Next-generation immunotherapy: regulatory T-cells

Cite item

Full Text

Open Access Open Access
Restricted Access Access granted
Restricted Access Subscription or Fee Access


Regulatory T lymphocytes (Treg) control the activity of immune cells and suppress the development of inflammation, maintaining the immune balance necessary for the body. Dysfunctions of Tregs are associated with the pathogenesis of autoimmune and oncological diseases. With systemic and organ-specific autoimmune reactions, as well as organ transplantation, a decrease in the function of Tregs is observed. While in the course of oncogenesis, the activity of Tregs prevents the development of an adequate immune response to tumor antigens, promotes the processes of angiogenesis and uncontrolled growth of transformed cells. Taking into account the important function of Tregs in the control of autoimmunity and oncogenesis, approaches to immunotherapy of inflammatory pathologies based on autologous and donor Tregs, as well as methods of activating an antitumor immune response as a result of selective blockade of the functional activity of Tregs, are being actively developed. The review provides an overview of technologies for modulating the activity of Tregs for the treatment of cancer, autoimmunity and adverse reactions after transplantation.

Full Text

Restricted Access

About the authors

A. V Churov

Karelian Research Center of the RAS; Center for Biomedical Research, KarRC RAS


A. V Novitskaya

Karelian Research Center of the RAS

G. A Zhulai

Karelian Research Center of the RAS


  1. Nishizuka Y., Sakakura T. Thymus and reproduction: sex-linked dysgenesia of the gonad after neonatal thymectomy in mice. Science 1969; 166 (3906): 753-5.
  2. Gershon R.K., Kondo K. Cell interactions in the induction of tolerance: the role of thymic lymphocytes. Immunol. 1970; 18(5): 723-37.
  3. Sakaguchi S., Sakaguchi N., Asano M. et al. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J. Immunol. 1995; 155(3): 1151-64.
  4. Read S., Malmstrom V., Powrie F. Cytotoxic T lymphocyte-associated antigen 4 plays an essential role in the function of CD25(+)CD4(+) regulatory cells that control intestinal inflammation. J. Exp. Med. 2000; 192(2): 295-302.
  5. Hori, S., Nomura, T., Sakaguchi, S., Control of regulatory T cell development by the transcription factor Foxp3. Science 2003; 299: 1057-61.
  6. Kumar P., Bhattacharya P., Prabhakar B.S. A comprehensive review on the role of co-signaling receptors and Treg homeostasis in autoimmunity and tumor immunity, J. Autoimmun. 2018; 95: 77-99.
  7. Liu C., Workman C.J., Vignali D.A. Targeting regulatory T cells in tumors, FEBS J. 2016; 283(14): 2731-48.
  8. Liu B., Shao Y., Liang X. et al. CTLA-4 and HLA-DQ are key molecules in the regulation of mDC-mediated cellular immunity by Tregs in severe aplastic anemia. J. Clin. Lab. Anal. 2020; e23443.
  9. Churov A.V., Mamashov K.Y., Novitskaia A.V. Homeostasis and the functional roles of CD4+ Treg cells in aging. Immunol. Lett. 2020; 226: 83-9.
  10. Abbas A.K., Benoist C., Bluestone J.A. et al., Regulatory T cells: recommendations to simplify the nomenclature. Nat. Immunol. 2013; 14 (4): 307-8.
  11. Georgiev P., Charbonnier L.M., Chatila T.A. Regulatory T Cells: the many faces of Foxp3. J. Clin. Immunol. 2019; 39(7): 623-40.
  12. Shu Y., Hu Q., Long H. et al. Epigenetic variability of CD4+CD25+ Tregs contributes to the pathogenesis of autoimmune diseases, Clin. Rev. Allergy Immunol. 2017; 52 (2): 260-72.
  13. Christoffersson G., von Herrath M. Regulatory Immune Mechanisms beyond Regulatory T Cells. Trends in Immunol. 2019; 40(6): 482-91.
  14. Cai J., Wang D., Zhang G. et al. The Role Of PD-1/PD-L1 Axis In Treg Development And Function: Implications For Cancer Immunotherapy. Onco-Targets Ther. 2019; 12: 8437-45.
