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NDT Advance Access originally published online on June 25, 2007
Nephrology Dialysis Transplantation 2007 22(11):3221-3227; doi:10.1093/ndt/gfm361
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© The Author [2007]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org


Treatment with recombinant human erythropoietin is associated with rejuvenation of CD8+ T cell compartment in chronic renal failure patients

Piotr Trzonkowski1, Alicja Debska-Slizien2, Andrzej Mysliwski1 and Boleslaw Rutkowski2

1Department of Histology and Immunology and 2Department of Nephrology, Transplantology and Internal Diseases, Medical University of Gdansk, Poland

Correspondence and offprint requests to: Piotr Trzonkowski, MD, PhD, Department of Histology and Immunology, Medical University of Gdansk, Ul. Debinki 1, 80-211 Gdansk, Poland. Email: ptrzon{at}amg.gda.pl; piotr.trzonkowski{at}surgery.oxford.ac.uk



   Abstract
Top
 Abstract
Introduction
 Subjects and methods
 Results
 Discussion
 Acknowledgements
 References
 
Background. A growing body of evidence suggests an impact of rHuEpo on the immune system.

Methods. We assessed the impact of recombinant human erythropoietin (rHuEpo) on the immunity of 11 chronic renal failure patients who did not require haemodialysis. Naïve (Tn), central (Tcm) and effectory memory (Tcm, Tem, TemRA) subsets of CD8+ T cells, memory-CMV-specific CD8+ T cells, titres of anti-CMV antibodies and activity of NK cells were evaluated during the first year of rHuEpo administration.

Results. While the number of CD8 T cells did not change, significant change was found in their proportions. Percentage of Tn cells increased at the expense of Tcm cells. Appearing Tn cells were CD28+ increasing the total pool of CD28+ T cells. Together with decreasing number, Tcm cells changed to mainly CD28– Tcm cells. A ‘move’ towards the naïve compartment was also confirmed as the level of memory-CMV-specific CD8+ T cells decreased. Humoral immunity analysed as titres of anti-CMV antibodies as well as innate immunity measured as cytotoxicity of NK cells did not change during the follow-up.

Conclusions. We found that the administration of rHuEpo caused rejuvenation of cellular CD8+ T-dependent immunity in our patients.

Keywords: CD8+ T cells; CD28- T cells; central memory T cells; chronic renal failure; naïve T cells; recombinant human erythropoietin



   Introduction
Top
 Abstract
 Introduction
Subjects and methods
 Results
 Discussion
 Acknowledgements
 References
 
Treatment of chronic renal insufficiency with recombinant human erythropoietin (rHuEpo) was found to affect functioning of the immune system. It was the most obvious in the case of innate immunity where its action down-modulated the proinflammatory profile of mononuclear leucocytes, notably in haemodialysis patients [1–3]. Nevertheless, there are also reports that rHuEpo may affect adoptive responses [3–6]. In a series of our previous studies made on chronic haemodialysis patients we found that the drug was able to rebuild the CD8+ T cell compartment inducing apoptosis of terminally differentiated CD28– cells in the TNFR-dependent pathway [2,4,7]. The drug was also able to induce secretion of the strong stimulant of cellular responses—interleukin 2 [2,5].

As the components of cellular immunity, such as functional CD8+ T cells and the CD28+/CD28– balance, are important due to their role in immune surveillance against infections and after eventual transplantation [8,9], we were curious whether rHuEpo might exert similar effects in other groups of renal patients. In the current study we checked whether the above described rejuvenation in the CD8+ T cell compartment might be a more common effect. In order to exclude the influence of haemodialysis, we made a ‘step back’ and analysed renal insufficiency patients treated with rHuEpo who did not require haemodialysis in a 1-year-lasting follow-up. The analysis was made more detailed as we implemented a current concept of naïve/memory/effector T cell homeostasis, and four subsets of CD8+ T cells were analysed [10,11]. As the analysis of the phenotype might still be only a matter of debate, we assessed the memory cells counting T cells specific to particular pathogen, i.e., cytomegalovirus (CMV).



   Subjects and methods
Top
 Abstract
 Introduction
 Subjects and methods
Results
 Discussion
 Acknowledgements
 References
 
Patients
The patients were informed about the purpose of the study and gave written consents to it. The study was approved by The Ethical Committee of The Medical University of Gdansk.

