Indoleamine 2,3‑dioxygenase suppresses humoral alloimmunity via pathways that different to those associated with its effects on T cells

  • Authors:
    • Maria Sounidaki
    • Georgios Pissas
    • Theodoros Eleftheriadis
    • Georgia Antoniadi
    • Spyridon Golfinopoulos
    • Vassilios Liakopoulos
    • Ioannis Stefanidis
  • View Affiliations

  • Published online on: May 16, 2019     https://doi.org/10.3892/br.2019.1212
  • Pages: 323-330
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

Chronic antibody‑mediated rejection remains a major cause of late graft loss. Regarding cellular alloimmunity, the immunosuppressive properties of indoleamine 2,3‑dioxygenase (IDO) have been well investigated; however, little is known of its effects on humoral alloimmunity. Therefore, the present study aimed to evaluate the effects of IDO on humoral alloimmunity. We developed a method for the induction of humoral alloimmunity in a one‑way mixed lymphocyte reaction (MLR), which was measured with an antibody‑mediated complement‑dependent cytotoxicity assay using resting cells, which are similar to the stimulator cells of the aforementioned MLR. In parallel, cellular alloimmunity was assessed in two‑way MLRs. The IDO inhibitor 1‑methyl‑DL‑tryptophan was used for evaluating the role of IDO. In order to investigate whether the pathways known to serve a role in the effects of IDO on T cells are applied in humoral alloimmunity, the general control nonderepressible‑2 (GCN‑2) kinase activator tryptophanol and the aryl hydrocarbon receptor (AhR) inhibitor CH223191 were employed. The IDO inhibitor was revealed to increased cellular autoimmunity, but was decreased by the GCN‑2 kinase activator. Unexpectedly, the AhR inhibitor decreased cellular alloimmunity. In addition, the IDO inhibitor was observed to suppress humoral alloimmunity, which may occur in manners independent of GCN‑2 kinase AhR. The present study proposed that IDO may decrease humoral alloimmunity in primary human peripheral blood mononuclear cells via pathways that differ to those associated with its effect on T cells.

References

1 

Solez K, Colvin RB, Racusen LC, Sis B, Halloran PF, Birk PE, Campbell PM, Cascalho M, Collins AB, Demetris AJ, et al: Banff '05 Meeting Report: Differential diagnosis of chronic allograft injury and elimination of chronic allograft nephropathy (‘CAN’). Am J Transplant. 7:518–526. 2007.PubMed/NCBI View Article : Google Scholar

2 

Solez K, Colvin RB, Racusen LC, Haas M, Sis B, Mengel M, Halloran PF, Baldwin W, Banfi G, Collins AB, et al: Banff 07 classification of renal allograft pathology: Updates and future directions. Am J Transplant. 8:753–760. 2008.PubMed/NCBI View Article : Google Scholar

3 

Munn DH, Zhou M, Attwood JT, Bondarev I, Conway SJ, Marshall B, Brown C and Mellor AL: Prevention of allogeneic fetal rejection by tryptophan catabolism. Science. 281:1191–1193. 1998.PubMed/NCBI View Article : Google Scholar

4 

King NJC and Thomas SR: Molecules in focus: Indoleamine 2,3-dioxygenase. Int J Biochem Cell Biol. 39:2167–2172. 2007.PubMed/NCBI View Article : Google Scholar

5 

Curti A, Trabanelli S, Salvestrini V, Baccarani M and Lemoli RM: The role of indoleamine 2,3-dioxygenase in the induction of immune tolerance: Focus on hematology. Blood. 113:2394–2401. 2009.PubMed/NCBI View Article : Google Scholar

6 

Munn DH, Sharma MD, Baban B, Harding HP, Zhang Y, Ron D and Mellor AL: GCN2 kinase in T cells mediates proliferative arrest and anergy induction in response to indoleamine 2,3-dioxygenase. Immunity. 22:633–642. 2005.PubMed/NCBI View Article : Google Scholar

7 

Mezrich JD, Fechner JH, Zhang X, Johnson BP, Burlingham WJ and Bradfield CA: An interaction between kynurenine and the aryl hydrocarbon receptor can generate regulatory T cells. J Immunol. 185:3190–3198. 2010.PubMed/NCBI View Article : Google Scholar

