Mathews Journal of Immunology & Allergy


Previous Issues Volume 2, Issue 1 - 2018

Mini Review Abstract PDF  

The Importance of Regulatory T Cells for the Tolerance Maintaining After Liver Transplantation

Velislava Terzieva1 ,Tsvetelina Velikova1*, Antoaneta Mihova1, Yordanka Uzunova2 , Andrey Goncharov2 , Nona Jurukova3 ,Victoria Georgieva3 ,Metodiya Sekulovsky4 ,Yassen Mutafov4 ,Ognian Chalamanov4 , Iskra Altankova1 , Lyubomir Spassov5

1Department of Clinical Immunology, University Hospital Lozenetz, Sofia.

2Department of Pediatrics, University Hospital Lozenetz, Sofia.

3Department of Gastroenterology, University Hospital Lozenetz, Sofia.

4Intensive care Unit, University Hospital Lozenetz, Sofia.

5Department of Surgery, University Hospital Lozenetz, Sofia.

Corresponding Author: Tsvetelina Velikova, Clinical Immunology, University Hospital Lozenetz, 1 Kozyak str, 1407 Sofia. Tel: +359883306049 ; E-Mail: [email protected]

Received Date: 06 Nov 2018   Accepted Date: 08 Nov 2018   Published Date: 12 Nov 2018

Copyright © 2018 Terzieva V

Citation: Terzieva V, Tsvetelina V, Antoaneta M, Yordanka U, et al. (2018). The Importance of Regulatory T Cells for the Tolerance Maintaining After Liver Transplantation. M J Immu. 2(1): 007. 


In some cases, spontaneous inhibition of immunological reactivity in transplantation, which is responsible for the graft rejection, has been observed, a phenomenon mediated by a specific T cell population defined as regulatory T cells (Tregs). This mini-review discusses the impact of Treg cells on the in initiation and maintenance of operational tolerance after liver transplantation, the Treg cells as a biomarker for post-transplantation tolerance assessment, and the novel approach of adoptive transfer of Treg cells after liver transplantation. Currently, the data are limited and do not allow for extensive comments. However, by virtue of the immunological background, Tregs are promising as diagnosing and therapeutic application that gives hope for successful liver transplantation.


T Regulatory Cells; Treg Cells; FoxP3; liver Transplantation; Operational Tolerance; Immunosuppressive Drugs.


Immunological mechanisms in transplantation are complex and in most cases are directed towards effector reactions, leading to the graft rejection. From clinical point of view, the control of this effector reaction and the establishment of immune tolerance towards graft is ensured by the immunosuppressive therapy. However, in some cases the immune system of the recipient spontaneously develops immune tolerant milieu, a phenomenon mediated by a specific T cell population defined as regulatory T cells (Tregs) [1].

Characteristics of Treg cells

The extensive research during last decade identified several subsets of T cells with regulatory properties. Among them of most importance for the establishment of immune tolerance are natural (nTregs) and inducible (iTregs) cells. Unlike iTregs, which originate from circulating naïve T cells and are involved mainly in the regulation of inflammation and immune responses to various pathogens in the periphery [2,3], nTregs are educated and selected into the thymus directly from Tcells precursors. Those cells that recognize their own antigens with high-avidity undergo clonal deletion or transform into Tregs by increasing the expression of a FoxP3 transcription factor. When nTregs leave the thymus, they are functionally active and with stable expression of FoxP3. In contrast, iTregs are population, which depends on various factors in the environment [2,4].

Currently, two mechanisms used by Tregs for inducing tolerance are known. The contact-dependent pathway is mediated by the expression of specific molecules on the surface of Tregs, like CTLA-4 / CD80-86 and PD-1 / PD-L1, and the activation of inhibitory signals on the target cell [5]. By the contactindependent mechanism, Tregs suppress the target cell via the potent immunosuppressive effect of IL-10, TGF-β, IL-34, and IL-35 perforin and granzymes and/or competing with effector cells for the available IL-2 in the surrounding area [6]. All of the described mechanisms are crucial in establishing tolerance after transplantation.

Treg cells and operational tolerance after liver transplantation

The outcome of transplantation depends on the establishment of post-transplantation immune tolerance. It is induced by the application of immunosuppressive regimen that should be followed by patients. However, in some cases of treatment interruption, the immune system of the recipient is able to control graft rejection by it self. This status is defined as Operation tolerance. Although it is observed in kidney transplantation also, the operational tolerance is attributed mainly to the liver transplantation.

