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Volume: 13 Issue: 1 April 2015 - Supplement - 1


T-Regulatory Cells in Chronic Rejection Versus Stable Grafts

Objectives: Studying regulatory T cells in kidney allograft acceptance versus chronic rejection may help in the understanding of more mechanisms of immune tolerance and, in the future, may enable clinicians to induce immune tolerance and decrease the use of immunosuppressive drugs. The aim of the current study was to evaluate regulatory T cells in kidney transplant patients with stable graft versus transplant with biopsy-proven chronic rejection.

Materials and Methods: The 3 groups that were studied included: kidney transplanted patients with no rejection episodes (n = 43); transplanted patients with biopsy-proven renal rejection (n = 27); and healthy age-matched nontransplanted individuals as controls (n = 42).The percentage of regulatory T cells (CD4+CD25+Foxp3+) in blood was determined by flow cytometry.

Results: The regulatory T cell percentage was significantly lower in chronic rejection patients than control or stable graft groups. No significant difference was observed in regulatory T cell percentage between the stable graft and control groups. In the stable graft group, patients on rapamycin had a significantly higher regulatory T cell percentage than patients on cyclosporine. No effect of donor type, infection, or duration after transplant was observed on regulatory T cell percentage.

Conclusions: The results of the current study are consistent with previous studies addressing the function of regulatory T cells in inducing immuno­tolerance after kidney transplant. Considering the established role of regulatory T cells in graft maintenance and our observation of high regulatory T cell percentage in patients receiving rapamycin than cyclosporine, we recommend including rapamycin when possible in immuno­suppressive protocols. The findings from the current study on the chronic rejection group support ongoing research of having treatment with regulatory T cells, which may constitute a novel, efficient antirejection therapy in the future.

Key words : Cyclosporine, End-stage renal disease, Rapamycin, Tacrolimus, Transplant


Many studies show that T cells have an important function in peripheral and central tolerance. Naturally arising CD4+ T cells that express interleukin 2 receptor (IL-2R) chain (CD25) are involved in the regulation of immune responses and maintenance of natural self tolerance. Regulatory T (Treg) cells (CD4+CD25+) are required to prevent immunologic rejection of the fetus and graft transplant.1 The Treg cells perform primary regulatory mechanisms that are used to maintain immune homeostasis and prevent autoimmunity and have regulatory functions in pregnancy and allograft tolerance.2-4

An important key transcription factor, forkhead box P3 (Foxp3), is required for Treg development, maintenance, and function. Lacking Foxp3 leads to the development of autoimmune like lymphoproliferative disease.5 The Tregs that represent 5% to 10% peripheral circulating CD4+ T cells in humans and rodents are observed in lymphoid tissue and at the graft site and can be isolated from the peripheral blood of recipients.6 Interleukin 10 (IL-10) is required for the generation and suppressor functions of Tregs.7 It was reported by van den Boogaardt and colleagues that more IL-10-producing cells were observed in kidney recipients with stable graft function than rejection.8 The Treg cells are present in 2 general categories: induced and naturally-occurring Tregs.9 There are 2 origins have been described for Foxp3+ cells. The first is the thymus, where Foxp3+ cells are generated approximately with positive selection of conventional CD4+ T cells. The second is the periphery, where a number of triggers induce the expression of Foxp3 in induced Treg cells.10 A 2-step Treg cell differentiation process occurs in which a Foxp3CD25+ population, already enriched in a T-cell-receptor sequence found in mature Treg cells, is the first intermediate. Exposure to interleukin 2 (IL-2) can convert these intermediates into fully differentiated CD25+Foxp3+ cells.11

However, some studies show that CD4+CD25+ Tregs also are found within tolerated allografts.12 The Treg cells suppress the function of the effector CD4+ T cells, CD8+ cytotoxic T cells, antigen-presenting cells, natural killer cells, and B cells.13 These are modes of action by which the Treg cells exert their regulatory effect in the induction and maintenance of transplant tolerance, anthropogenically. These include physical cell-to-cell contact with potential target cells, autocrine properties, and paracrine properties.5,14