8 

Eleftheriadis T, Pissas G, Yiannaki E, Markala D, Arampatzis S, Antoniadi G, Liakopoulos V and Stefanidis I: Inhibition of indoleamine 2,3-dioxygenase in mixed lymphocyte reaction affects glucose influx and enzymes involved in aerobic glycolysis and glutaminolysis in alloreactive T-cells. Hum Immunol. 74:1501–1509. 2013.PubMed/NCBI View Article : Google Scholar

9 

Eleftheriadis T, Pissas G, Antoniadi G, Spanoulis A, Liakopoulos V and Stefanidis I: Indoleamine 2,3-dioxygenase increases p53 levels in alloreactive human T cells, and both indoleamine 2,3-dioxygenase and p53 suppress glucose uptake, glycolysis and proliferation. Int Immunol. 26:673–684. 2014.PubMed/NCBI View Article : Google Scholar

10 

Eleftheriadis T, Pissas G, Antoniadi G, Liakopoulos V and Stefanidis I: Indoleamine 2,3-dioxygenase depletes tryptophan, activates general control non-derepressible 2 kinase and down-regulates key enzymes involved in fatty acid synthesis in primary human CD4+ T cells. Immunology. 146:292–300. 2015.PubMed/NCBI View Article : Google Scholar

11 

Eleftheriadis T, Pissas G, Antoniadi G, Tsogka K, Sounidaki M, Liakopoulos V and Stefanidis I: Indoleamine 2,3 dioxygenase downregulates T cell receptor complex ζ chain and c Myc, and reduces proliferation, lactate dehydrogenase levels and mitochondrial glutaminase in human T cells. Mol Med Rep. 13:925–932. 2016.PubMed/NCBI View Article : Google Scholar

12 

Eleftheriadis T, Pissas G, Sounidaki M, Tsogka K, Antoniadis N, Antoniadi G, Liakopoulos V and Stefanidis I: Indoleamine 2,3-dioxygenase, by degrading L-tryptophan, enhances carnitine palmitoyltransferase I activity and fatty acid oxidation, and exerts fatty acid-dependent effects in human alloreactive CD4+ T-cells. Int J Mol Med. 38:1605–1613. 2016.PubMed/NCBI View Article : Google Scholar

13 

Vavrincova-Yaghi D, Deelman LE, Goor H, Seelen M, Kema IP, Smit-van Oosten A, Zeeuw D, Henning RH and Sandovici M: Gene therapy with adenovirus-delivered indoleamine 2,3-dioxygenase improves renal function and morphology following allogeneic kidney transplantation in rat. J Gene Med. 13:373–381. 2011.PubMed/NCBI View Article : Google Scholar

14 

Sun X, Gong ZJ, Wang ZW, Li T, Zhang JY, Sun HC, Liu S, Huang L, Huang C and Peng ZH: IDO-competent-DCs induced by IFN-γ attenuate acute rejection in rat liver transplantation. J Clin Immunol. 32:837–847. 2012.PubMed/NCBI View Article : Google Scholar

15 

Iken K, Liu K, Liu H, Bizargity P, Wang L, Hancock WW and Visner GA: Indoleamine 2,3-dioxygenase and metabolites protect murine lung allografts and impair the calcium mobilization of T cells. Am J Respir Cell Mol Biol. 47:405–416. 2012.PubMed/NCBI View Article : Google Scholar

16 

Hosseini-Tabatabaei A, Jalili RB, Khosravi-Maharlooei M, Hartwell R, Kilani RT, Zhang Y and Ghahary A: Immunoprotection and Functional Improvement of Allogeneic Islets in Diabetic Mice, Using a Stable Indoleamine 2,3-Dioxygenase Producing Scaffold. Transplantation. 99:1341–1348. 2015.PubMed/NCBI View Article : Google Scholar

17 

Xie FT, Cao JS, Zhao J, Yu Y, Qi F and Dai XC: IDO expressing dendritic cells suppress allograft rejection of small bowel transplantation in mice by expansion of Foxp3+ regulatory T cells. Transpl Immunol. 33:69–77. 2015.PubMed/NCBI View Article : Google Scholar