  15. Saleh R., Elkord E. FoxP3+ T regulatory cells in cancer: Prognostic biomarkers and therapeutic targets. Cancer Lett. 2020; 490: 174-85.
  16. Ovcinnikovs V., Ross E.M., Petersone L. et al. CTLA-4-mediated transendocytosis of costimulatory molecules primarily targets migratory dendritic cells. Sci. Immunol. 2019; 4 (35): eaaw0902.
  17. Munn D.H., Sharma M.D., Mellor A.L. Ligation of B7-1/ B7-2 by human CD4+ T cells triggers indoleamine 2,3-dioxygenase activity in dendritic cells. J. Immunol. 2004; 172(7): 4100-10.
  18. Zhulai G.A., Oleinik E.K., Churov A.V. et al. Significance of treg cells for adenosine-mediated immune suppression in colorectal cancer. Medical Immunol. (Russia) 2017; 19 (1): 89-94.
  19. Churov A., Zhulai G. Targeting adenosine and regulatory T cells in cancer immunotherapy. Hum. Immunol. 2021; 82(4): 270-8.
  20. Wu D., Levings M.K. A New Mechanism of Action in Human and Mouse Treg Cells: The Ke(y)to Suppression. Immunity 2019; 50(5): 1122-4.
  21. Kochin V., Nishikawa, H. Meddling with meddlers: curbing regulatory T cells and augmenting antitumor immunity. Nagoya J. Med. Sci. 2019; 81: 1-18.
  22. Okeke E.B., Uzonna J.E., The pivotal role of regulatory T cells in the regulation of innate immune cells. Front. Immunol. 2019; 10: 680.
  23. Schaefer C., Kim G.G., Albers A. et al. Characteristics of CD4+CD25+ regulatory T cells in the peripheral circulation of patients with head and neck cancer. Br.J. Cancer. 2005; 92: 913-20.
  24. Liyanage U.K., Moore T.T., Joo H-G. et al. Prevalence of regulatory T cells is increased in peripheral blood and tumor microenvironment of patients with pancreas or breast adenocarcinoma. J. Immunol. 2002; 169: 2756-61
  25. Wolf A.M., Wolf D., Steurer M. et al. Increase of regulatory T cells in the peripheral blood of cancer patients. Clin. Cancer Res. 2003; 9: 606-12.
  26. Ormandy L.A., Hillemann T., Wedemeyer H. et al. Increased populations of regulatory T cells in peripheral blood of patients with hepatocellular carcinoma. Cancer Res. 2005; 65: 2457-64.
  27. Ichihara F., Kono K., Takahashi A. et al. Increased populations of regulatory T cells in peripheral blood and tumor-infiltrating lymphocytes in patients with gastric and esophageal cancers. Clin. Cancer Res. 2003; 9: 4404-8.
  28. Hiraoka N., Onozato K., Kosuge T. et al. Prevalence of FOXP3+ regulatory T cells increases during the progression of pancreatic ductal adenocarcinoma and its premalignant lesions. Clin. Cancer Res. 2006; 12: 5423-34.
  29. Sato E., Olson S.H., Ahn J. et al.Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. PnAs USA 2005; 102: 18538-43.
  30. Son J., Cho J.W., Park H.J. et al. Tumor-Infiltrating Regulatory T-cell Accumulation in the Tumor Microenvironment Is Mediated by IL33/ST2 Signaling. Cancer Immunol. Res. 2020; 8(11): 1393-406.
  31. Wang B., Zhao Q., Zhang Y. et al. Targeting hypoxia in the tumor microenvironment: a potential strategy to improve cancer immunotherapy. J. Exp. Clin. Cancer Res. 2021; 40(1): 24.
  32. Sasidharan N.V., Saleh R., Toor S.M. et al. Metabolic reprogramming of T regulatory cells in the hypoxic tumor microenvironment. Cancer Immunol. Immunother. 2021; 70: 2103-21.
  33. Angelin A., Gil-de-Gomez L., Dahiya S. et al. Foxp3 Reprograms T Cell Metabolism to Function in Low-Glucose, High-Lactate Environments. Cell Metab. 2017; 25(6): 1282-93.
  34. Alvaro T., Lejeune M., Salvado M.T. et al. Outcome in Hodgkin's lymphoma can be predicted from the presence of accompanying cytotoxic and regulatory T cells. Clin Cancer Res. 2005; 11(4): 1467-73.
  35. Frey D.M., Droeser R.A., Viehl C.T. et al. High frequency of tumor-infiltrating FOXP3(+) regulatory T cells predicts improved survival in mismatch repair-proficient colorectal cancer patients.Int. J. Cancer 2010; 126(11): 2635-43.
  36. Ward-Hartstonge K.A., Kemp R.A. Regulatory T-cell heterogeneity and the cancer immune response. Clin Transl Immunology. 2017; 6(9): e154.