Calcineurin inhibitors are widely used such as cyclosporine, tacrolimus, and rapamycin, which down-regulate IL-2.15 Mycophenolate mofetil has a marked effect on interleukin 4 (IL-4) expression, alloantibody deposition, and expression of other cytokines. Both mycophenolate mofetil and mammalian target of rapamycin inhibitor (mTORi) inhibit proliferation of T and B lymphocytes, which is a key mechanism thought to cause their immunosuppressive effects.16,17 Rapamycin (RAPA) (also known as sirolimus) is a macrolide antibiotic produced by Streptomyces hygroscopicus. The RAPA binds to FK506-binding protein-12, a highly conserved cytoplasmic receptor. The FK506-binding protein-12-RAPA complex binds to and inhibits the activities of the serine/threonine protein kinase mammalian target of RAPA (mTOR), the activation of which is essential for protein translation and cell cycle initiation in T cells. The RAPA can convert peripheral CD4+CD25− naive T cells to CD4+Foxp3+ Treg cells using B cells as antigen-presenting cells, and this subtype of Tregs can potently suppress T-cell effector (Teff) proliferation and maintain antigenic specificity.18 The CD25-specific monoclonal antibodies such as daclizumab and basiliximab have positive effects on the ratio of Tregs to Teff cells.14,19 In addition, Bloom and coworkers showed that alemtuzumab promotes an increase in peripheral Tregs and may act as an intrinsic generator of Tregs in vivo.20 Immunosuppressive agents used also have an effect on Tregs, to generate Treg transcription factor Foxp3 and expand or induce alloantigen-reactive Tregs in vivo and in vitro. This maintains and induces specific immune tolerance for long graft survival.21,22

The hypothesis of this study was that there is an increase in the percentage of CD4+CD25+Foxp3+ Tregs with successful renal allograft. In contrast, in patients with frequent episodes of immune-mediated (biopsy-proven) rejection, Treg cells are reduced. Studying immune tolerance induced by Treg cells (CD4+CD25+) in allograft acceptance may improve the understanding of the mechanisms involved. Understanding these immunesuppressive mechanisms might allow us to manipulate them to boost immuno­suppression and decrease the dose of immuno­suppressive drugs and their well-known serious adverse events.

Materials and Methods

Study design
This prospective study was done on kidney transplanted patients in the Nephrology Transplant Unit, Salmaniya Medical Complex, Ministry of Health, Kingdom of Bahrain. This study was a population-based case-control study that included selected kidney transplanted subjects, based on their graft stability status (either stable or having graft rejection), in which we tested the function of Treg cells in graft tolerance.

Study subjects
Individuals having the following diseases or conditions were excluded from the study: autoimmune disease, malignancy, pregnancy, or allergy. In addition, pediatric (age < 15 y) transplanted cases were excluded from this study.

The subjects were studied in 3 groups: (1) group 1, kidney transplanted patients with no rejection episodes (n = 56); (2) group 2, transplanted patients with biopsy-proven renal rejection (n = 27); 3 patients had acute rejection and the other patients had chronic rejection; and (3) group 3, healthy age-matched nontransplanted individuals as controls (n = 43). Group 1 and 2 were further divided according to duration to transplant (< 5 y, 5 - 10 y, and > 10 years) and immunosuppressive drug used (cyclosporine, RAPA, or tacrolimus).

Flow cytometry
Whole blood (2 mL) was collected from the patients and controls in tubes that contained ethylenediamine­tetraacetic acid. Peripheral blood mononuclear cells were isolated by density gradient centrifugation (Ficoll-Paque, Pharmacia, Uppsala, Sweden). The cells were used directly after isolation (control group) or frozen (-80°C). Frozen cells were first treated with 10% dimethylsulfoxide in fetal calf serum and frozen at -23°C for 30 minutes and then at -80°C until processed.

Flow cytometry analysis with 3 colors was used to detect CD4+CD25+Foxp3+ cells. A commercial kit was used that was composed of fluorochrome-conjugated antihuman CD4, CD25, and Foxp3 antibodies and the needed buffers (Human Treg Flow Kit FOXP3 Alexa Fluor 488/CD4 PE-Cy5/CD25PE, Biolegend, San Diego, CA, USA), and that had been designed and formulated specifically for flow cytometry analysis of human Treg (CD25+CD4+) cells in a mixed lymphocyte population. The test procedure was performed according to instructions from the manufacturer. Samples were read with the flow cytometer (FC500 Flow cytometer Beckman Coulter, Brea, CA, USA).

