Soluble CD-4 and CD-8 as markers of immunological activation in renal transplant recipients
R. Willi Grunewald,
G. Martin Fiedler,
Birgit Stock,
Julia M. Grunewald and
Gerhard A. Müller
Division of Nephrology and Rheumatology, Department of Internal Medicine, University of Göttingen, Germany
Correspondence and offprint requests to:
R. W. Grunewald, Zentrum Innere Medizin, Abteilung Nephrologie und Rheumatologie, Universitätsklinik Göttingen, Robert Koch Straße 40, D-37075 Göttingen, Germany.
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Abstract
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Background. T lymphocytes are activated following kidney transplantation in cases of acute graft rejection and viral infections. In plasma, elevated levels of T-cell markers can be measured in soluble form. The reason for this shedding is still not entirely understood.
Methods. Plasma concentrations of soluble CD-4 and CD-8 (sCD-4, sCD-8) were determined in 78 patients following kidney transplantation by commercially available enzyme-linked immunosorbent assay (ELISA) test kits.
Results. The concentrations of both soluble T-cell markers increased significantly in the course of acute allograft rejections and cytomegalovirus (CMV) infections. Frequently, the parameters increased shortly before clinical diagnosis and decreased under successful therapy. Additionally, sCD-8 showed significant higher plasma concentrations in cases of CMV infection as compared with acute allograft rejections. Accordingly, the sCD-4/sCD-8 ratio increased in cases of acute allograft rejection and decreased during CMV infections. Cyclosporin A nephrotoxicity caused no significant changes in the sCD-4 and sCD-8 levels in plasma.
Conclusion. The present study demonstrates that sCD-4 and sCD-8 are markers of immunological activation and may enable a further differentiation of T-cell activation if serial measurements are performed. However, further prospective investigations are necessary to elucidate the diagnostic potential of sCD-4 and sCD-8 for monitoring acute rejection and viral infection in kidney graft recipients.
Keywords: CMV infection; cyclosporin A nephrotoxicity; immune monitoring; renal allograft rejection; soluble CD-4; soluble CD-8
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Introduction
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T lymphocytes are involved in acute allograft rejection [1,2]. T-cell receptor (TCR), CD-3, CD-4 or CD-8 receptors play an important role in antigen recognition and T-cell activation. TCR/CD-3 and CD-4 recognize antigen in combination with major histocompatibility complex (MHC) class II, TCR/CD-3 and CD-8 recognize antigen in combination with MHC class I molecules [35]. Both, CD-4 and CD-8 co-receptors are transmembrane proteins [6]. The cytoplasmic tails of CD-4 and CD-8 are associated with tyrosine kinases which transmit signals for the regulation of T-cell growth and play an important role in T-cell activation [7,8]. T-cell activation and proliferation are also modulated by soluble lymphokines which bind to lymphokine receptors, such as interleukin-2 receptor (IL-2R) [9]. For optimal T-cell activation, cooperation of these receptors is necessary.
Under certain not entirely understood circumstances, CD-4 and CD-8 receptors are released from the cell surface and circulate in the plasma as soluble CD-4 and CD-8 (sCD-4, sCD-8). Abnormally high levels of sCD-8 or sCD4 can be detected in the plasma of patients with infectious diseases (e.g. Kawasaki disease, infectious mononucleosis, chronic viral hepatitis, AIDS) [1015], haematological malignancies (e.g. hairy cell leukaemia, childhood acute lymphoblastic leukaemia), lymphomas (e.g. non-Hodgkin's lymphoma, Hodgkin's disease) [1618] and autoimmune conditions (e.g. rheumatoid arthritis, polymyalgia rheumatica, autoimmune hepatitis, systemic lupus erythematosus, insulin-dependent diabetes mellitus) [1924]. Increased sCD-8 levels were found in the cerebrospinal fluid of patients with multiple sclerosis and other inflammatory neurologic diseases [25]. High sCD-8 levels were correlated with advanced disease and poor prognosis [14,17].
In the present study, we measured sCD-4 and sCD-8 concentrations in plasma of renal transplant recipients to obtain further information about T-cell subset activation in the course of immunological processes following kidney transplantation. Additionally, we investigated whether soluble T-cell markers may contribute to a better monitoring of allograft rejection and viral infection in kidney transplant recipients.
