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Table of Contents
ORIGINAL ARTICLE
Year : 2021  |  Volume : 15  |  Issue : 3  |  Page : 241-250

Peripheral lymphocyte subsets in acute cellular rejection in living donor liver-transplant recipients: A prospective observational study


1 Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
2 Department of Hepato-Pancreato-Biliary Surgery, Institute of Liver and Biliary Sciences, New Delhi, India
3 Department of Pathology, Institute of Liver and Biliary Sciences, New Delhi, India
4 Department of Paediatric Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India

Date of Submission08-Dec-2020
Date of Decision04-Jul-2021
Date of Acceptance24-May-2021
Date of Web Publication30-Sep-2021

Correspondence Address:
Dr. Nirupma Trehanpati
Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi - 110 070
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijot.ijot_151_20

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  Abstract 

Introduction: The aim of the study was to assess the peripheral blood lymphocyte subsets as immune markers for acute cellular rejection (ACR) in the living donor liver-transplant (LDLT) recipients using high-dimensional flow cytometry. Materials and Methods: This is a prospective observational study in which 19 LDLT recipients undergoing liver biopsy for suspected rejection were enrolled after informed and written consent. They were divided into two groups as rejection group (11/19) and no rejection group (6/19). In addition to this, nine healthy subjects were also enrolled as controls. Biochemical and immune parameters were analyzed among these groups. Results: It was observed that hematocrit, total protein, and serum albumin levels were significantly higher in rejection group as compared to no rejection group (P = 0.021, 0.006, and 0.044, respectively), whereas aspartate transaminase was significantly lower in rejection group compared to no rejection group (P = 0.027). It was seen that central memory (CM) helper T (TH) cells and CM cytotoxic T (TC) cells were significantly lower in no rejection group when compared to healthy controls (P = 0.02 and 0.009, respectively). The effector TH cells and TH1 cells were significantly higher in the rejection group when compared to healthy controls (P = 0.03 and 0.04, respectively). However, the effector CD8+ T cell and memory B cell subsets were significantly higher in rejection and no rejection group compared with healthy controls (P = 0.03, 0.01 and P = 0.02, 0.009 respectively). The activated regulatory T cells (TREG) and plasmablasts were significantly higher in no rejection group when compared with healthy control (P = 0.038 and 0.016, respectively). The naïve B cells were significantly lower in rejection and no rejection group compared to healthy controls (P = 0.001 and 0.01, respectively). However, when immune profile was compared among the rejection and no rejection group, we could not arrive at statistically significant results owing to the small sample size. Conclusion: The data in this study show that there is difference in immune profile of lymphocyte subsets among rejection and no rejection groups compared to healthy controls and hence can be used to characterize these patients. The promising immune subsets that can serve as biomarkers for ACR post-LDLT are TH1 cells, CM TH cells, effector TH cells, CM TC cells, effector TC cells, activated TREG cells, naïve B cells, memory B cells, and plasmablasts.

Keywords: Acute rejection, flow cytometry, liver transplantation, lymphocyte subsets


How to cite this article:
Kumar P, Pamecha V, Rastogi A, Khanna R, Trehanpati N. Peripheral lymphocyte subsets in acute cellular rejection in living donor liver-transplant recipients: A prospective observational study. Indian J Transplant 2021;15:241-50

How to cite this URL:
Kumar P, Pamecha V, Rastogi A, Khanna R, Trehanpati N. Peripheral lymphocyte subsets in acute cellular rejection in living donor liver-transplant recipients: A prospective observational study. Indian J Transplant [serial online] 2021 [cited 2021 Nov 29];15:241-50. Available from: https://www.ijtonline.in/text.asp?2021/15/3/241/327389


  Introduction Top


Liver transplantation (LT), which is considered as gold standard treatment for end-stage liver failure, was first conducted from cadaver donor and later from living donor in view of mitigating the deceased donor organ shortages and reducing the mortality on liver-transplant waiting lists. This gained a greater attention around the world, especially in Asian countries where deceased donation rates are low.[1],[2] Although there are immunological advantages of living donor liver-transplant (LDLT) over deceased donor LT, acute rejection (AR) is a common morbidity faced following successful living donor LT. With the introduction of better immunosuppressive regimens, there has been a steady decline in the incidence of AR, yet it remains to be a major complication in around 20%–80% of the transplants.[2],[3]