Statistical analyses
Descriptive statistics were performed to compare the various parameters between the different groups. Statistical analysis was performed using a spreadsheet (Excel 2007, Microsoft, Redmond, WA, USA) and statistical software (SPSS, Version 15.0, SPSS Inc., Chicago, IL, USA). Data were expressed as mean ± standard deviation (SD), percentage, range, and median. Differences were analyzed for statistical significance with the chi-square test. Significant differences were defined by P ≤ .05.

Ethical research approval
Transplanted patients and healthy controls recruited for the study were asked to complete and sign an informed consent form to participate in the study. After explaining to them the purpose of the study and its implications, they were asked to complete a standardized questionnaire form. Approval of the Salmaniya Medical Complex and Ministry of Health research committees was obtained, and all of the protocols conformed to the ethical guidelines of the 1975 Helsinki Declaration.


The study population included 3 groups: transplanted patients with a stable graft, transplanted patients with graft rejection, and a healthy control group with no history of transplant. There were 112 samples that were tested for percentage of Treg cells. The age of subjects ranged from 17 to 70 years. Further subgrouping was done according to sex, immunosuppressive medication (cyclosporine, RAPA, or tacrolimus), donor type (living-related, living-nonrelated, or deceased), posttransplant period (< 5 y, 5 - 10 y, or > 10 y) and presence of infection (urinary tract infection, cytomegalovirus, hepatitis B virus, or hepatitis C virus) (Table 1). Percentage of Tregs was calculated from total peripheral blood lymphocytes. Flow cytometry dot plots were generated (Figure 1).

To investigate the relation between the percentage of Tregs and graft outcome (stable or chronic rejection), we compared the percentages in the 3 groups; our results showed that percentage of Tregs was significantly lower in chronic rejection patients (0.442% ± 0.321%) than control subjects (1.576% ± 0.607%; P ≤ .001) or patients with a stable graft (1.814% ± 0.775%; P ≤ .001) (Figure 2). Comparing 2 groups simultaneously showed that the total rejection group (n = 27) had a significantly lower mean Treg percentage (0.534% ± 0.534%) than the control group (n = 42) (1.576% ± 0.607%; P ≤ .001) (Similarly, the chronic rejection group [n = 24] had a significantly lower mean Treg percentage [0.442% ± 0.321%] than the stable graft group [n = 43] [1.814% ± 0.775%; P ≤ .001]). However, no significant difference was observed in the percentage of Tregs between the stable graft group (n = 43) (1.814% ± 0.775%) and control group (n = 42) (1.576% ± 0.607%; P = .119).

To examine the effect of the immunosuppressive drug (cyclosporine, RAPA, or tacrolimus) on the percentage of Tregs, we compared the percentage of Tregs in the stable graft group according to the immunosuppressive medication. Patients on RAPA had the highest mean Treg percentage compared with the other 2 drugs and the control group (Figure 3); transplanted patients with stable graft on RAPA (n = 12) had a significantly higher Treg percentage (2.475% ± 0.638%) than patients on cyclosporine (n = 18) (1.550% ± 0.734%; P = .001); transplanted patients with stable graft on RAPA (n = 12) had a significantly higher Treg percentage (2.475% ± 0.638%) than patients on tacrolimus (n = 13) (1.569% ± 0.598%; P = .001); and transplanted patients with stable graft on RAPA (n = 12) had a significantly higher Treg percentage (2.475% ± 0.638%) than the control group (n = 42) (1.576% ± 0.607%; P < .001).

No significant difference was observed in the percentage of Tregs according to the type of donor, whether living-nonrelated (n = 39) (1.280% ± 0.860%) or living-related donor (n = 28) (1.280% ± 0.860%; P = .636) in all examined transplant recipients (n = 67). Similar findings were observed in the stable graft group (n = 43), in which there was no significant difference in the percentage of Tregs between the living-nonrelated (n = 23) (1.80% ± 0.659%) and living-related donors (n = 19) (1.744% ± 0.845%; P = .821).