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Subjects and methods
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Patients
Plasma samples from 19 healthy individuals without impairment of renal function (10 female and nine male) and a mean age of 34 years (range 2440 years) were examined (controls). Seventy eight kidney transplant recipients, 25 females and 53 males with an age range of 2367 years, were studied. Seventy six patients had received their first transplant and two patients the second transplant. The mean follow-up was 43 days post-transplant (range 2572 days). Patients were immunosuppressed with a combination of prednisolone and cyclosporin A (CsA). In 32 patients, azathioprine was added to a `triple-therapy' regime because of unstable graft function. Anti-rejection therapy commonly consisted of methylprednisolone bolus therapy (500 mg i.v. for three consecutive days).
The patients could be divided into four groups:
- Stable graft function. Stable graft function was defined when serum creatinine, sIL-2R, urine excretion and ultrasonography was not pathological and an infection could be excluded. Serum creatinine should not exceed 150 µmol/l. Volume of urine excretion should be >1.8 l/day under constant body weight.
- Acute rejection. All cases of acute rejection were documented with allograft histology. Acute rejection was clinically suspected when the serum creatinine was increased above 250 µmol/l or showed an increasing tendency of 20 µmol/l per day, and urine excretion declined. Additionally, plasma levels of sIL-2R increased [26,27]. Allograft ultrasonography (renal enlargement in all dimensions, prominent hypoechoic pyramids or effacement of renal sinus) and Doppler ultrasonography (resistance index of Pourcelot (RI)
0.8 with an increment of 0.10.2/day) showed pathological changes [28]. A renal biopsy was performed in all patients when an acute allograft rejection was clinically suspected.
- CMV infection. The diagnosis of cytomegalovirus (CMV) infection was made by the detection of CMV-pp65-EA or CMV-PCR. Serologic detection of specific CMV immunoglobulin M by enzyme immunoassay assisted in confirming a CMV infection.
- Cyclosporin A nephrotoxicity. CsA-induced renal dysfunction was differentiated from acute rejection by renal allograft biopsy. For statistical analysis, the measured values of soluble T-cell markers on the day with the highest CsA level and the following 3 days were chosen.
Samples
Plasma samples were obtained three times a week. Heparinized blood was collected and stored frozen at -20°C after centrifugation.
Creatinine measurement
Creatinine was measured with a Beckman creatinine analyser according to Jaffé's test. A 25 µl aliquot of plasma was added to a modified Jaffé solution. The increase in absorption was measured during 25.6 s at a wavelength of 520 nm.
Soluble T-cell marker assays
sCD-4 and sCD-8 were determined in triplicate by commercially available enzyme-linked immunosorbent assay (ELISA)-test kits `cell-free CD-4 test kit' and `T-8 test kit' (T Cell Science, Cambridge, MA) according to the manufacturer's instructions with slight modification in terms of the length of the incubation periods. The first monoclonal mouse antibody was coated onto polystyrene microtitre plate wells. For sCD-4, 50 µl and for sCD-8 10 µl of standards or plasma samples were added to the wells, washed and incubated with a mouse anti-mouse antibody conjugated with horseradish peroxidase for the same length of time. After incubation, the wells were washed again and a substrate solution of o-phenylenediamine was applied. The reaction was stopped with 2 M H2SO4 following incubation for 45 min, and absorbance was measured at 490 nm. The ELISA reader Milenia Kinetic EIA System and Kinetic Analyser (DPC, Los Angeles, CA) were used to determine the standard curve and the sample values.
The sIL-2R levels in plasma were measured with a commercially available ELISA (Immunotech S.A., Marseilles, France). Briefly, 50 µl of plasma sample were incubated with 100 µl of anti sIL-2R monoclonal antibody conjugated with alkaline phosphatase for 120 min at room temperature. Soluble IL-2R present in the plasma sample bound to antibody on the well and, after washing of the unreacted materials, 200 µl of vial substrate buffer (pNPP) were added for 60 min. Thereafter, the reaction was stopped with 50 µl of 1 M NaOH and the absorbance was determined at 405 nm.