18 

He Y, Zhou S, Liu H, Shen B, Zhao H, Peng K and Wu X: Indoleamine 2,3-Dioxgenase Transfected Mesenchymal Stem Cells Induce Kidney Allograft Tolerance by Increasing the Production and Function of Regulatory T cells. Transplantation. 99:1829–1838. 2015.PubMed/NCBI View Article : Google Scholar

19 

Ebrahimi A, Kardar GA, Teimoori-Toolabi L, Ghanbari H and Sadroddiny E and Sadroddiny E: Inducible expression of indoleamine 2,3-dioxygenase attenuates acute rejection of tissue-engineered lung allografts in rats. Gene. 576:412–420. 2016.PubMed/NCBI View Article : Google Scholar

20 

Li C, Liu T, Zhao N, Zhu L, Wang P and Dai X: Dendritic cells transfected with indoleamine 2,3-dioxygenase gene suppressed acute rejection of cardiac allograft. Int Immunopharmacol. 36:31–38. 2016.PubMed/NCBI View Article : Google Scholar

21 

Na N, Luo Y, Zhao D, Yang S, Hong L, Li H, Miao B and Qiu J: Prolongation of kidney allograft survival regulated by indoleamine 2, 3-dioxygenase in immature dendritic cells generated from recipient type bone marrow progenitors. Mol Immunol. 79:22–31. 2016.PubMed/NCBI View Article : Google Scholar

22 

Khosravi-Maharlooei M, Pakyari M, Jalili RB, Kilani RT and Ghahary A: Intraperitoneal injection of IDO-expressing dermal fibroblasts improves the allograft survival. Clin Immunol. 174:1–9. 2017.PubMed/NCBI View Article : Google Scholar

23 

Jia L, Schweikart K, Tomaszewski J, Page JG, Noker PE, Buhrow SA, Reid JM, Ames MM and Munn DH: Toxicology and pharmacokinetics of 1-methyl-d-tryptophan: Absence of toxicity due to saturating absorption. Food Chem Toxicol. 46:203–211. 2008.PubMed/NCBI View Article : Google Scholar

24 

Alexander AM, Crawford M, Bertera S, Rudert WA, Takikawa O, Robbins PD and Trucco M: Indoleamine 2,3-dioxygenase expression in transplanted NOD Islets prolongs graft survival after adoptive transfer of diabetogenic splenocytes. Diabetes. 51:356–365. 2002.PubMed/NCBI View Article : Google Scholar

25 

Sakurai K, Zou J-P, Tschetter JR, Ward JM and Shearer GM: Effect of indoleamine 2,3-dioxygenase on induction of experimental autoimmune encephalomyelitis. J Neuroimmunol. 129:186–196. 2002.PubMed/NCBI View Article : Google Scholar

26 

Uyttenhove C, Pilotte L, Théate I, Stroobant V, Colau D, Parmentier N, Boon T and Van den Eynde BJ: Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase. Nat Med. 9:1269–1274. 2003.PubMed/NCBI View Article : Google Scholar

27 

Lowe G and Tansley G: An investigation of the mechanism of activation of tryptophan by tryptophanyl-tRNA synthetase from beef pancreas. Eur J Biochem. 138:597–602. 1984.PubMed/NCBI View Article : Google Scholar

28 

Kim SH, Henry EC, Kim DK, Kim YH, Shin KJ, Han MS, Lee TG, Kang JK, Gasiewicz TA, Ryu SH, et al: Novel compound 2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazo-phenyl)-amide (CH-223191) prevents 2,3,7,8-TCDD-induced toxicity by antagonizing the aryl hydrocarbon receptor. Mol Pharmacol. 69:1871–1878. 2006.PubMed/NCBI View Article : Google Scholar

29 

Eleftheriadis T, Pissas G, Antoniadi G, Liakopoulos V, Tsogka K, Sounidaki M and Stefanidis I: Differential effects of the two amino acid sensing systems, the GCN2 kinase and the mTOR complex 1, on primary human alloreactive CD4+ T-cells. Int J Mol Med. 37:1412–1420. 2016.PubMed/NCBI View Article : Google Scholar