No significant difference was observed in the percentage of Tregs according to presence of infection in the stable graft (n = 43) group when comparing patients with no infection (n = 39) (1.826% ± 0.754%) and patients with infection (n = 4) (1.450% ± 0.191%; P = .027). Similar findings were observed in the graft rejection group (n = 27), in which no significant difference was observed in the percentage of Tregs between patients with no infection (n = 21) (0.527% ± 0.453%) and patients with infection (n = 6) (0.560% ± 0.397%; P = .875). The small number of patients with infection affected the validity of the statistical comparison in both groups.

No significant difference was observed in the percentage of Tregs according to sex in the stable graft group (n = 43) when comparing males (n = 32) (1.745% ± 0.711%) with females (n = 11) (2.036% ± 0.682%; P = .244). Similar findings were observed in the graft rejection group (n = 27), in which no significant difference was found in the percentage of Tregs between males (n = 13) (0.418% ± 0.253%) and females (n = 14) (0.485% ± 0.372%; P = .605).

No significant difference in percentage of Tregs was observed when comparing the studied 3 periods; < 5 years (n = 24) (1.416% ± 0.817%) versus > 10 years (n = 17) (1.089% ± 0.871%; P = .215); < 5 years (n =24) (1.416% ± 0.817%) versus 5 to 10 years (n = 29) (1.430% ± 0.952%; P = .953); or 5 to 10 years (n = 29) (1.430% ± 0.952%) versus > 10 years (n = 17) (1.089% ± 0.871%; P = .239).

In summary, the results of the current study did not show any significant effect of donor type, infection, or duration posttransplant on the percentage of Tregs. However, the percentage of Tregs was affected by the immunosuppressive medication and was significantly lower in patients with graft rejection.


The current study explored the role of Tregs in kidney transplant as an immunotolerance tool of the immune system. There were 3 different groups studied: patients with stable grafts, patients with graft rejection, and healthy controls with no history of kidney transplant. The Tregs were identified as CD4+CD25+Foxp3+.

To evaluate whether clinical parameters affected the frequency of Tregs, we evaluated some transplant factors such as donor origin (whether the kidney was from related [living-related donor] vs nonrelated donor [living-nonrelated or deceased donor]) and infectious factors (BK virus, cytomegalovirus, hepatitis B virus, and hepatitis C virus). The results of our study revealed that neither the type of donor nor the presence of infection had an effect on circulating Tregs; this also was reported in other studies.6,13,23

Regarding the effect of sex, we found no significant difference in Treg percentage between male and female patients. To study the effect of duration posttransplant on Tregs, we divided the patients according to the period posttransplant into 3 subgroups: < 5 years; 5 to 10 years; and > 10 years. No significant difference was found between the 3 groups.

In this study, we showed that there was a significantly lower Treg population in patients with chronic graft rejection than stable graft. The lower percentage of Treg cells with graft rejection reflects the role of Tregs in graft acceptance. The Tregs play a central role in the induction and maintenance of transplant tolerance.24 In addition, a significant difference was found between healthy control and chronic graft rejection patients in the current study, which agrees with findings of Karczewski and coworkers.13 However, there was no significant difference between healthy controls and patients with graft acceptance, in agreement with findings of Kim and associates,6 but not with findings of other studies that found an increase in patients with graft acceptance13,25 or a significant decrease of Tregs in transplant patients compared with healthy controls.23 The variation between the different studies could be explained by the heavy immunosuppressive regimen posttransplant that may differ from 1 center to another and that affects Tregs.

We were able to measure the percentage of Tregs in 2 patients, at 2 different times: the first during the acute rejection phase and later when reaching the chronic rejection state. We observed that the level of Tregs decreased to half, which supports the role played by Tregs in maintaining immunotolerance and emphasizes the prominent role Tregs have in reversing acute rejection and preventing patients from reaching chronic rejection state. This hypothesis was supported by Zheng and coworkers, who suggested that Tregs generated ex vivo can act like a vaccine that generates host suppressor cells, with the potential to protect major histocompatibility complex-mismatched organ grafts from rejection.26 They showed this in an animal model in which they injected nontransplanted mice with a single dose of CD4+ and CD8+ Tregs, transferred donor cells every 2 weeks to mimic the continuous stimulation of a transplant, and observed increased splenic Tregs that were of recipient origin. This is further supported by another group that reported that levels of urinary mRNA for Foxp3 were correlated with the reversal of acute rejection in renal transplant patients receiving conventional immunosuppressive therapy.27