AR occurring due to a T cell-dependent process corresponds to acute cellular rejection (ACR).[4] ACR typically occurs within the first 5–30 days after transplantation, but may occur as early as 2 days or as late as months to years after transplantation, and is usually the result of suboptimal immunosuppression. Patients with ACR may experience fever, liver tenderness, and nonspecific malaise, and some may be asymptomatic with abnormal hepatic biochemistry tests and peripheral eosinophilia. The liver function tests (LFTs) usually lack specificity, and its abnormalities in ACR are due to portal inflammation, bile duct inflammation, and endothelial inflammation, which are characteristic histological criteria for diagnosing ACR in liver grafts. However, in few occasions, liver biochemical tests may remain entirely normal despite ACR.[5],[6] Many immune markers such as interleukin (IL)-2, IL-6, IL-9, IL-15, IL-17, IL-18, IL-23, interferon γ, and tumor necrosis factor α have been implicated in detecting ACR; however, in this study, we assess the new immune markers for ACR in the peripheral blood using high-dimensional flow cytometry.[7]


  Materials and Methods Top


This is a prospective observational study conducted between January 2020 and July 2020 in the Department of Molecular and Cellular Medicine in collaboration with Departments of Transplant Surgery, Hepatology, and Paediatric Hepatology at Institute of Liver and Biliary Sciences, after approval by the institutional ethics committee. Liver-transplant recipients undergoing liver biopsy for suspected rejection posttransplantation were enrolled after informed and written consent. In addition to this, healthy subjects were also enrolled in the study as controls.

Patients and subjects

A total of 19 liver-transplant recipients (adults, n = 12 and pediatric, n = 7) suspected with rejection posttransplantation before undergoing biopsy were recruited in this study. Out of the 19 patients, 11 were confirmed on liver biopsy as ACR and were considered in “rejection group.” Six patients showed no rejection in liver biopsy and were considered in “no rejection group.” Two patients showed indeterminate rejection on liver biopsy and were excluded from the study. Three patients in the rejection group were also followed up, and the second blood sample was collected 7 days posttreatment with pulsing steroid therapy. Blood from healthy subjects (healthy control; n = 9) was collected to compare the immune parameters.

Biochemical parameters

Complete blood count, LFT, and kidney function test (KFT) of the subjects enrolled in the study were taken from the hospital information system.

Blood sampling

A peripheral blood sample of around 9–10 ml was collected from all patients and healthy controls.

Analysis of immune markers

Multicolor immunophenotyping was performed in the peripheral blood of all patients and healthy controls. 70–100 μl of whole blood was used for immunophenotyping of T and B cell subsets, namely helper T (TH) cells, cytotoxic T (TC) cells, naïve T cells, effector T cells, memory T cells, central memory (CM) T cells, effector memory (EM) T cells, regulatory T (TREG) cells, naïve B cells, transitional B cells, plasmablasts, and memory B cells. Antibodies conjugated with different fluorochromes to CD3, CD4, CD8, CD45RO, CCR6, CCR7, and CXCR3 were added in the panel to identify TH cell and TC cell subsets (naïve, effector, CM, EM, TH1, TH2, and TH17 cells). Antibodies to CD3, CD4, CD25, CCR4, CD127, CD45RO, and HLA-DR were added in the second panel to identify TREG subsets (naïve, activated, and memory). Antibodies to CD19, CD20, CD24, CD27, CD38, and immunoglobulin D (IgD) were added in the third panel to identify B cell subsets (naïve, transitional, memory and plasmablasts).

In brief, 70–100 μl of whole blood was incubated with T, B, and TREG cell antibody cocktail for 30 min at room temperature. After incubation, red blood cells (RBCs) were lysed using ×1 RBC lysis buffer. Cells were centrifuged twice at 300 g for 5 min and pellet was washed with ×1 phosphate buffer saline (PBS). Finally, cell pellet was re-suspended in 200 μl of ×1 PBS and acquired on BD FACS Verse™ flow cytometer. Unstained whole blood and single color tubes were also processed as experimental controls. A total of 1 × 105–6 events were acquired as lymphocytes per tube. All cell subsets were analyzed in lymphocyte, and analysis was done using FlowJo v.10 (Ashland, OR, USA).