The study was performed on 11 patients with chronic renal insufficiency who were not haemodialysed during the first year of rHuEpo treatment (Table 1). Anaemia [haemoglobin (Hb) concentration <11 g/dl] was the main reason for initiating the treatments with rHuEpo. The rHuEpo β (NeoRecormon, Roche) was administered on a weekly basis subcutaneously with a starting dose of 2000 IU per injection adjusted according to haemoglobin values aiming at a target level of 12.5 g/dl (Table 1). None of the patients received blood transfusions, or any other treatment known to interfere with the immune system, from 6 months before the beginning of the study to its end. Before the study all the patients were screened for iron metabolism and iron supplementation was administered if necessary. The indices of iron metabolism, TSAT and ferritin (Table 1), were then monitored throughout the study and intravenous iron sucrose was administered to keep them at their appropriate levels (reference values: TSAT > 20% and ferritin >200 µg/l). Iron metabolism did not affect measured lymphocyte parameters as proved in our earlier works [2,7]. None of the patients suffered from infections, severe hyperparathyroidism, uncontrolled hypertension, circulatory insufficiency or neoplasms during the study.


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  		Table 1. Patient characteristics

 
Specimen collection and preparation
Fasting venous blood samples (15 ml) were collected before the beginning of rHuEpo treatment, at 6 weeks and, at 6 and 12 months after the beginning. Additional blood samples (5 ml) were collected into tubes without any additives in order to obtain the sera at the same time. The sera were separated by centrifugation and stored at –80°C.

Reagents
The following monoclonal antibodies conjugated with the following fluorochromes: FITC, PE, ECD, PerCP, PE-Cy5 and, PE-Cy7 were used in the flow cytometric studies (clones in the brackets): anti-CD3 (UCHT1 and SK7), anti-CD8 (RPA-T8), anti-CD28 (CD28.2), anti-CD45RO (UCHL1), anti-CD45RA (HI100), anti-CD62L (Dreg 56), and appropriate isotype controls from BDBioscience, Belgium; anti-CD4 (SFCI12T4D11), anti-CD8 (SFCI21Thy2D3) and appropriate isotype controls from Immunotech, USA.

Flow cytometry
Data were acquired using an EPCS XL flow cytometer (Coulter, USA) and analysed using Winmidi 2.8 software (provided by Dr Trotter). The following phenotypes were examined in CD3+CD8+ T cells: naïve T cells (Tn) CD45RA+CD62L+, central memory T cells (Tcm) CD45RA–CD62L+ and effector memory T cells (Tem) CD45RA–CD62L– and effector memory CD45RA (TemRA) CD45RA+CD62L–. In addition, the expression of CD28 was examined in each distinguished region. The absolute number of cells was determined by multiplying the respective percentages obtained by flow cytometry by respective absolute counts from clinical laboratory reports.

Tetramer staining
To assess cellular immune memory, the number of CMV-specific CD8+ T cells in the patients was examined. Tetramer staining was performed using recombinant soluble dimeric HLA-A2:Ig (BDBioscience, UK) loaded with cytomegalovirus (CMV)-specific peptide (pp65, synthesised at the Technical University of Gdansk, Department of Biochemistry). Loading and staining was performed strictly according to the manufacturer's instructions. The samples from HLA-A2-positive patients (n = 3) were analysed at each point of the study.

Assessment of serum anti-CMV antibody titres
Titres of IgM and IgG anti-CMV antibodies from sera were measured automatically using standard Enzyme Linked Fluorescent Assay (Vidas CMV, Biomeriéux, France) according to the manufacture's suggestions.

Assessment of NK cytotoxic activity
K562 cells, the NK-sensitive erythromyeloid cell line, were harvested during the log-phase and used for the 4-h non-radioactive NK assay. The Cytotoxicity Detection Kit (BoehringerMannheim, Germany) was performed strictly according to the manufacture's suggestions.

Statistics
Data were computed using the software Statistica 7.0 (Statsoft, Poland). The analysis of data obtained from the patients was based on non-parametric tests as indicated by data distribution. P < 0.05 was recognized as significant. Only the most critical statistics are shown for clarity.



   Results
Top
 Abstract
 Introduction
 Subjects and methods
 Results
Discussion
 Acknowledgements
 References
 
Treatment with rHuEpo moved the CD8+T compartment to younger forms
Treatment with rHuEpo was associated with rejuvenation of the CD8+ T cell compartment (Figure 1B). There was significant increase in the proportion of Tn CD8+ T cells at the expense of Tcm CD8+ T cells after 1 year of the therapy. At the same time proportions of effector subsets were similar to the baseline. It has to be highlighted that the statistical significance of the switch between Tn and Tcm was achieved as early as after 1 year of the therapy (Friedman ANOVA: Tn cells: {chi}2 = 3.48 P = 0.006, Tcm cells: {chi}2 = 4.79 P = 0.002), while changes in the absolute number of these cells were still insignificant after this time (Friedman ANOVA P > 0.05).