Statistical analyses
The median (minimum maximum) values were calculated for each parameter in each group. The significance of differences between groups was calculated using the Mann Whitney U test for unpaired data or multivariate analysis (ANOVA). The sCD-4/sCD-8 ratio of every patient was calculated. The median (minimum maximum) of all sCD-4/sCD-8 ratios are shown in Table 3
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Results
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Two typical courses are demonstrated as follows: the first patient (Figure 1
) had a normal graft function during the first 3 weeks following kidney transplantation. From the 24th day after transplantation, serum creatinine slowly increased. The increment of the soluble T-cell markers in plasma appeared shortly before the increase in serum creatinine. On day 28 after transplantation, an acute interstitial rejection could be diagnosed by graft biopsy. An anti-rejection therapy with 500 mg of methylprednisolone i.v. for three consecutive days was started. Shortly after, the concentrations of the soluble T-cell markers in plasma decreased, whereas serum creatinine showed a delayed decrease.
The second patient (Figure 2
) had also a normal graft function and was doing well until 5 weeks after transplantation. Thereafter, sCD-4 and sCD-8 plasma concentrations increased and a delayed serum creatinine elevation followed. However, in contrast to the previously described patient, sCD-8 showed a more pronounced increase compared with sCD-4. A renal allograft biopsy was performed and an acute rejection or CsA nephrotoxicity could be excluded. The patient developed fever (40°C) and the laboratory tests revealed a leukopenia (2.1x109/l), anaemia (haemoglobin 8.5 g/dl) and an increase in AST (90 U/l) and ALT (140 U/l). The diagnosis of CMV infection was made by the detection of specific CMV-pp65-EA in blood specimens. The immunosuppressive regimen was reduced and ganciclovir (adjusted for renal dysfunction) was administered for 15 days. The clinical symptoms regressed, and sCD-4 and sCD-8 decreased followed by a delayed reduction of serum creatinine.
Patients with stable allograft function showed plasma sCD-4 and sCD-8 levels in the range of those of healthy persons with normal kidney function. In cases of acute allograft rejection, sIL-2R (data not shown), sCD-4 and sCD-8 levels increased significantly compared with cases with stable allograft function (Tables 1 and 2
). Soluble CD-4 showed a more pronounced increase in cases of acute rejection than did sCD-8. CMV infections also caused a significant increment of sCD-4 and sCD-8 plasma levels compared with cases with stable graft function. Additionally, sCD-8 showed significant higher plasma concentrations in cases of CMV infection compared with cases of acute rejection. Soluble T-cell markers of healthy individuals showed no significant differences compared with transplant recipients with stable graft function.
During acute allograft rejections, the sCD-4/sCD-8 ratio in plasma increased, during CMV infections the sCD-4/sCD-8 ratio decreased (Table 3
). The sensitivity, specificity and predictive values of sCD-4 and sCD-8 are shown in Table 4
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Table 4. Sensitivity, specificity and predictive values of sCD-4 and sCD-8 for the diagnosis of acute allograft rejection and CMV infection
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Discussion
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As a sign of early activation of T lymphocytes during episodes of acute rejection and viral infection following renal transplantation, significantly elevated plasma levels of sCD-4 and sCD-8 were found. Soluble CD-4 showed a 3.2-fold increase during acute allograft rejection with no further significant difference from episodes of CMV infections. Soluble CD-8, however, was remarkably elevated in plasma during CMV infections (3.2-fold) compared with acute rejection episodes (1.5-fold). Thus, the sCD-4/sCD-8 ratio in plasma increased in cases of acute allograft rejections and decreased during CMV infections as a sign of activation of different T-cell subsets.
These data underline the importance of CD4+ cells for initiating graft rejection [29,30]. Biopsy studies revealed that both CD4+ and CD8+ T cells infiltrate allograft tissue with a different pattern in the course of acute rejection. However, the relative proportions of both T-cell subsets vary between different reports [for review, see 2]. Peripheral blood lymphocyte analysis by serial flow cytometry following renal transplantation failed to differentiate between lymphocyte activation indicative of acute allograft rejection or viral infection [31,32]. This failure could be accounted for by the poor correlation between peripheral blood lymphocyte findings and the events within the renal graft [33]. Therefore, we assume that the evaluation of soluble T-cell markers, especially of sCD-4, is a superior indicator to flow cytometric analysis of peripheral blood lymphocytes in cases of acute allograft rejection.