The CD4+CD25+Foxp3+ Tregs are the most important subpopulation involved in immuno­regulation. These cells have been suggested to prevent acute and chronic graft rejection. The absence of CD4+CD25+Foxp3+ T cells within the grafted kidney appears to be associated with irreversible acute rejection, indicating their role in local immuno­regulation.10 Chauhan and associates showed that the frequencies of Tregs remain the same in allograft-rejecter and allograft-acceptor patients.28 However, the frequency of Tregs isolated from the lymph nodes of the allograft-acceptor patients is significant higher than those isolated from allograft rejecters. In addition, those highly expressed Foxp3+ Tregs are functionally highly effective in preventing rejection.28 Indeed, Foxp3 is the major transcription factor associated with Treg development and function. Mutations within the Foxp3 gene locus can lead to immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) disease, type 1 diabetes, thyroiditis, hemolytic anemia, and thrombocytopenia.29

According to Kim and associates, who studied patients before and after kidney transplant and healthy matched individuals, the median frequency of Tregs in the recipients was 4.2% (range, 2.5% to 9.7%) and healthy controls was 2.7% (range, 1.6% to 5.7%).6 However, there was no significant difference between the recipients and healthy controls before transplant. They further compared the median frequencies of Tregs in patients with different underlying diseases and found no significant differences based on the underlying disease in kidney transplanted patients. According to their study, the frequency of Tregs decreased significantly after transplant. They reported the median frequency of circulating Tregs as 2% (1% to 3.6%) at 1 week, 1.6% (0.5% to 3.3%) at 2 weeks, and 2.5% (1.7% to 3.7%) at 8 weeks.6

To study the effect of immunosuppressive drugs on Tregs, we divided our patients into 3 subgroups according to the therapy taken: RAPA, cyclosporine, or tacrolimus. Patients with stable graft on RAPA had a significantly higher level of Tregs than control subjects, and patients on cyclosporine had significantly lower levels. The RAPA had the significant effect of increasing the production of Tregs, unlike cyclosporine which had an inhibitory effect. This finding is supported by several other studies.19,30-32 In contrast, other studies reported that everolimus is best, and RAPA is second best, at increasing Tregs23; we had no study patients on everolimus.

In conclusion, the results of the current study are consistent with previous studies addressing the role of Tregs in inducing immunotolerance after kidney transplant.

In summary, the following results were observed:

  • Treg percentage was significantly decreased in chronic rejection patients than control subjects or stable graft patients.
  • There was no significant difference between the percentage of Tregs in the stable graft and control groups.
  • Patients on RAPA in the stable graft group maintained a significantly higher Treg percentage than transplanted patients on cyclosporine.
  • There was no effect of donor type, infection, or duration posttransplant on Tregs.

Considering the established role of Tregs in graft maintenance, and our observation of higher Treg percentage in patients receiving RAPA than cyclosporine, we recommend that clinicians include RAPA when possible in their immunosuppressive protocols. The findings from the current study on the chronic rejection group support ongoing research about treatment with Tregs that, in the future, may constitute a novel, efficient antirejection therapy and a way to monitor progress of transplant patients.


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Volume : 13
Issue : 1
Pages : 170 - 176
DOI : 10.6002/ect.mesot2014.O149

PDF VIEW [284] KB.

From the 1Department of Microbiology and Immunology, College of Medicine, Arabian Gulf University; and the 2Departments of Pathology and 3Nephrology, Salmaniya Medical Complex, Manama, Kingdom of Bahrain
Acknowledgements: Fatima Al-Wedaie and Eman Farid have contributed equally to this work and are shared first authors. The authors have no conflicts of interest to declare. No funding was received for this study.
Corresponding author: Dr. Eman Farid, Pathology Department-Salmaniya Medical Complex-
Ministry of Health-Kingdom of Bahrain-PO Box 12
Phone: +973 17285022 Fax: +973 17285730
e-mail: -