Figure 1
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  		Fig. 1. Changing phenotype of CD8+ T cells during first year of rHuEpo treatment. (A) Example of flow cytometry quadrant analysis of CD8+ T cell subsets: Tcm, T central memory; Tn, naïve; Tem, T effector memory; TemRA, T effector memory CD45RA. (B) Percentage and number of CD8+ T cells within particular subsets during the first year of rHuEpo therapy. Percentage values (filled square) are linked to left ‘y’-axes and absolute numbers (open circle) to the right ones. (C) Percentage of CD28+ cells within CD8+ Tcm (open circle) and CD8+ Tn (filled circle) cells during the first year of rHuEpo therapy. Effector subsets are not shown for clarity of the figure. The results throughout the figure are presented as medians (symbols inside the boxes), 20–80% percentiles (boundaries of the boxes) and minimum–maximum (error bars outside the boxes).

 
In addition, we detailed increase in the proportion of CD8+CD28+ T cells after rHuEpo found in our previous study. It seems that it was dependent on naïve compartment (Figure 1C). The increase in the percentage of CD8+CD28+ Tn cells was a very early event as it was found 6 weeks after beginning of the therapy (Wilcoxon test: Z = 5.01 P = 0.01). On the other hand, the proportion of CD8+CD28+ T cells was found to be gradually decreasing within Tcm cells. Compared to Tn cells, the process in Tcm cells was slower and statistically significant difference was achieved not before 1 year of the follow-up (Friedman ANOVA: {chi}2 = 2.08 P = 0.02).

rHuEpo affected specifically cellular response
Three major components of the immune system dependent on lymphocytes, adoptive cellular and humoral compartments and innate compartment were measured in order to investigate targets of rHuEpo action (Figure 2). Adoptive immunity was assessed against particular pathogen, i.e. CMV, as the carrier status of this virus is very common among adult kidney patients.


Figure 2
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  		Fig. 2. Cellular and humoral memory and innate immunity during first year of rHuEpo treatment. (A) The number of CMV-specific CD8+ T cells assessed using dimeric HLA-A2:Ig HLA-A2 loaded with CMV pp65-peptide-specific peptide and measured in HLA-A2-positive patients (n = 3). The proportion of tetanus-specific CD8+ T cells was measured using flow cytometry and the percentage of cells was assessed within total CD8+ T cells. Each line presents single patient. (B) Levels of anti-CMV IgG antibodies in the sera. IgM antibodies were not found during the entire follow-up. (C) Percentage of NK cytotoxic activity in LDH-release test. The results in B and C are presented as medians (symbols inside the boxes), 20–80% percentiles (boundaries of the boxes) and minimum–maximum (error bars outside the boxes).

 
We found that cellular response, measured as the percentage of CMV-specific cells within total CD8+ T cells, was affected (Figure 2A). As the analysis was limited to three HLA A2+ patients, we did not include statistics but the decrease in the proportion of CMV-reactive CD8+ T cells was clear in all analysed subjects. On the other hand, there were no differences in the level of humoral immunity measured as the titre of IgG anti-CMV (Figure 2B). IgM anti-CMV were not found in any of the patients during the entire follow-up. Like humoral immunity, innate immunity measured as the cytotoxic activity of NK cells did not change either (Figure 2C) (Friedman ANOVA P > 0.05).



   Discussion
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
Acknowledgements
 References
 
In the current study we found that treatment with rHuEpo was associated with rejuvenation of the CD8+ T cell compartment. After 1 year of therapy all patients were characterized by a significant switch from memory to Tn cells. At the same time, humoral and innate compartments of immunity maintained by lymphocytes were not affected.

The currently analysed cohort represented patients different from those analysed by us previously, as they did not require haemodialysis. Thus, we might conclude that the rejuvenation of CD8+ T cell compartment after administration of rHuEpo is a quite universal phenomenon. Previously, in haemodialysis patients, we were concerned by the fact that although rHuEpo treatment left the CD8+ T compartment younger, as revealed by the increased proportion of CD8+CD28+ T cells, yet the number of total CD8+ T cells remained decreased after 1 year of the treatment [2,7]. Sadly, despite some optimistic reports [12], it confirmed the presence of impairment in the functioning of the lymphatic system in haemodialysed patients [13–15]. This was surprising, as the current views on the regulation of lymphocyte number at the periphery, especially those of memory-like phenotype, suggest that their number is actively kept at a stable individual-specific level [16]. This so-called homeostatic regulation ultimately restores the number of lymphocytes, notably CD8+ T cell number, even after so radical treatment as peripheral depletion with thymoglobulin or CAMPATH-1H at the time of kidney transplantation [17–19]. Indeed, such regulation could be fully followed in the current study, when disappearing Tcm cells were replaced by Tn cells keeping the number of CD8+ T cells at a stable level. Increased percentage of ‘new’ Tn cells at the periphery was also suggested by increasing proportion of CD28+ cells within this compartment. At the same time, decreasing proportion of CD28+ Tcm cells together with reduction in their number might suggest that these cells transformed to more differentiated effector forms. At this point we have to admit that our assumptions are based on phenotypic changes and further functional tests should be performed to show that rejuvenated immune cells actually restore immune functions in patients with renal failure. However, some indication of improved immunity after introduction of rHuEpo might be noted as changed TH1/TH2 balance towards TH1 cytokines as found in our earlier work [2].