  37. Saito T., Nishikawa H., Wada H. et al. Two FOXP3(+)CD4(+) T cell subpopulations distinctly control the prognosis of colorectal cancers. Nat. Med. 2016; 22(6): 679-84.
  38. Delacher M., Imbusch C.D., Weichenhan D. et al. Genome-wide DNA-methylation landscape defines specialization of regulatory T cells in tissues. Nat. Immunol. 2017; 18(10): 1160-72.
  39. Stockis J., Roychoudhuri R., Halim T.Y.F. Regulation of regulatory T cells in cancer. Immunol. 2019; 157(3): 219-31.
  40. Yano H., Andrews L.P., Workman C.J., Vignali D.A.A.Intratumoral regulatory T cells: markers, subsets and their impact on anti-tumor immunity. Immunol. 2019; 157(3): 232-47.
  41. Paluskievicz C.M., Cao X., Abdi R. et al. T regulatory cells and priming the suppressive tumor microenvironment. Front. Immunol. 2019; 10: 2453.
  42. Luke J.J., Zha Y., Matijevich K., Gajewski T. Single dose denileukin diftitox does not enhance vaccine-induced T cell responses or effectively deplete Tregs in advanced melanoma: immune monitoring and clinical results of a randomized phase II trial. J. Immunother. Cancer 2016; 4(1): 35.
  43. A Pilot Study Evaluating the Efficacy of Regulatory T-cell (T-reg) Suppression by Denileukin Diftitox (Ontak) in Metastatic Pancreatic Cancer
  44. Phase I-II Study of Denileukin Diftitox (ONTAK®) in Patients With Advanced Refractory Breast Cancer
  45. Mitchell DA, Cui X, Schmittling RJ, et al. Monoclonal antibody blockade of IL-2 receptor a during lymphopenia selectively depletes regulatory T cells in mice and humans. Blood 2011; 118(11): 3003-12.
  46. Kreitman R.J., Stetler-Stevenson М., Jaffe E.S. et al.Complete remissions of adult T cell leukemia with anti-CD25 recombinant immunotoxin LMB-2 and chemotherapy to block immunogenicity. Clin. Cancer Res. 2015; 22: 310-8.
  47. Sampson J.H., Schmittling R.J., Archer G.E. et al. A pilot study of IL-2Ra blockade during lymphopenia depletes regulatory T-cells and correlates with enhanced immunity in patients with glioblastoma. PloS One 2012; 7(2): e31046.
  48. Rech A.J., Mick R., Martin S. et al. CD25 blockade depletes and selectively reprograms regulatory T cells in concert with immunotherapy in cancer patients. Sci. Transl. Med. 2012; 4(134): 134ra62.
  49. Jacobs J.F.M., Punt C.J.A., Lesterhuis W.J. et al. Dendritic cell vaccination in combination with anti-CD25 monoclonal antibody treatment: a phase I/II study in metastatic melanoma patients. Clin. Cancer Res.2010; 16(20): 5067-78.
  50. Sharma A., Subudhi S.K., Blando J. et al., Anti-CTLA-4 immunotherapy does not deplete FOXP3+regulatory T cells (Tregs) in human cancers-response. Clin. Cancer Res. 2019; 25: 3469-70.
  51. Kamada T., Togashi Y., Tay C. et al. PD-1 + regulatory T cells amplified by PD-1 blockade promote hyperprogression of cancer. PNAS USA 2019; 116(20): 9999-10008.
  52. Yoshida K., Okamoto M., Sasaki J. et al. Anti-PD-1 antibody decreases tumour-infiltrating regulatory T cells. BMC Cancer 2020; 20(1): 25.
  53. Sasidharan N.V., Elkord, E. Immune checkpoint inhibitors in cancer therapy: a focus on T-regulatory cells. Immunol. Cell Biol. 2018; 96, 21-33.
  54. Cinier J., Hubert M., Besson L. et al. Recruitment and Expansion of Tregs Cells in the Tumor Environment-How to Target Them? Cancers (Basel) 2021; 13(8): 1850.
  55. Zappasodi R., Sirard C., Li Y. et al. Rational design of anti-GITR-based combination immunotherapy. Nat. Med. 2019; 25(5): 759-66.
  56. Gonzalez A.M., Breous E., Manrique M.L. et al. A novel agonist antibody (INCAGN01876) that targets the costimulatory receptor GITR. AACR 2016; 76(14): 3220.
  57. Zhulai GA, Churov A.V., Oleinik E.K. et al. Activation of CD4+CD39+ т cells in colorectal cancer, Bull.Russian State Medical University 2018; 7(3): 47-53.