Statistical analysis

After the data have been collected, it was entered in a Microsoft Excel spreadsheet. Continuous variables were summarized as median and interquartile range. Categorical variables were summarized as percentage. The data were analyzed by IBM IBM SPSS v.22.0 (IBM Corp., Armonk, NY, USA) software. Wilcoxon rank-sum test was used to find any significant difference between two groups. Kruskal–Wallis test was used to find any significant difference between three groups (post hoc test was used to find a significant difference among the different groups). A P < 0.05 was considered statistically significant. Graphs were made with GraphPad Prism v.8 (San Diego, CA, USA).

Confidentiality of data

Confidentiality of the information obtained from the patient was maintained and the identity of the patient was not revealed.

Declaration of patient consent

The patient consent has been taken for participation in the study and for publication of clinical details and images. Patients understand that the names and initials would not be published, and all standard protocols will be followed to conceal their identity.

Ethical statement

Ethical approval for this study (IEC/2020/73/NA03) was provided by the Institutional Ethical Committee / Institutional Review Board of Institute of Liver and Biliary Sciences, New Delhi, India on 26 February 2020. The procedure was carried out in accordance with the Declaration of Helsinki and International Council for Harmonization-Good Clinical Practice (ICH-GCP).


  Results Top


Demography

Among 11 patients in the “rejection group,” 8 (72.7%) were male and 3 (27.3%) were female while 7 (63.6%) were adults and 4 (36.4%) were pediatric patients. The mean age in the rejection group was 33.8 ± 17.9 years (±standard deviation [SD]) (with median age of 30 years). All six patients (100%) were male among which 4 (66.7%) were adults and 2 (33.3%) were pediatric patients in the “no rejection group.” The mean age in the “no rejection group” was 31.58 ± 18.35 years (±SD) (with median age of 38.5 years) [Table 1].
Table 1: Biochemical parameters

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Biochemical parameters

It was observed that hematocrit (HCT) value was significantly lower in no rejection group compared to rejection group (P = 0.021). However, there was no significant difference in total leukocyte count, platelet count, and differential leukocyte count between the two groups. The total protein and serum albumin levels were significantly higher in rejection group as compared to no rejection group (P = 0.006 and P = 0.044, respectively). However, aspartate transaminase levels were significantly lower in rejection group compared to no rejection group (P = 0.027). Other parameters of LFT as well as KFT showed no significant difference between two groups. There was no statistically significant difference in the results of these biochemical tests between the adults and pediatric patients [Table 1].

Immune parameters

Helper T and cytotoxic T cell subsets

In this study, we have analyzed distribution of T cells (CD3+) and their subsets, i.e., TH (CD4+) and TC (CD8+) cells. On the basis of CD45RO and CCR7 surface expression levels, both TH and TC cells were further divided into four subsets each, i.e., naive (CD4+CD45RO−CCR7+), CM (CD4+CD45RO+CCR7+), EM (CD4+CD45RO+CCR7), and effector cells (CD4+CD45RO-CCR7−). In addition to these, other subsets of TH cells, i.e., TH1 (CD4+CXCR3+CCR6), TH2 (CD4+CXCR3−CCR6), and TH17 (CD4+CXCR3−CCR6+) were also analyzed. Gating strategies for same are depicted in [Figure 1].
Figure 1: Gating strategy for T cell subsets (TH – Helper T cells; EM – Effector memory; CM – Central memory; Eff – effector)

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There was no significant difference in total T, TH, and TC cells between the three groups [Figure 2]. When we analyzed TH subsets, it was seen that CM TH cells were significantly lower in no rejection group (P = 0.02); effector TH cells and TH1 cells were significantly higher in rejection group when compared to healthy controls (P = 0.03 and P = 0.04, respectively). Similarly, analysis of TC cells showed that percentage frequency of CM TC cells was significantly lower in no rejection group compared to healthy controls (P = 0.009). However, the effector CD8+ T cell subset was significantly higher in rejection and no rejection group compared with healthy controls (P = 0.03 and P = 0.01, respectively). Rest of the TH and TC subsets showed no significant difference between the three groups [Figure 3] and [Table 2], [Table 3]. When the T cell subsets were compared between the adult and pediatric patients, it was seen that TH cells were significantly higher in adults than in pediatric patients.
Figure 2: Comparison of CD3+ T cells, TH cells, and TC cells among healthy controls, patients with rejection and no rejection. (TH – Helper T cells; TC – Cytotoxic T cells)