Improvement in cellular responses associated with administration of rHuEpo was reported by several centres [2,5,14,20,21]. We have to admit that, at least in our hands, the effect was not direct since rHuEpo receptors have not been found on mature lymphocytes, and also the majority of our in vitro studies excluded such direct interactions [7]. There are few hypotheses on possible links between rHuEpo treatment and the immune system. They are focused mainly on improvement in general condition of the patients [6]. Following this concept, recovery of cellular immunity seems to be secondary to the normalization of haemoglobin levels [20]. However, recently described protective actions of both endogenous Epo or rHuEpo on the cells of epithelium, cardiac muscle, pancreatic islets and brain implicate that a much wider range of possible interactions might exist [22–24]. It is also very likely that the action of rHuEpo on lymphopoiesis might be mediated through the inhibition of proinflammatory cytokines [2,25]. These cytokines, notably the IL6 family, are known to be associated with fast involution of thymus and, as a consequence, with negative regulation of lymphopoiesis [1,26,27].

Rejuvenation of the CD8+ T compartment associated with supplementation of rHuEpo seems to be beneficial for the patients as it may contribute to substantial restoration of adaptive immunity compromised by chronic renal failure. Impairment of the immunity in patients with renal failure starts very early during the course of disease as a consequence of uraemic toxins [28,29]. Ironically, introduction of haemodialysis further deteriorates immune function which is visible as a high incidence of bacterial and viral infections and poor outcome of vaccinations in haemodialysed patients [30–32]. Thus, any therapeutic intervention that may improve immunity of those subjects seems to be advantageous. Nevertheless, rejuvenation of the CD8+ T compartment found after rHuEpo has to be discussed in relation to eventual transplantation. In theory, ‘younger’ immune system may imply more robust response to the graft. However, the recently proposed hypothesis of ‘heterologous immunity’ pointed at memory cells generated prior to transplantation as an important cause of rejections [33]. Thus, paradoxically, rejuvenation of cellular immunity associated with administration of rHuEpo has little effect on rejection rate [34]. Moreover, increased percentage of Tn cells might be beneficial in a perspective of immunosuppressive therapy administered after transplantation. Finally, it has to be noted that increased proportion of CD28– cells within the Tcm compartment found in our patients was described as a factor associated with tolerance in immunosuppression-free kidney recipients [8].

The fact that described effects were limited to CD8+ T compartment is apparently in contrast with previously described stimulatory effects of rHuEpo on humoral immunity. However, the majority of cited studies analysed antibody responses after immunisation with vaccines, i.e., after strong stimulation [35,36]. The current model was designed to analyse immune memory under steady conditions without additional boosting. CMV was chosen as a relatively common infection, which might have affected the patients previously and left immune memory, both cellular and humoral. Indeed, only one person did not reveal IgG anti-CMV and none of the patients revealed IgM anti-CMV and clinical symptoms of the infection. Thus, we might be sure that the immune memory analysed in the study was not additionally stimulated by recent antigenic challenge during the follow-up.

In summary, we found discrete change in the immune system associated with administration of rHuEpo, i.e., improved cellular immunity visible as rejuvenation of the CD8+ T cell compartment.



   Acknowledgements
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 Acknowledgements
References
 
We would like to thank the staff at the Department of Nephrology, Transplantology and Internal Diseases, Medical University of Gdansk, who provided excellent care to the patients treated and for taking all of the blood samples required for successful completion of the study. We also thank Mrs. Anita Dobyszuk for perfect technical assistance during the laboratory phase of the study. The article was supported by Medical University of Gdansk (grants: ST4 to B.R. and ST12 to A.M)

Conflict of interest statement. None declared.



   References
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 Acknowledgements
 References
 

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Received for publication: 25. 1.07
Accepted in revised form: 11. 5.07


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