The liver has particular tolerogenic characteristics that distinguish it from other solid organs and are consequences of anatomical, biochemical and immunological features. Among them are: i) liver immune cells, incl. lymphocytes and liver parenchymal cells, ii) blood flow - systematically introducing huge range of antigens to the liver immune cells, and iii) liver cells metabolism. In addition, a number of factors of natural and acquired immunity are synthesized in the liver as complement components, acute phase proteins, cytokines, and chemokines [7-9]. The unique anatomic together with the specific cellular community suggest that the immunologic approach after the surgical operation in liver transplantation might be different from those in other solid organ transplantations.

A good example confirming it is the operational tolerance. Although several immune subsets were reported associated with it, like NK and Ƴ∂Tcells [10], Treg cells are considered as the principal one [11]. A number of studies have shown that prolonged high percentages of Tregs were seen in patients with operational tolerance alone and this observation did not depend on the immunosuppressive therapy administered in adults and children [12]. Other immunosuppressive mechanisms were shown to work in concert with the abovementioned subsets. For example, the non-classical HLA class I molecule HLA-G was associated with a decreased incidence of the liver graft acute rejection. From the other hand, the high expression of HLA-G on circulating monocytoid dendritic cells from tolerant recipients has been correlated with the increased expression of Foxp3 in T cells. This is an example of a two-way process (Tregs and HLA-G) for inducing tolerance, which are mutually potentiated [13].

Treg cells and immunosuppressive therapy after liver transplantation

From the immunosuppressive therapy, Everolimus alone has a stimulating effect on Treg cells [14, 15]. While plasma levels of the immunosuppressive drugs are the subject of clinical laboratory and pharmacology, the degree of immunosuppression is determined by the swing between activation and tolerance [15, 16]. Thus, Treg cells could be employed as a biomarker for post-transplantation tolerance. The ONE Study has already offered a specific Tregs analysis algorithm [17]. Barcelona Consensus (2016) on immunosuppressive therapy also listed Tregs as one of the possible indicators of graft rejection and control of the effectiveness of immunosuppressive therapy [18]. Some authors showed that in patients after liver transplantation the percentage of Tregs was increased significantly reaching values close to or greater than those in healthy subjects at the end of the first week after surgery [19]. We also found such tendency at the end of the first week after liver transplantation (unpublished our data).

Adoptive transfer of Treg cells after liver transplantation

Over the past few years, Tregs have been on focus not only as a diagnostic tool but also for therapeutic purposes in transplantation. At present, several studies employing Treg cells transfer in solid organ and hematopoietic stem cell transplantations are ongoing [1]. The aim of this novel therapeutic approach is to increase the number of regulatory T cells in the recipients to achieve immune tolerance and reduce the possibility of rejection. For the first time, a protocol for isolation of Tregs according to the requirements of GMP was performed in 2006 [20, 21], and adoptive Tregs transfer in 2009 [22]. Cells can be isolated from peripheral blood or umbilical cord. In most laboratories, Tregs are sorted by the CliniMACS system (CliniMACS TM Instruments, Miltenyi Biotec Bergisch Gladbach, Germany) under sterile conditions, multiplied by specific stimulation and re-injected into the patient. The second option is a flow cytometric sorting. Currently, three centers have been authorized for this operations - two in the USA (University of Minnesota, USA [23]; University of California, USA [24] and one in Europe - University of Gdansk, Poland [22].

Interestingly, of the currently ongoing eleven studies, four are for Tregs in liver transplantation. Despite the fact that they are still at an early stage, and there are many issues regarding the amount and frequency of injection of the cells, the adoptive transfer of regulatory T cells is a promising therapeutic approach [1].

Conclusion remarks

In conclusion, it is already known that regulatory T cells are essential for providing an immune-friendly environment in liver transplants. Moreover, their measurement in the peripheral blood could be useful as a diagnostic tool for early detection of graft rejection. The possibility of an adoptive transfer of regulatory T cells is a very new approach to transplantation therapy in humans. Currently, the data are limited and do not allow for extensive comments. However, by virtue of its immunological background, the evaluation and functions of Treg cells for diagnostic and follow up of immune state in liver transplantation, as well as eventual therapeutic approach, gives hope for a successful application in transplantation practice.


This mini review article is supported by the Grant No 80-10- 122/24.04.2018, Sofia University.