30 

Eleftheriadis T, Pissas G, Antoniadi G, Liakopoulos V and Stefanidis I: Kynurenine, by activating aryl hydrocarbon receptor, decreases erythropoietin and increases hepcidin production in HepG2 cells: A new mechanism for anemia of inflammation. Exp Hematol. 44:60–7, e1. 2016.PubMed/NCBI View Article : Google Scholar

31 

Berridge MV, Herst PM and Tan AS: Tetrazolium dyes as tools in cell biology: New insights into their cellular reduction. Biotechnol Annu Rev. 11:127–152. 2005.PubMed/NCBI View Article : Google Scholar

32 

Eleftheriadis T, Pissas G, Karioti A, Antoniadi G, Liakopoulos V, Dafopoulou K, Pournaras S, Koukoulis G and Stefanidis I: The indoleamine 2,3-dioxygenase inhibitor 1-methyl-tryptophan suppresses mitochondrial function, induces aerobic glycolysis and decreases interleukin-10 production in human lymphocytes. Immunol Invest. 41:507–520. 2012.PubMed/NCBI View Article : Google Scholar

33 

Meo T: The MLR test in the mouse. In: Immunological methods. Lefkovits I and Pernis B (eds). Academic Press, New York, NY. pp227–239. 1979.

34 

Rümke HC, Terpstra FG, Huis B, Out TA and Zeijlemaker WP: Immunoglobulin production in human mixed lymphocyte cultures: Implications for co-cultures of cells from patients and healthy donors. J Immunol. 128:696–701. 1982.PubMed/NCBI

35 

Konishi E, Kitai Y and Kondo T: Utilization of complement-dependent cytotoxicity to measure low levels of antibodies: Application to nonstructural protein 1 in a model of Japanese encephalitis virus. Clin Vaccine Immunol. 15:88–94. 2008.PubMed/NCBI View Article : Google Scholar

36 

Sato T, Deiwick A, Raddatz G, Koyama K and Schlitt HJ: Interactions of allogeneic human mononuclear cells in the two-way mixed leucocyte culture (MLC): Influence of cell numbers, subpopulations and cyclosporin. Clin Exp Immunol. 115:301–308. 1999.PubMed/NCBI View Article : Google Scholar

37 

Cai LJ, Yu DW, Gao Y, Yang C, Zhou HM and Chen ZK: Activation of aryl hydrocarbon receptor prolongs survival of fully mismatched cardiac allografts. J Huazhong Univ Sci Technolog Med Sci. 33:199–204. 2013.PubMed/NCBI View Article : Google Scholar

38 

Lee JA, Hwang JA, Sung HN, Jeon CH, Gill BC, Youn HJ and Park JH: 2,3,7,8-Tetrachlorodibenzo-p-dioxin modulates functional differentiation of mouse bone marrow-derived dendritic cells Downregulation of RelB by 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicol Lett. 173:31–40. 2007.PubMed/NCBI View Article : Google Scholar

39 

Julliard W, Fechner JH and Mezrich JD: The aryl hydrocarbon receptor meets immunology: Friend or foe? A little of both. Front Immunol. 5(458)2014.PubMed/NCBI View Article : Google Scholar

40 

Panchanathan R, Liu H and Choubey D: Activation of p53 in Human and Murine Cells by DNA-Damaging Agents Differentially Regulates Aryl Hydrocarbon Receptor Levels. Int J Toxicol. 34:242–249. 2015.PubMed/NCBI View Article : Google Scholar

41 

Shinde R, Shimoda M, Chaudhary K, Liu H, Mohamed E, Bradley J, Kandala S, Li X, Liu K and McGaha TL: B cell-Intrinsic IDO1 Regulates Humoral Immunity to T cell-Independent Antigens. J Immunol. 195:2374–2382. 2015.PubMed/NCBI View Article : Google Scholar

42 

Criado G, Simelyte E, Inglis JJ, Essex D and Williams RO: Indoleamine 2,3 dioxygenase-mediated tryptophan catabolism regulates accumulation of Th1/Th17 cells in the joint in collagen-induced arthritis. Arthritis Rheum. 60:1342–1351. 2009.PubMed/NCBI View Article : Google Scholar