  58. Antonioli L., Fornai M., Blandizzi C. et al. Adenosine signaling and the immune system: When a lot could be too much. Immunol. Lett. 2019; 205: 9-15.
  59. Phase1/1b Clinical Trial of E7777 for the Treatment of Patients With Peripheral T-Cell Lymphoma
  60. Phase II Evaluation of Peptide Immunization and LMB-2 in Metastatic Melanoma
  61. A Study of hTERT/Survivin Multi-peptide Vaccine With Daclizumab and Prevnar for Patients With Metastatic Breast Cancer
  62. Augmentation of Dendritic Cell Based Vaccines in Melanoma Patients by Depletion of Regulatory T Cells With an Anti-CD25 Monoclonal Antibody (Daclizumab). A Clinical Study
  63. REGULATory T-Cell Inhibition With Basiliximab (Simulect®) During Recovery From Therapeutic Temozolomide-induced Lymphopenia During Antitumor Immunotherapy Targeted Against Cytomegalovirus in Patients With Newly-Diagnosed Glioblastoma Multiforme
  64. An Open-label, Multicenter Phase 1 Study to Evaluate Safety, Tolerabil-ity, PK (Pharmacokinetics)/PD (Pharmacodynamics) of RO7296682, a T-regu-latory Cell Depleting Antibody in Participants With Advanced and/or Metastatic Solid Tumors.
  65. A Phase 1b, Open-label, Dose-escalation and Dose-expansion Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Antitumor Activity of Camidanlumab Tesirine (ADCT-301) as Monotherapy or in Combination in Patients With Selected Advanced Solid Tumors
  66. A Phase 1b, Open-label, Dose-escalation and Dose-expansion Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Antitumor Activity of Camidanlumab Tesirine (ADCT-301) as Monotherapy or in Combination in Patients With Selected Advanced Solid Tumors
  67. A Phase 1 Study of TRX518 Monotherapy and TRX518 in Combination With Gemcitabine, Pembrolizumab, or Nivolumab in Adults With Advanced Solid Tumors
  68. Part A: A First-in-Human Single Ascending Dose Study of TRX518 in Subjects With Unresectable Stage III or Stage IV Malignant Melanoma or Other Solid Tumor Malignancies Part B: A Dose-Escalation Study of Multi-dose TRX518 Monotherapy Part C: An Expansion Cohort of Multi-dose TRX518 Monotherapy at the Maximum Tolerated Dose
  69. A Phase I/Ib Open-label, Multi-center, Dose Escalation Study of GWN323 (Anti-GITR) as a Single Agent and in Combination With PDR001 (Anti-PD-1) in Patients With Advanced Solid Tumors and Lymphomas
  70. A Phase 1/2 Safety and Efficacy Study of INCAGN01876 in Combination With Immune Therapies in Subjects With Advanced or Metastatic Malignancies
  71. A Phase 1 Study of MEDI1873 (GITR Agonist) in Adult Subjects With Select Advanced Solid Tumors
  72. Phase 1 Trial of a Monoclonal Antibody to OX40 in Patients With Advanced Cancer.
  73. Phase Ib Study of a Monoclonal Antibody to OX40 (MEDI6469) Administered Prior to Definitive Surgical Resection Patients With Locore-gionally Advanced, Oral Head and Neck Squamous Cell Carcinoma
  74. Hodi F.S., O'Day Steven J., McDermott D.F. et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 2010; 363: 711-23.
  75. A Multi-center, Randomized, Double-Blind, Two-Arm, Phase III Study in Patients With Untreated Stage III (Unresectable) or IV Melanoma Receiving Dacarbazine Plus 10 mg/kg Ipilimumab (MDX-010) vs. Dacarbazine With Placebo
  76. Phase 2, Randomized, Double Blinded, Study of Nivolumab (BMS-936558) in Combination With Ipilimumab vs Ipilimumab Alone in Subjects With Previously Untreated, Unresectable or Metastatic Melanoma
  77. Phase I/IIa First-In-Human Study of EOS884448 in Participants With Advanced Cancers
  78. A Phase 1 Multiple-Dose Study to Evaluate the Safety and Toler-ability of XmAb®23104 in Subjects With Selected Advanced Solid Tumors
  79. A First-in-human, Multicenter, Open-label, Phase 1 Study in Patients With Advanced and/or Refractory Solid Malignancies to Evaluate the Safety of Intravenously Administered ATOR-1015