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Figure 3: Comparison of TH and TC cell subsets among healthy controls, patients with rejection and no rejection. (TH – Helper T cells; EM – Effector memory; CM – Central memory; TC – Cytotoxic T cells)

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Table 2: T cell subsets in healthy controls and patients without rejection and with rejection

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Table 3: Comparison of significant P values among individual groups

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Regulatory T subsets

We have also analyzed TREG (CD3+CD4+CCR4+ CD25+CD127LO) and its subsets by following gating strategies. On the basis of surface expression levels of CD45RO and HLADR, TREG cells were divided into naïve TREG (CD3+CD4+CCR4+CD25+CD127LOCD45RO), memory TREG (CD3+CD4+CCR4+CD25+CD127LOCD45RO+), and activated TREG (CD3+CD4+CCR4+CD25+CD127LOHLADR+). Gating strategies for same are depicted in [Figure 4].
Figure 4: Gating strategy for TREG subsets. (TREG – Regulatory T cells)

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There was no significant difference in total TREG cells among three groups. However, the activated TREG cells were significantly higher in no rejection group when compared with healthy control (P = 0.038). Other TREG subsets showed no significant difference between the three groups [Figure 5] and [Table 2], [Table 3]. It was observed that TREG cells were significantly higher in adults than in pediatric patients.
Figure 5: Comparison of TREG subsets among healthy controls and patients with rejection and no rejection. (TREG – Regulatory T cells)

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B cell subsets

We have analyzed the distribution of B cells (CD19+) and its subsets on the basis of surface expression levels of CD24, CD38, CD21, CD27, CD20, and IgD as naïve B cells (CD19+CD27), transitional B cells (CD19+CD24hiCD38hi), memory B cells (CD19+CD27+IgD+), and plasmablasts (CD19+CD27+CD20−CD38+). Gating strategies for same are depicted in [Figure 6].
Figure 6: Gating strategy for B cell subsets

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There was no significant difference in percentage frequency of total B cells among the three groups. However, the memory B cells were significantly higher in rejection and no rejection group compared to healthy controls (P = 0.02 and P = 0.009, respectively). On the contrary, naïve B cells were significantly lower in rejection and no rejection group compared to healthy controls (P = 0.001 and P = 0.01, respectively). However, the plasmablasts were significantly higher in no rejection group when compared to healthy controls (P = 0.016) [Figure 7] and [Table 3], [Table 4]. When B cell subsets of adult rejection patients were compared with pediatric rejection patients, it was seen that naïve B cells were significantly lower in adults than in pediatric rejection patients.
Figure 7: Comparison of B cell subsets among healthy controls and patients with rejection and no rejection

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Table 4: Comparison of B cell subsets in patients with rejection-no rejection and healthy controls

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Immune parameters post treatment

The trend of each lymphocyte subset among three patients with rejection before biopsy and after treatment is shown in [Figure 8]. The lymphocyte subsets TH1 cells and CM TH cells showed a uniform declining trend, whereas TH2 cells and total B cells showed an increasing trend posttreatment. Other lymphocyte subsets showed nonuniform trend posttreatment.
Figure 8: Lymphocyte subsets among patients with rejection prebiopsy and post treatment. (TH – Helper T cells; CM – Central memory)

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  Discussion Top


Post-LT, patients are under immunosuppression which will lead to reduction in lymphocyte subsets in these patients. ACR, one of the common complications in these patients, is usually the result of suboptimal immunosuppression.[6] In accordance with this, our results also showed higher T and B cells in rejection group than in no rejection group. However, the results are not statistically significant which could be due to small sample size of no rejection group.

CM T cells are potent in mediating the rejection response but can also be converted to FoxP3+ T cells that has a regulatory role.[8],[9] Therefore, the reduced CM TH cells in no rejection group could be due to their conversion to TREG cells.