43 

Scott GN, DuHadaway J, Pigott E, Ridge N, Prendergast GC, Muller AJ and Mandik-Nayak L: The immunoregulatory enzyme IDO paradoxically drives B cell-mediated autoimmunity. J Immunol. 182:7509–7517. 2009.PubMed/NCBI View Article : Google Scholar

44 

Xu H, Oriss TB, Fei M, Henry AC, Melgert BN, Chen L, Mellor AL, Munn DH, Irvin CG, Ray P, et al: Indoleamine 2,3-dioxygenase in lung dendritic cells promotes Th2 responses and allergic inflammation. Proc Natl Acad Sci USA. 105:6690–6695. 2008.PubMed/NCBI View Article : Google Scholar

45 

Merlo LMF, Pigott E, DuHadaway JB, Grabler S, Metz R, Prendergast GC and Mandik-Nayak L: IDO2 is a critical mediator of autoantibody production and inflammatory pathogenesis in a mouse model of autoimmune arthritis. J Immunol. 192:2082–2090. 2014.PubMed/NCBI View Article : Google Scholar

46 

Merlo LMF, DuHadaway JB, Grabler S, Prendergast GC, Muller AJ and Mandik-Nayak L: IDO2 Modulates T cell-Dependent Autoimmune Responses through a B Cell-Intrinsic Mechanism. J Immunol. 196:4487–4497. 2016.PubMed/NCBI View Article : Google Scholar

47 

Yoshida T, Katsuya K, Oka T, Koizumi S, Wakita D, Kitamura H and Nishimura T: Effects of AhR ligands on the production of immunoglobulins in purified mouse B cells. Biomed Res. 33:67–74. 2012.PubMed/NCBI View Article : Google Scholar

48 

Wourms MJ and Sulentic CEW: The aryl hydrocarbon receptor regulates an essential transcriptional element in the immunoglobulin heavy chain gene. Cell Immunol. 295:60–66. 2015.PubMed/NCBI View Article : Google Scholar

49 

Eleftheriadis T, Liakopoulos V, Antoniadi G, Stefanidis I and Galaktidou G: Indoleamine 2,3-dioxygenase is increased in hemodialysis patients and affects immune response to hepatitis B vaccination. Vaccine. 29:2242–2247. 2011.PubMed/NCBI View Article : Google Scholar

50 

Eleftheriadis T, Sparopoulou T, Antoniadi G, Liakopoulos V, Stefanidis I and Galaktidou G: Suppression of humoral immune response to hepatitis B surface antigen vaccine in BALB/c mice by 1-methyl-tryptophan co-administration. Daru. 19:236–239. 2011.PubMed/NCBI

51 

Patel AA, Zhang Y, Fullerton JN, Boelen L, Rongvaux A, Maini AA, Bigley V, Flavell RA, Gilroy DW, Asquith B, et al: The fate and lifespan of human monocyte subsets in steady state and systemic inflammation. J Exp Med. 214:1913–1923. 2017.PubMed/NCBI View Article : Google Scholar

Related Articles

Journal Cover

June 2019
Volume 10 Issue 6

Print ISSN: 2049-9434
Online ISSN:2049-9442

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
APA
Sounidaki, M., Pissas, G., Eleftheriadis, T., Antoniadi, G., Golfinopoulos, S., Liakopoulos, V., & Stefanidis, I. (2019). Indoleamine 2,3‑dioxygenase suppresses humoral alloimmunity via pathways that different to those associated with its effects on T cells. Biomedical Reports, 10, 323-330. https://doi.org/10.3892/br.2019.1212
MLA
Sounidaki, M., Pissas, G., Eleftheriadis, T., Antoniadi, G., Golfinopoulos, S., Liakopoulos, V., Stefanidis, I."Indoleamine 2,3‑dioxygenase suppresses humoral alloimmunity via pathways that different to those associated with its effects on T cells". Biomedical Reports 10.6 (2019): 323-330.
Chicago
Sounidaki, M., Pissas, G., Eleftheriadis, T., Antoniadi, G., Golfinopoulos, S., Liakopoulos, V., Stefanidis, I."Indoleamine 2,3‑dioxygenase suppresses humoral alloimmunity via pathways that different to those associated with its effects on T cells". Biomedical Reports 10, no. 6 (2019): 323-330. https://doi.org/10.3892/br.2019.1212