  80. A Phase 1 Study of AGEN1223, a Bispecific Fc-Engineered Antibody as a Single Agent and in Combination With Balstilimab, an Anti-PD-1 Monoclonal Antibody, in Subjects With Advanced Solid Tumors
  81. Open-Label, Multi-Center, Randomized Study of Anti-CCR4 Monoclonal Antibody KW-0761 (Mogamulizumab) Versus Vorinostat in Subjects With Previously Treated Cutaneous T-Cell Lymphoma https://clinicaltrials. gov/ct2/show/NCT01728805.
  82. Phase I Study of Pre-operative Combination Therapy With Mogamulizumab (Anti-CCR4) and Nivolumab (Anti-PD-1) Against Solid Cancer Patients
  83. Phase 1/1b Study of the Safety of TTX-030 as a Single Agent and in Combination With Pembrolizumab or Chemotherapy in Patients With Lymphoma or Solid Tumor Malignancies
  84. A Phase 1 Study of SRF617 in Patients With Advanced Solid Tumors
  85. A Phase 2 Open-label, Multicenter, Randomized, Multidrug Platform Study of Durvalumab (MEDI4736) Alone or in Combination With Novel Agents in Subjects With Locally Advanced, Unresectable (Stage III) Non-small Cell Lung Cancer (COAST)
  86. Dao T., Mun S.S., Scott A.C. et al. Depleting T regulatory cells by targeting intracellular Foxp3 with a TCR mimic antibody. Oncoimmunol. 2019; 8(7): 1570778.
  87. A Phase I First-in-Human Study to Evaluate the Safety, Pharmacokinetics, Pharmacodynamics and Efficacy of AZD8701 Administered Intravenously as Monotherapy and in Combination With Durvaluamb (MEDI4736) in Participants With Advanced Solid Tumours.
  88. Wang H., Wang Z., Zhang H. et al. Bispecific human IL2-CCR4 immunotoxin targets human cutaneous T-cell lymphoma. Mol. Oncol. 2020; 14(5): 991-1000.
  89. A First-in-human, Multicenter, Open-label, Phase 1 Study in Patients With Advanced and/or Refractory Solid Malignancies to Evaluate the Safety of Intravenously Administered ATOR-1015
  90. Kvarnhammar A.M., Veitonmaki N., Hagerbrand K. et al. The CTLA-4 x OX40 bispecific antibody ATOR-1015 induces anti-tumor effects through tumor-directed immune activation. J. Immunother. Cancer 2019; 7(1): 103.
  91. Wu L., Seung E., Xu et al., Trispecific antibodies enhance the therapeutic efficacy of tumor-directed T cells through T cell receptor costimulation. Nature Cancer 2020; 1: 86-98.
  92. Nakatsukasa H., Oda M., Yin J. et al. Loss of TET proteins in regulatory T cells promotes abnormal proliferation, Foxp3 destabilization and IL-17 expression.Int. Immunol. 2019; 31(5): 335-47.
  93. Scherm M.G., Serr I., Zahm A.M. et al. miRNA142-3p targets Tet2 and impairs Treg differentiation and stability in models of type 1 diabetes. Nat.Commun. 2019; 10(1): 5697.
  94. Lu J., Cheng Y., Zhang G. et al. Increased expression of neuropilin 1 in melanoma progression and its prognostic significance in patients with melanoma. Mol. Med. Rep. 2015; 12: 2668-76.
  95. Overacre-Delgoffe A.E., Chikina M., Dadey R.E. et al.Interferon-y drives Treg fragility to promote anti-tumor immunity. Cell 2017; 169: 1130-41.
  96. Abu-Eid R., Samara R.N., Ozbun L. et al. Selective inhibition of regulatory T cells by targeting the PI3K-Akt pathway. Cancer Immunol. Res. 2014; 2: 1080-9.
  97. Grinberg-Bleyer Y., Oh H., Desrichard A. et al. NF-кр c-Rel Is crucial for the regulatory T cell immune checkpoint in cancer. Cell 2017; 170: 1096-108.
  98. Denis M., Duruisseaux M., Brevet M. Dumontet C. How can immune checkpoint inhibitors cause Hyperprogression in solid tumors? Front. Immunol. 2020; 11: 492.
  99. Wood K.J., Sakaguchi S. Regulatory T cells in transplantation tolerance. Nat. Rev. Immunol. 2003; 3: 199-210.
  100. Miyara M., Yoshioka Y., Kitoh A. et al. Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor. Immunity 2009; 30: 899-911.
  101. Afeltra A., Gigante A., Margiotta D.P. et al. The involvement of T regulatory lymphocytes in a cohort of lupus nephritis patients: a pilot study.Intern. Emerg. Med. 2015; 10677-83.