In contrast to allograft rejection, a decreased CD4/CD8 T-cell ratio was found in blood during CMV infections [34,35]. Preceding other manifestations of CMV infection in immuno-compromised patients, CD4/CD8 inversion turned out to be the most reliable and earliest indicator of infection [34,35]. These data show that especially CD8+ T lymphocytes increase during systemic CMV infections. Analysis of the peripheral blood CD8+CD38+ subset by dual-colour cytometry promises to be a sensitive method to monitor CMV infection in kidney transplant recipients [36]. These results are in accordance with our observation that especially sCD-8 was remarkably increased in the plasma of patients with CMV infection. Comparable results were found in a study with liver transplant recipients [37]. Thus, in cases of systemic immunological reactions, such as systemic viral infections, peripheral blood lymphocyte findings might reflect the immunological events. Therefore, the analysis of soluble T-cell markers is not superior to flow cytometric analysis of peripheral T lymphocytes in cases of CMV infections. These data confirm that the finding of activation of CD8+ T lymphocytes during viral infections is more important than during acute allograft rejection.
The results of patients with CsA nephrotoxicity were all in the range of stable graft function and apparently do not reflect a state of immunological activation. CsA nephrotoxicity seems to be caused by haemodynamically mediated changes [38,39]. Therefore, the measurement of soluble T-cell markers may contribute to the distinction between allograft rejection or viral infection and CsA nephrotoxicity in patients suffering from an acute deterioration in allograft function.
Different individual renal function might influence the basal level of soluble T-cell markers. This might be responsible for the overlapping of the different study groups. Studies regarding soluble IL-2R demonstrated that basal plasma levels of soluble T-cell markers are influenced by kidney function [40,41]. Therefore, the authors recommended serial measurements of soluble IL-2R to increase the sensitivity and specificity [40]. From our data regarding sCD-4 and sCD-8, a similar conclusion can be drawn.
The investigation of soluble T-cell markers and their role in immunological events leads to the questions of where they originate and what is their function. The mechanism of release of sCD-4 and sCD-8 is not known, but there are several possibilities. The shedding of cell surface molecules could be a part of their normal turnover [15], or molecules initially present in the cell membrane could be removed by enzymatic cleavage [42,43]. Another possibility is that through alternative splicing of mRNA, activated cells synthesize distinct soluble molecules, predetermined to be secreted; this mechanism is thought to account for sCD-8 [44,45]. Elevated concentrations of soluble T-cell markers may represent a sensitive marker for the level of T lymphocyte activation [15,46]. Our data support this thesis. However, the immunological function of the soluble T-cell markers remains uncertain. It is possible that sCD-8 exerts an important immunoregulatory function. It is conceivable that soluble T-cell markers could compete with cellular CD4 or CD8 for interactions with MHC molecules of allograft or antigen-presenting cells and effectively interfere with T-lymphocytetarget cell interactions. In this way, they could be immunosuppressive and decrease the acute graft rejection. A similar function was demonstrated for soluble tumour necrosis factor receptors (sTNF-RS) [47]. In addition, sCD-4 induced a migration of polymorphonuclear neutrophils (PMN) in vivo and in vitro. Thus, it is speculated that sCD-4 could be another chemotactic factor and, as such, constitutes a link within the immune system between specific and non-specific inflammatory responses [48]. The functional significance of soluble T-cell markers still awaits clarification.
In conclusion, the present study demonstrates that sCD-4 and sCD-8 are markers of immunological activation and may enable a further differentiation of T-cell activation. Therefore, a serial measurement of these soluble T-cell markers in a transplant recipient may contribute to more precise characterization of the immunological processes following kidney transplantation. However, further prospective investigations are necessary to elucidate the diagnostic potential of sCD-4 and sCD-8 for monitoring acute rejection and viral infection in kidney graft recipients.
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Received for publication: 11. 1.99
Accepted in revised form: 30. 8.99