  1. Romano M, Tung SL, Smyth LA and Lombardi G. (2017). Treg therapy in transplantation: a general overview. Transplant International. 30(8): 745-753.
  2. Lee JH, Kang SG and Kim CH. (2011). Lymphoid Tissue Homing Receptors in Thymus but Receptors in Secondary Lymphoid Tissues 1. The Journal of Immunology.
  3. Terzieva V, Dora N Popova, Maya Kicheva and M Yankova. (2009). Correlation between the degree of immune activation, production of IL-2 and FOXP3 expression in CD4+CD25+ T regulatory cells in HIV-1 infected persons under HAART. International immunopharmacology. 9(7- 8): 831-836.
  4. Piccioni M, Chen Z, Tsun A and Li B. (2014). T Helper Cell Differentiation and Their Function. (Vol. 841).
  5. Zhang YH, Tian M, Tang MX, Liu ZZ, et al. (2015). Recent Insight into the Role of the PD-1/PD-L1 Pathway in FetoMaternal Tolerance and Pregnancy. American Journal of Reproductive Immunology. 74(3): 201-208.
  6. Sawant DV, Hamilton K and Vignali DAA. (2015). Interleukin-35: Expanding Its Job Profile. Journal of Interferon & Cytokine Research. 35(7): 499-512
  7. Nemeth E, Baird AW and O'Farrelly C. (2009). Microanatomy of the liver immune system. Semin Immunopathol. 31(3): 333-343.
  8. Crispe IN. (2009). The liver as a lymphoid organ. Annu Rev Immunol. 27: 147-163.
  9. Robinson MW, Harmon C and O'Farrelly C. (2016). Liver immunology and its role in inflammation and homeostasis. Cellular and Molecular Immunology. 13(3). 267-276.
  10. Li Y, Koshiba T, Yoshizawa A, Yonekawa Y, et al. (2004). Analyses of peripheral blood mononuclear cells in operational tolerance after pediatric living donor liver transplantation. Am J Transplant. 4(12):2118-2125.
  11. Martinez-Llordella M, Puig-Pey I, Orlando G, Ramoni M, et al. (2007). Multiparameter immune profiling of operational tolerance in liver transplantation. Am J Transplant. 7(2): 309-319.
  12. Adams DH, Sanchez-Fueyo A and Samuel D. (2015). From immunosuppression to tolerance. Journal of Hepatology. 62(S1). S170-S185. jhep.2015.02.042
  13. Amiot L, Vu N and Samson M. (2015). Biology of the immunomodulatory molecule HLA-G in human liver diseases. Journal of Hepatology. 62(6): 1430-1437.
  14. Tokiko Nagamura-Inoue, Yuki Yamamoto, Seiichiro Kobayashi, Kazuo Ogami, et al. (2012). Unique Role of mTOR Inhibitor, Everolimus in Inducible Regulatory T Cells | Blood Journal. Blood. 120: 4349.
  15. Levitsky J, Miller J, Huang X, Gallon L, et al. (2016). Immunoregulatory effects of everolimus on in vitro alloimmune responses. PLoS ONE. 11(6).
  16. Behnam Sani K and Sawitzki B. (2017). Immune monitoring as prerequisite for transplantation tolerance trials. Clinical and Experimental Immunology. 189(2): 158-170.
  17. Sebastiaan Heidt and Kathryn J Wood. (2013). Europe PMC Funders Group Europe PMC Funders Author Manuscripts BIOMARKERS OF OPERATIONAL. TOLERANCE IN SOLID ORGAN TRANSPLANTATION. 6(4): 281-293. https://
  18. Streitz M, Miloud T, Kapinsky M, Reed MR, et al. (2013). Standardization of whole blood immune phenotype monitoring for clinical trials: panels and methods from the ONE study. Transplantation Research. 2(1): 17.
  19. Brunet M, Shipkova M, Gelder T Van, Wieland E, et al. (2016). Barcelona Consensus on Biomarker-Based Immunosuppressive Drugs Management in Solid Organ Transplantation. 38(2): 1-20.
  20. Haarer J, Riquelme P, Hoffmann P, Schnitzbauer A, et al. (2016). Early Enrichment and Restitution of the Peripheral Blood Treg Pool Is Associated With Rejection-Free Stable Immunosuppression After Liver Transplantation. Transplantation. 100(7): e39-e40.
  21. Hoffmann P, Boeld T, Eder R, Albrecht J, et al. (2006). Isolation of CD4+CD25+ regulatory T cells for clinical trials. Biol Blood Marrow Transplant. 12(3): 267-274.
  22. Trzonkowski P, Bieniaszewska M, Juscinska J, Dobyszuk A, et al. (2009). First-in-man clinical results of the treatment of patients with graft versus host disease with human ex vivo expanded CD4+CD25+CD127 T regulatory cells. Clin Immunol. 133(1): 22-26.
  23. Brunstein CG, Miller JS, Cao Q, McKenna DH, et al. (2011). Infusion of ex vivo expanded T regulatory cells in adults transplanted with umbilical cord blood: safety profile and detection kinetics. Blood. 117(3): 1061-1070.
  24. Yadav M, Louvet C, Davini D, Gardner JM, et al. (2012). Neuropilin-1 distinguishes natural and inducible regulatory T cells among regulatory T cell subsets in vivo. The Journal of Experimental Medicine. 209(10): 1713-1722.

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