TREG cells play a regulatory role by suppressing TH cell activation and proliferation, by causing apoptosis of TC cells, and by reducing the induction of high affinity effector and memory TC cells.[10] The higher activated TREG in no rejection group is the likely reason why these patients did not progress to the rejection of their allograft.

It has been shown that TH1 cells are involved in the acute allograft rejection and several mechanisms have been explained by which they participate in transplant rejection and hence were significantly higher in rejection group compared to healthy controls.[11]

Similar to TH compartment, CM TC cells were significantly lower in no rejection group compared to healthy controls. As it is shown that CM T cells are potent in mediating the rejection response, reduction of these subsets in no rejection group is explained.[8] However, the effector TC cell subset was significantly higher in rejection and no rejection group compared with healthy controls. This shows that there is clear shift of the TC subsets from resting to activated state in posttransplant patients, due to suboptimal immunosuppression.[6]

We have observed drastic decline of naïve B cells in patients with and without rejection compared to healthy controls. This may be due to the calcineurin inhibitor (tacrolimus) which affects humoral immunity directly by suppressing naive B cells.[12] At the same time, memory B cells were significantly higher in patients with and without rejection compared to healthy controls. Pallier et al. confirmed the elevated peripheral blood B cell numbers with an increase in memory phenotype of B cells in posttransplant patients under immunosuppression.[13] The plasmablasts were significantly higher in patients without rejection when compared to healthy controls. The likely reason could be due to immune response to major histocompatibility complex components of the graft over time as a result of inadequate immunosuppression.[6]

Pulse steroid therapy induces apoptosis and suppresses cytokine secretion in TH1 cells and CM TH cells, thereby explaining the declining trend of this T lymphocyte subset in rejection patients posttreatment.[14]

Comparison in patients with rejection and without rejection

HCT values increase over time in patients after LT, and this explains the higher levels of HCT in rejection group compared to no rejection group.[15]

The total T cells were higher in rejection group when compared to no rejection group. The T lymphocyte subsets such as TC cells, EM TC cells, CM TC cells, naïve TC cells, and TH1 cells were higher rejection group when compared to no rejection group. These results clearly depicts that there is increased cell-mediated immune response in rejection group which may be due to suboptimal immunosuppression.[6] The T lymphocyte subsets, such as TH cells, CM TH cells, naïve TH cells, effector TH cells, TH2 cells, and TH17 cells, are lower in rejection group when compared to no rejection group which may be due to increased differentiation of T cells toward TC cell subsets.[4] However, the results are not statistically significant. However, in the study conducted by Fan et al.,[16] TH17 cells were higher in patients with rejection.

The B cells were higher in rejection group when compared to no rejection group. The B lymphocyte subsets, i.e., transitional B cells and memory B cells, were higher in rejection group when compared to no rejection group. These results suggest that humoral component may also have been involved in the rejection process.[6] However, the plasmablasts and naïve B cells are lower in rejection group when compared to no rejection group. However, the results are not statistically significant.

The TREG, memory TREG, and activated TREG cells are lower in rejection group when compared to no rejection group, which implies that peripheral tolerance is very much reduced in these patients which might have contributed to the rejection process. However, the naïve TREG cells are higher in rejection group when compared to no rejection group. However, the results are not statistically significant. The results of TREG cells were in accordance with the studies conducted by He et al.[17] and Demirkiran et al.[18] However, the result of activated TREG cells was not in accordance with the study conducted by Boix et al.[19]

Limitations of the study

The study was limited by small sample size.


  Conclusion Top


The data in our study show that there is difference in immune profile of lymphocyte subsets among posttransplant patients with and without rejection compared to healthy controls and hence can be used to characterize these patients. When immune profile of lymphocyte subsets was compared among the patients with and without rejection, it was seen that there was difference between the two groups, but we could not arrive at statistically significant results owing to the small sample size. The promising immune subsets that can serve as biomarkers for ACR post-LDLT are TH1 cells, CM TH cells, effector TH cells, CM TC cells, effector TC cells, activated TREG cells, naïve B cells, memory B cells, and plasmablasts.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

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Bozkurt B, Dayangac M, Tokat Y. Living donor liver transplantation. Chirurgia (Bucur) 2017;112:217-28.  Back to cited text no. 1
    