  102. Comte D., Karampetsou M.P., Kis-Toth K. et al. Brief Report: CD4+ T Cells From Patients With Systemic Lupus Erythematosus Respond Poorly to Exogenous Interleukin-2. Arthritis Rheumatol. 2017; 69(4): 808-13.
  103. Liu Y., Teige I., Birnir B. et al. Neuron-mediated generation of regulatory T cells from encephalitogenic T cells suppresses EAE. Nat. Med. 2006; 12(5): 518-25.
  104. Korn T., Reddy J., Gao W. et al. Myelin-specific regulatory T cells accumulate in the CNS but fail to control autoimmune inflammation. Nat. Med. 2007; 13(4): 423-31.
  105. Viglietta V., Baecher-Allan C., Weiner H. L. et al. Loss of functional suppression by CD4+CD25+ regulatory T cells in patients with multiple sclerosis. J. Exp. Med. 2004; 199: 971-9.
  106. Kravchenko P.N., Zhulai G.A., Churov A.V. et al. Subpopulations of regulatory T-lymphocytes in the peripheral blood of patients with rheumatoid arthritis, Vestn. Ross. Akad. Med. Nauk. 2016; 71 (2): 148-53.
  107. Morita T., Shima Y., Wing J.B. et al. The proportion of regulatory T cells in patients with rheumatoid arthritis: a meta-analysis. PLoS One 2016; 11(9): e0162306.
  108. Moradi B., Schnatzer P., Hagmann S. et al. CD4(+)CD25(+)/ highCD127low/(-) regulatory T cells are enriched in rheumatoid arthritis and osteoarthritis joints-analysis of frequency and phenotype in synovial membrane, synovial fluid and peripheral blood. Arthritis Res. Ther. 2014; 16(2): R97.
  109. Marwaha A.K., Crome S.Q., Panagiotopoulos C. et al. Cutting edge: Increased IL-17-secreting T cells in children with new-onset type 1 diabetes. J. Immunol. 2010; 185(7): 3814-8.
  110. Long S.A., Cerosaletti K., Bollyky P.L. et al. Defects in IL-2R signaling contribute to diminished maintenance of FOXP3 expression in CD4(+) CD25(+) regulatory T-cells of type 1 diabetic subjects. Diabetes 2010; 59(2): 407-15.
  111. Schneider A., Rieck M., Sanda S. et al. The effector T cells of diabetic subjects are resistant to regulation via CD4+FOXP3+ regulatory T cells. J. Immunol. 2008; 181(10): 7350-5.
  112. Thiruppathi M., Rowin J., Ganesh B. et al. Impaired regulatory function in circulating CD4(+)CD25(high)CD127(low/-) T cells in patients with myasthenia gravis. Clin. Immunol. 2012; 145(3): 209-23.
  113. Masuda M., Matsumoto M., Tanaka S. et al. Clinical implication of peripheral CD4+CD25+ regulatory T cells and Th17 cells in myasthenia gravis patients. J. Neuroimmunol. 2010; 225(1-2): 123-31.
  114. Alahgholi-Hajibehzad M., Oflazer P., Aysal F. et al. Regulatory function of CD4+CD25++ T cells in patients with myasthenia gravis is associated with phenotypic changes and STAT5 signaling: 1,25-Dihydroxyvitamin D3 modulates the suppressor activity. J Neuroimmunol. 2015; 281: 51-60.
  115. Sugiyama H., Gyulai R., Toichi E. et al. Dysfunctional blood and target tissue CD4+CD25high regulatory T cells in psoriasis: mechanism underlying unrestrained pathogenic effector T cell proliferation. J. Immunol. 2005; 174(1): 164-73.
  116. Zhang K., Li X., Yin G. et al. Functional characterization of CD4+CD25+ regulatory T cells differentiated in vitro from bone marrow-derived haematopoietic cells of psoriasis patients with a family history of the disorder. Br.J. Dermatol. 2008; 158(2): 298-305.
  117. Soler D.C., Sugiyama H., Young A.B. Psoriasis patients exhibit impairment of the high potency CCR5(+) T regulatory cell subset. Clin. Immunol. 2013; 149(1): 111-8.
  118. Harden J.L., Krueger J.G., Bowcock A.M. The immunogenetics of psoriasis: a comprehensive review. J. Autoimmun. 2015; 64: 66-73.
  119. Bovenschen H.J., van de Kerkhof P.C., van Erp P.E. Foxp3+ regulatory T cells of psoriasis patients easily differentiate into IL-17A-producing cells and are found in lesional skin. J. Invest. Dermatol. 2011; 131(9): 1853-60.
  120. Pedros C., Duguet F., Saoudi A. Disrupted regulatory T cell homeostasis in inflammatory bowel diseases. World J. Gastroenterol. 2016; 22(3): 974-95.
