a state of reduced immune competency, with increased prevalence of Candida and other systemic infections.4 5 6 7 8 9
Progressive CD4 T-cell depletion and increased prevalence of infections
associated with defects in cell-mediated immunity are features that are
common to HIV-infected individuals. One proposed mechanism to account
for these abnormalities in HIV-1 infection is inappropriate induction
of apoptotic T-cell death resulting from HIV-mediated
interactions between CD95 (Fas) and CD95L
(FasL).21 22 32 33 HIV-infected dendritic cells appear to
be particularly effective at inducing T-cell expression of CD95 and
delivering apoptosis-inducing signals to uninfected T
cells.25 26 In this regard, cells of monocyte or dendritic
lineage are present on the LVAD surface at the time of
explantation34 and are functionally activated as
defined by nuclear factor- 
B expression35
and augmented production of cytokines and coagulation
factors.27 These results suggest that
antigen-presenting cells, which are aberrantly
activated by the implanted LVAD, deliver excessive
costimulatory signals to T cells, inducing T-cell apoptosis by
way of a CD95-dependent pathway.
Although both CD4 and CD8 T cells from LVAD recipients demonstrated greater levels of apoptosis than T cells from heart failure controls, susceptibility to induction of apoptosis was >2-fold greater for CD4 T cells from LVAD recipients than for CD8 T cells. The explanation for this may lie in the selective susceptibility of CD4 T cells to CD95-mediated apoptosis. After cross-linkage of CD95, the cytoplasmic domain of this receptor binds the adaptor molecule FADD,28 36 enabling interactions with another protein, called FLICE (caspase-8). Activation of FLICE leads to catalytic activation of a cascade of caspases, with the ultimate result of cellular apoptosis.37 38 The binding of FLICE to FADD can be competitively inhibited by a negative regulator of apoptosis, FLIP.39 40 Because IL-2 inhibits transcription of FLIP and enhances transcription of CD95 ligand (FasL),41 IL-2–producing Th1 CD4 cells are selectively susceptible to apoptosis after CD95 engagement.42 43 44 45 This provides a mechanism to account for the progressive reduction in CD4 T-cell levels in LVAD recipients and for the high prevalence of infections associated with defects in cellular immunity. Due to the cross-sectional nature of this study and the relatively small number of patients studied, we were not able to make specific correlations among degree of CD4 T-cell apoptosis, soluble CD95 levels, and infectious episodes. A separate longitudinal study is required to address the relationship between CD95-mediated T-cell apoptosis, reduction in CD4 T-cell numbers, and infectious complications in LVAD recipients. Because CD95-mediated apoptosis is an IL-2–dependent process, one potential approach to prevent T-cell depletion and defects in cellular immunity in LVAD recipients is the use of cyclosporine A and FK506, 2 drugs that inhibit mRNA transcription of IL-2 and consequently of CD95 ligand.46 We are currently evaluating the use of these and other agents in studies aimed at reducing aberrant immune activation in LVAD recipients.
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