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Goldaracena N, Barbas AS. Living donor liver transplantation. Curr Opin Organ Transplant 2019;24:131-7.  Back to cited text no. 2
    
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Wei Q, Wang K, He Z, Ke Q, Xu X, Zheng S. Acute liver allograft rejection after living donor liver transplantation: Risk factors and patient survival. Am J Med Sci 2018;356:23-9.  Back to cited text no. 3
    
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Moreau A, Varey E, Anegon I, Cuturi MC. Effector mechanisms of rejection. Cold Spring Harb Perspect Med 2013;3:a015461.  Back to cited text no. 4
    
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Kok B, Dong V, Karvellas CJ. Graft dysfunction and management in liver transplantation. Crit Care Clin 2019;35:117-33.  Back to cited text no. 5
    
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Koo J, Wang HL. Acute, chronic, and humoral rejection: Pathologic features under current immunosuppressive regimes. Surg Pathol Clin 2018;11:431-52.  Back to cited text no. 6
    
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Germani G, Rodriguez-Castro K, Russo FP, Senzolo M, Zanetto A, Ferrarese A, et al. Markers of acute rejection and graft acceptance in liver transplantation. World J Gastroenterol 2015;21:1061-8.  Back to cited text no. 7
    
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Li XC, Kloc M, Ghobrial RM. Memory T cells in transplantation - Progress and challenges. Curr Opin Organ Transplant 2013;18:387-92.  Back to cited text no. 8
    
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Chen W, Ghobrial RM, Li XC. The evolving roles of memory immune cells in transplantation. Transplantation 2015;99:2029-37.  Back to cited text no. 9
    
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Romano M, Fanelli G, Albany CJ, Giganti G, Lombardi G. Past, present, and future of regulatory T cell therapy in transplantation and autoimmunity. Front Immunol 2019;10:43.  Back to cited text no. 10
    
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Liu Z, Fan H, Jiang S. CD4(+) T-cell subsets in transplantation. Immunol Rev 2013;252:183-91.  Back to cited text no. 11
    
12.
De Bruyne R, Bogaert D, De Ruyck N, Lambrecht BN, Van Winckel M, Gevaert P, et al. Calcineurin inhibitors dampen humoral immunity by acting directly on naive B cells. Clin Exp Immunol 2015;180:542-50.  Back to cited text no. 12
    
13.
Pallier A, Hillion S, Danger R, Giral M, Racapé M, Degauque N, et al. Patients with drug-free long-term graft function display increased numbers of peripheral B cells with a memory and inhibitory phenotype. Kidney Int 2010;78:503-13.  Back to cited text no. 13
    
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Banuelos J, Lu NZ. A gradient of glucocorticoid sensitivity among helper T cell cytokines. Cytokine Growth Factor Rev 2016;31:27-35.  Back to cited text no. 14
    
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Zingone F, Santonicola A, Mancusi A, Ciacci C, Parrilli G. The Hct values after liver transplantation. Gastroenterol Hepatol Endosc 2017;2:1-3.  Back to cited text no. 15
    
16.
Fan H, Li LX, Han DD, Kou JT, Li P, He Q. Increase of peripheral Th17 lymphocytes during acute cellular rejection in liver transplant recipients. Hepatobiliary Pancreat Dis Int 2012;11:606-11.  Back to cited text no. 16
    
17.
He Q, Fan H, Li JQ, Qi HZ. Decreased circulating CD4+CD25highFoxp3+ T cells during acute rejection in liver transplant patients. Transplant Proc 2011;43:1696-700.  Back to cited text no. 17
    
18.
Demirkiran A, Kok A, Kwekkeboom J, Kusters JG, Metselaar HJ, Tilanus HW, et al. Low circulating regulatory T-cell levels after acute rejection in liver transplantation. Liver Transpl 2006;12:277-84.  Back to cited text no. 18
    
19.
Boix F, Millan O, San Segundo D, Mancebo E, Miras M, Rimola A, et al. Activated regulatory T cells expressing CD4(+) CD25(high) CD45RO(+)CD62L(+) biomarkers could be a risk factor in liver allograft rejection. Transplant Proc 2015;47:2380-1.  Back to cited text no. 19
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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