  121. Monteleone G., Kumberova A., Croft N.M. et al. Blocking Smad7 restores TGF-beta1 signaling in chronic inflammatory bowel disease. J. Clin. Invest. 2001; 108(4): 601-19.
  122. Agus A., Planchais J., Sokol H. Gut microbiota regulation of tryptophan metabolism in health and disease. Cell Host Microbe 2018; 23: 716-24.
  123. Hoffmann P., Eder R., Kunz-Schughart L.A. et al. Edinger Large-scale in vitro expansion of polyclonal human CD4(+)CD25high regulatory T cells. Blood 2004; 104: 895-903.
  124. Liu W., Putnam A.L., Xu-Yu Z. et al. CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ Treg cells J. Exp. Med. 2006; 203: 1701-11.
  125. Trzonkowski P., Bieniaszewska M., Juscinska J. et al. 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. 2009; 133(1): 22-6.
  126. Desreumaux P., Foussat A., Allez M. et al. Safety and efficacy of antigen-specific regulatory T-cell therapy for patients with refractory Crohn's disease. Gastroenterol. 2012; 143(5): 1207-17.e2.
  127. Bluestone J.A., Buckner J.H., Fitch M. et al. Type 1 diabetes immunotherapy using polyclonal regulatory T cells. Sci Transl Med. 2015; 7(315): 315ra189.
  128. A Phase I Safety Trial of CD4+CD127lo/-CD25+ Polyclonal Treg Adoptive Immunotherapy for the Treatment of Type 1 Diabetes
  129. Marek-Trzonkowska N., Mysliwiec M., Dobyszuk A. et al. Therapy of type 1 diabetes with CD4(+)CD25(high)CD127-regulatory T cells prolongs survival of pancreatic islets - results of one year follow-up. Clin. Immunol. 2014; 153(1): 23-30.
  130. Marek-Trzonkowska N., Mysliwiec M., Iwaszkiewicz-Grzes D. et al. Factors affecting long-term efficacy of T regulatory cell-based therapy in type 1 diabetes. J. Transl. Med. 2016; 14(1): 332.
  131. A Prospective Randomized Placebo-Controlled Double Blind Clinical Trial to Evaluate the Safety and Efficacy of CLBS03 (Autologous Ex Vivo Expanded Polyclonal Regulatory T-cells) in Adolescents With Recent Onset Type 1 Diabetes Mellitus (T1DM)
  132. Wiesinger M., Stoica D., Roessner S. et al. Good Manufacturing Practice-Compliant Production and Lot-Release of Ex Vivo Expanded Regulatory T Cells As Basis for Treatment of Patients with Autoimmune and Inflammatory Disorders. Front. Immunol. 2017; 8: 1371.
  133. MacMillan M.L., Hippen K.L., McKenna D.H. et al. First-in-human phase 1 trial of induced regulatory T cells for graft-versus-host disease prophylaxis in HLA-matched siblings. Blood Adv. 2021; 5(5): 1425-36.
  134. Multiple Donor Regulatory T Cell (Treg) Infusions (T Reg DLI) for Severe Refractory Chronic Graft Versus Host Disease (GVHD) After Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)
  135. The ONE Study: A Unified Approach to Evaluating Cellular Immunotherapy in Solid Organ Transplantation - nTregs Trial
  136. Roemhild A., Otto N.M., Moll G. et al. Regulatory T cells for minimising immune suppression in kidney transplantation: phase I/IIa clinical trial. BMJ. 2020; 37: m3734.
  137. Sanchez-Fueyo A., Whitehouse G., Grageda N. et al. Applicability, safety, and biological activity of regulatory T cell therapy in liver transplantation. Am J Transplant. 2020; 20(4): 1125-36.
  138. Polyclonal Regulatory T Cell (PolyTreg) Immunotherapy in Islet Transplantation
  139. A Phase 1 Trial of CD4+CD127lo/-CD25+ Polyclonal Treg Adoptive Immunotherapy With Interleukin-2 for the Treatment of Type 1 Diabetes
  140. Phase 1 Clinical Trial Using Regulatory T Cells as Individualized Medicine to Evaluate the Safety and Efficacy in Autoimmune Hepatitis
  141. A Double-blind, Placebo Controlled, First Into Human Clinical Trial of T Regulatory Cells (TR004) for Inflammatory Bowel Disease Using (ex Vivo) Treg Expansion
  142. Dall'Era M, Pauli ML, Remedios K, Taravati K, Sandova PM, Putnam AL et al. Adoptive Treg Cell Therapy in a Patient With Systemic Lupus Erythematosus. Arthritis Rheumatol. 2019; 71(3): 431-40.
  143. A Phase I, Open-Label, Multicenter Trial Exploring the Safety and Tol-erability of Autologous Polyclonal Regulatory T Cell Therapy in Adults With Active Pemphigus (APG01)
  144. Brunstein C.G., Blazar B.R., Miller J.S. et al. Adoptive transfer of umbilical cord blood-derived regulatory T cells and early viral reactivation. Biol. Blood Marrow Transplant. 2013; 19(8): 1271-3.
  145. Putnam A.L., Safinia N., Medvec A. et al. Clinical grade manufacturing of human alloantigen-reactive regulatory T cells for use in transplantation. Am.J. Transplant. 2013; 13(11): 3010-20.
  146. Lee K., Nguyen V., Lee K.M. et al. Attenuation of donor-reactive T cells allows effective control of allograft rejection using regulatory T cell therapy. Am.J. Transplant. 2014; 14(1): 27-38.
  147. Donor-Alloantigen-Reactive Regulatory T Cell (darTreg) Therapy in Renal Transplantation: A ONE Study Clinical Trial
  148. Safety of Donor Alloantigen Reactive Tregs to Facilitate Minimization and/or Discontinuation of Immunosuppression in Adult Liver Transplant Recipients (CTOTC-12)
  149. A Phase I/II Drug Withdrawal Study of Alloantigen-Specific Tregs in Liver Transplantation
  150. Multicentre Open-Label Single Ascending Dose Dose-Ranging Phase I/IIa Study to Evaluate Safety and Tolerability of an Autologous Antigen-Specific Chimeric Antigen Receptor TRegulatory Cell Therapy in Living Donor Renal Transplant Recipients
  151. A Phase IIb, Multicentre, Randomised, Double-blinded, Placebo-controlled, Multi-dose and Multi-injection, Parallel Groups Study to Evaluate the Efficacy and the Safety of Ovasave in Patients With Active Refractory Crohn's Disease
  152. Jenkins M.K., Moon J.J. The role of naive T cell precursor frequency and recruitment in dictating immune response magnitude. J. Immunol. 2012; 188(9): 4135-40.
  153. Archila L.L., Kwok W.W. Tetramer-Guided Epitope Mapping: A Rapid Approach to Identify HLA-Restricted T-Cell Epitopes from Composite Allergens. Methods Mol. Biol. 2017; 1592: 199-209.
  154. Ge X., Gebe J.A., Bollyky P.L. et al. Peptide-MHC cellular microarray with innovative data analysis system for simultaneously detecting multiple CD4 T-cell responses. PLoS One. 2010; 5(6): e11355.
  155. Iorio A., Halimeh S., Holzhauer S. et al. Rate of inhibitor development in previously untreated hemophilia A patients treated with plasma-derived or recombinant factor VIII concentrates: a systematic review. J. Thromb. Haemost. 2010; 8(6): 1256-65.
  156. Khalilian S., Motovali-Bashi M., Rezaie H. Factor VIII: Perspectives on Immunogenicity and Tolerogenic Strategies for Hemophilia A Patients.Int. J. Mol. Cell Med. 2020; 9(1): 33-50.
  157. Calderon H., Mamonkin M., Guedan S. Analysis of CAR-Mediated Tonic Signaling. In: Swiech K., Malmegrim K., Picango-Castro V., editors. Chimeric Antigen Receptor T Cells. Methods in Molecular Biology. New York: Humana; 2020: 223-6.
  158. Siegler E.L., Kenderian S.S. Neurotoxicity and Cytokine Release Syndrome After Chimeric Antigen Receptor T Cell Therapy: Insights Into Mechanisms and Novel Therapies. Front. Immunol. 2020; 11: 1973.
  159. Helsen, C.W., Hammill, J.A., Lau, V.W.C. et al. The chimeric TAC receptor co-opts the T cell receptor yielding robust anti-tumor activity without toxicity. Nat.Commun. 2018; 9: 3049.
  160. Okada M., Kanamori M., Someya K. et al. Stabilization of Foxp3 expression by CRISPR-dCas9-based epigenome editing in mouse primary T cells. Epigenetics Chromatin 2017; (10): 24.

Copyright (c) 2021 Eco-Vector

СМИ зарегистрировано Федеральной службой по надзору в сфере связи, информационных технологий и массовых коммуникаций (Роскомнадзор).
Регистрационный номер и дата принятия решения о регистрации СМИ: ПИ № ФС 77 - 85657 от 21.07.2023 от 11.03.2014.

This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies