Immune Netw.  2017 Jun;17(3):152-162. 10.4110/in.2017.17.3.152.

Dendritic Cell Dysfunction in Patients with End-stage Renal Disease

• Kim JU
• Kim M
• Kim S
• Nguyen TT
• Kim E
• Lee S
• Kim S
• Kim H

• KMID: 2383353
• DOI: http://doi.org/10.4110/in.2017.17.3.152

Abstract

End-stage renal disease (ESRD) with immune disorder involves complex interactions between the innate and adaptive immune responses. ESRD is associated with various alterations in immune function such as a reduction in polymorphonuclear leukocyte bactericidal activity, a suppression of lymphocyte proliferative response to stimuli, and a malfunction of cell-mediated immunity at the molecular level. ESRD also increases patients' propensity for infections and malignancies as well as causing a diminished response to vaccination. Several factors influence the immunodeficiency in patients with ESRD, including uremic toxins, malnutrition, chronic inflammation, and the therapeutic dialysis modality. The alteration of T-cell function in ESRD has been considered to be a major factor underlying the impaired adaptive cellular immunity in these patients. However, cumulative evidence has suggested that the immune defect in ESRD can be caused by an Ag-presenting dendritic cell (DC) dysfunction in addition to a T-cell defect. It has been reported that ESRD has a deleterious effect on DCs both in terms of their number and function, although the precise mechanism by which DC function becomes altered in these patients is unclear. In this review, we discuss the effects of ESRD on the number and function of DCs and propose a possible molecular mechanism for DC dysfunction. We also address therapeutic approaches to improve immune function by optimally activating DCs in patients with ESRD.

Keyword

Antigen presenting cells; Costimulatory molecule; Dendritic cells; End-stage renal disease; Immunodeficiency

MeSH Terms

Antigen-Presenting Cells
Dendritic Cells*
Dialysis
Humans
Immune System Diseases
Immunity, Cellular
Inflammation
Kidney Failure, Chronic*
Lymphocytes
Malnutrition
Neutrophils
T-Lymphocytes
Vaccination

Figure

• 

  Figure 1 Effect of kidney failure on dendritic cells and therapeutic approaches involving the modulation of dendritic cell maturation. The loss of kidney function causes an accumulation of uremic toxins and proinflammatory molecules, leading to chronic low grade inflammation and increased oxidative stress. Kidney failure also leads to disturbed renal metabolic and endocrinologic activities, resulting in abnormalities such as increased parathyroid hormone production and a decreased circulating concentration of erythropoietin. The results of these defects associated with renal failure have detrimental effects on dendritic cells. After sensing a foreign Ag via TLRs and then capturing and processing it, dendritic cells undergo maturation and begin to express Ag–MHCs and appropriate costimulatory molecules like CD80 and CD86 at the cell surface. This process is associated with T-cell activation. Several therapeutic modalities can induce the terminal differentiation of immature dendritic cells into their fully matured immunogenic form through activating TLRs or inducing the upregulation of costimulatory molecules. The red line and plus sign indicate activation. The blue line and minus sign indicate inhibition. EPO, erythropoietin; GM-CSF, granulocyte macrophage colony-stimulating factor; HD, hemodialysis; MHC, major histocompatibility complex; MPL, monophosphoryl lipid; TCR, T-cell receptor; TLR, Toll-like receptor.

Reference

1. Webster AC, Nagler EV, Morton RL, Masson P. Chronic Kidney Disease. Lancet. 2017; 389:1238–1252.

2. Anding K, Gross P, Rost JM, Allgaier D, Jacobs E. The influence of uraemia and haemodialysis on neutrophil phagocytosis and antimicrobial killing. Nephrol Dial Transplant. 2003; 18:2067–2073.

3. Verkade MA, van de Wetering J, Klepper M, Vaessen LM, Weimar W, Betjes MG. Peripheral blood dendritic cells and GM-CSF as an adjuvant for hepatitis B vaccination in hemodialysis patients. Kidney Int. 2004; 66:614–621.

4. Sester M, Sester U, Clauer P, Heine G, Mack U, Moll T, Sybrecht GW, Lalvani A, Köhler H. Tuberculin skin testing underestimates a high prevalence of latent tuberculosis infection in hemodialysis patients. Kidney Int. 2004; 65:1826–1834.

5. Yoon JW, Gollapudi S, Pahl MV, Vaziri ND. Naïve and central memory T-cell lymphopenia in end-stage renal disease. Kidney Int. 2006; 70:371–376.

6. Lim WH, Kireta S, Leedham E, Russ GR, Coates PT. Uremia impairs monocyte and monocyte-derived dendritic cell function in hemodialysis patients. Kidney Int. 2007; 72:1138–1148.

7. Litjens NH, Huisman M, van den Dorpel M, Betjes MG. Impaired immune responses and antigen-specific memory CD4+ T cells in hemodialysis patients. J Am Soc Nephrol. 2008; 19:1483–1490.

8. Hauser AB, Stinghen AE, Kato S, Bucharles S, Aita C, Yuzawa Y, Pecoits-Filho R. Characteristics and causes of immune dysfunction related to uremia and dialysis. Perit Dial Int. 2008; Suppl 3. S183–S187.

9. Kato S, Chmielewski M, Honda H, Pecoits-Filho R, Matsuo S, Yuzawa Y, Tranaeus A, Stenvinkel P, Lindholm B. Aspects of immune dysfunction in end-stage renal disease. Clin J Am Soc Nephrol. 2008; 3:1526–1533.

10. Cohen G, Hörl WH. Immune dysfunction in uremia–an update. Toxins (Basel). 2012; 4:962–990.

11. Girndt M, Sester M, Sester U, Kaul H, Köhler H. Molecular aspects of T- and B-cell function in uremia. Kidney Int Suppl. 2001; 78:S206–S211.

12. Girndt M, Köhler H, Schiedhelm-Weick E, Meyer zum Büschenfelde KH, Fleischer B. T cell activation defect in hemodialysis patients: evidence for a role of the B7/CD28 pathway. Kidney Int. 1993; 44:359–365.

13. Verkade MA, van Druningen CJ, Vaessen LM, Hesselink DA, Weimar W, Betjes MG. Functional impairment of monocyte-derived dendritic cells in patients with severe chronic kidney disease. Nephrol Dial Transplant. 2007; 22:128–138.

14. Betjes MG, Litjens NH, Zietse R. Seropositivity for cytomegalovirus in patients with end-stage renal disease is strongly associated with atherosclerotic disease. Nephrol Dial Transplant. 2007; 22:3298–3303.

15. Hubo M, Trinschek B, Kryczanowsky F, Tuettenberg A, Steinbrink K, Jonuleit H. Costimulatory molecules on immunogenic versus tolerogenic human dendritic cells. Front Immunol. 2013; 4:82.

16. Ganguly D, Haak S, Sisirak V, Reizis B. The role of dendritic cells in autoimmunity. Nat Rev Immunol. 2013; 13:566–577.

17. Hesselink DA, Betjes MG, Verkade MA, Athanassopoulos P, Baan CC, Weimar W. The effects of chronic kidney disease and renal replacement therapy on circulating dendritic cells. Nephrol Dial Transplant. 2005; 20:1868–1873.

18. Lim WH, Kireta S, Thomson AW, Russ GR, Coates PT. Renal transplantation reverses functional deficiencies in circulating dendritic cell subsets in chronic renal failure patients. Transplantation. 2006; 81:160–168.

19. Verkade MA, van Druningen CJ, de Hoek OP, Weimar W, Betjes MG. Decreased antigen-specific T-cell proliferation by moDC among hepatitis B vaccine non-responders on haemodialysis. Clin Exp Med. 2007; 7:65–71.

20. Lim WH, Kireta S, Leedham E, Russ GR, Coates PT. Uremia impairs monocyte and monocyte-derived dendritic cell function in hemodialysis patients. Kidney Int. 2007; 72:1138–1148.

21. Robinson SP, Patterson S, English N, Davies D, Knight SC, Reid CD. Human peripheral blood contains two distinct lineages of dendritic cells. Eur J Immunol. 1999; 29:2769–2778.

22. Martínez del Hoyo G, Martín P, Anjuère F, Arias CF, Marín AR, Ruiz S, Parrillas V, Hernández H. Origin and differentiation of dendritic cells. Trends Immunol. 2001; 22:691–700.

23. Chowdhury F, Johnson P, Williams AP. Enumeration and phenotypic assessment of human plasmacytoid and myeloid dendritic cells in whole blood. Cytometry A. 2010; 77:328–337.

24. Jarrossay D, Napolitani G, Colonna M, Sallusto F, Lanzavecchia A. Specialization and complementarity in microbial molecule recognition by human myeloid and plasmacytoid dendritic cells. Eur J Immunol. 2001; 31:3388–3393.

25. Agrawal S, Gollapudi P, Elahimehr R, Pahl MV, Vaziri ND. Effects of end-stage renal disease and haemodialysis on dendritic cell subsets and basal and LPS-stimulated cytokine production. Nephrol Dial Transplant. 2010; 25:737–746.

26. Paul K, Kretzschmar D, Yilmaz A, Bärthlein B, Titze S, Wolf G, Busch M. GCKD-Study Investigators. Circulating dendritic cell precursors in chronic kidney disease: a cross-sectional study. BMC Nephrol. 2013; 14:274.

27. Merad M, Manz MG. Dendritic cell homeostasis. Blood. 2009; 113:3418–3427.

28. Yilmaz A, Weber J, Cicha I, Stumpf C, Klein M, Raithel D, Daniel WG, Garlichs CD. Decrease in circulating myeloid dendritic cell precursors in coronary artery disease. J Am Coll Cardiol. 2006; 48:70–80.

29. Yilmaz A, Schaller T, Cicha I, Altendorf R, Stumpf C, Klinghammer L, Ludwig J, Daniel WG, Garlichs CD. Predictive value of the decrease in circulating dendritic cell precursors in stable coronary artery disease. Clin Sci (Lond). 2009; 116:353–363.

30. Kretzschmar D, Betge S, Windisch A, Pistulli R, Rohm I, Fritzenwanger M, Jung C, Schubert K, Theis B, Petersen I, Drobnik S, Mall G, Figulla HR, Yilmaz A. Recruitment of circulating dendritic cell precursors into the infarcted myocardium and pro-inflammatory response in acute myocardial infarction. Clin Sci (Lond). 2012; 123:387–398.

31. Wen J, Wen Y, Zhiliang L, Lingling C, Longxing C, Ming W, Qiang F. A decrease in the percentage of circulating mDC precursors in patients with coronary heart disease: a relation to the severity and extent of coronary artery lesions? Heart Vessels. 2013; 28:135–142.

32. Chen L, Flies DB. Molecular mechanisms of T cell co-stimulation and co-inhibition. Nat Rev Immunol. 2013; 13:227–242.

33. Harding FA, McArthur JG, Gross JA, Raulet DH, Allison JP. CD28-mediated signalling co-stimulates murine T cells and prevents induction of anergy in T-cell clones. Nature. 1992; 356:607–609.

34. Choi HM, Woo YS, Kim MG, Jo SK, Cho WY, Kim HK. Altered monocyte-derived dendritic cell function in patients on hemodialysis: a culprit for underlying impaired immune responses. Clin Exp Nephrol. 2011; 15:546–553.

35. Cao Q, Zheng D, Wang YP, Harris DC. Macrophages and dendritic cells for treating kidney disease. Nephron Exp Nephrol. 2011; 117:e47–e52.

36. Lim WH, Kireta S, Russ GR, Coates PT. Uremia impairs blood dendritic cell function in hemodialysis patients. Kidney Int. 2007; 71:1122–1131.

37. Gluba A, Banach M, Hannam S, Mikhailidis DP, Sakowicz A, Rysz J. The role of Toll-like receptors in renal diseases. Nat Rev Nephrol. 2010; 6:224–235.

38. Koc M, Toprak A, Arikan H, Odabasi Z, Elbir Y, Tulunay A, Asicioglu E, Eksioglu-Demiralp E, Glorieux G, Vanholder R, Akoglu E. Toll-like receptor expression in monocytes in patients with chronic kidney disease and haemodialysis: relation with inflammation. Nephrol Dial Transplant. 2011; 26:955–963.

39. Ando M, Shibuya A, Tsuchiya K, Akiba T, Nitta K. Reduced expression of Toll-like receptor 4 contributes to impaired cytokine response of monocytes in uremic patients. Kidney Int. 2006; 70:358–362.

40. Kuroki Y, Tsuchida K, Go I, Aoyama M, Naganuma T, Takemoto Y, Nakatani T. A study of innate immunity in patients with end-stage renal disease: special reference to toll-like receptor-2 and -4 expression in peripheral blood monocytes of hemodialysis patients. Int J Mol Med. 2007; 19:783–790.

41. Gollapudi P, Yoon JW, Gollapudi S, Pahl MV, Vaziri ND. Leukocyte toll-like receptor expression in endstage kidney disease. Am J Nephrol. 2010; 31:247–254.

42. Geara AS, Castellanos MR, Bassil C, Schuller-Levis G, Park E, Smith M, Goldman M, Elsayegh S. Effects of parathyroid hormone on immune function. Clin Dev Immunol. 2010; 2010:pii: 418695.

43. Guy B. The perfect mix: recent progress in adjuvant research. Nat Rev Microbiol. 2007; 5:505–517.

44. Girndt M, Lengler S, Kaul H, Sester U, Sester M, Köhler H. Prospective crossover trial of the influence of vitamin E-coated dialyzer membranes on T-cell activation and cytokine induction. Am J Kidney Dis. 2000; 35:95–104.

45. Contin-Bordes C, Lacraz A, de Précigout V. Potential role of the soluble form of CD40 in deficient immunological function of dialysis patients: new findings of its amelioration using polymethylmethacrylate (PMMA) membrane. NDT Plus. 2010; 3:Suppl 1. i20–i27.

46. Martínez-Miguel P, de Sequera P, Albalate M, Medrano D, Sánchez-Villanueva R, Molina A, Sousa F, Benito J, Nuñez J, Vozmediano C, Aragoncillo I, Barril G, Rodríguez-Puyol D, Pérez-García R, López-Ongil S. Evaluation of a polynephron dialysis membrane considering new aspects of biocompatibility. Int J Artif Organs. 2015; 38:45–53.

47. Rama I, Llaudó I, Fontova P, Cerezo G, Soto C, Javierre C, Hueso M, Montero N, Martínez-Castelao A, Torras J, Grinyó JM, Cruzado JM, Lloberas N. Online haemodiafiltration improves inflammatory state in dialysis patients: A longitudinal study. PLoS One. 2016; 11:e0164969.

48. Ward RA, Schmidt B, Hullin J, Hillebrand GF, Samtleben W. A comparison of on-line hemodiafiltration and high-flux hemodialysis: a prospective clinical study. J Am Soc Nephrol. 2000; 11:2344–2350.

49. Karkar A, Abdelrahman M, Locatelli F. A randomized trial on health-related patient satisfaction level with high-efficiency online hemodiafiltration versus high-flux dialysis. Blood Purif. 2015; 40:84–91.

50. Dede F, Yıldız A, Aylı D, Colak N, Odabaş AR, Akoğlu H, Eskioğlu E, Covic A. Modulation of the immune response to HBV vaccination by hemodialysis membranes. Int Urol Nephrol. 2010; 42:1069–1075.

51. Sasaki R. Pleiotropic functions of erythropoietin. Intern Med. 2003; 42:142–149.

52. Arcasoy MO. The non-haematopoietic biological effects of erythropoietin. Br J Haematol. 2008; 141:14–31.

53. Nairz M, Sonnweber T, Schroll A, Theurl I, Weiss G. The pleiotropic effects of erythropoietin in infection and inflammation. Microbes Infect. 2012; 14:238–246.

54. Rocchetta F, Solini S, Mister M, Mele C, Cassis P, Noris M, Remuzzi G, Aiello S. Erythropoietin enhances immunostimulatory properties of immature dendritic cells. Clin Exp Immunol. 2011; 165:202–210.

55. Kazmi WH, Kausz AT, Khan S, Abichandani R, Ruthazer R, Obrador GT, Pereira BJ. Anemia: an early complication of chronic renal insufficiency. Am J Kidney Dis. 2001; 38:803–812.

56. Prutchi Sagiv S, Lifshitz L, Orkin R, Mittelman M, Neumann D. Erythropoietin effects on dendritic cells: potential mediators in its function as an immunomodulator? Exp Hematol. 2008; 36:1682–1690.

57. Lifshitz L, Prutchi-Sagiv S, Avneon M, Gassmann M, Mittelman M, Neumann D. Non-erythroid activities of erythropoietin: Functional effects on murine dendritic cells. Mol Immunol. 2009; 46:713–721.

58. Cravedi P, Manrique J, Hanlon KE, Reid-Adam J, Brody J, Prathuangsuk P, Mehrotra A, Heeger PS. Immunosuppressive effects of erythropoietin on human alloreactive T cells. J Am Soc Nephrol. 2014; 25:2003–2015.

59. Sennesael J, van Der Niepen P, Verbeelen DL. Treatment with recombinant human erythropoietin increases antibody titers after hepatitis B vaccination in dialysis patients. Kidney Int. 1991; 40:121–128.

60. Anandh U, Thomas PP, Shastry JC, Jacob CK. A randomised controlled trial of intradermal hepatitis B vaccination and augmentation of response with erythropoietin. J Assoc Physicians India. 2000; 48:1061–1063.

61. Hassan K, Shternberg L, Alhaj M, Giron R, Reshef R, Barak M, Kristal B. The effect of erythropoietin therapy and hemoglobin levels on the immune response to Engerix-B vaccination in chronic kidney disease. Ren Fail. 2003; 25:471–478.

62. Katz O, Gil L, Lifshitz L, Prutchi-Sagiv S, Gassmann M, Mittelman M, Neumann D. Erythropoietin enhances immune responses in mice. Eur J Immunol. 2007; 37:1584–1593.

63. Oster HS, Prutchi-Sagiv S, Halutz O, Shabtai E, Hoffman M, Neumann D, Mittelman M. Erythropoietin treatment is associated with an augmented immune response to the influenza vaccine in hematologic patients. Exp Hematol. 2013; 41:167–171.

64. Fabrizi F, Dixit V, Martin P, Messa P. Erythropoietin use and immunogenicity of hepatitis B virus vaccine in chronic kidney disease patients: A meta-analysis. Kidney Blood Press Res. 2012; 35:504–510.

65. Kausz A, Pahari D. The value of vaccination in chronic kidney disease. Semin Dial. 2004; 17:9–11.

66. Stevens CE, Alter HJ, Taylor PE, Zang EA, Harley EJ, Szmuness W. Hepatitis B vaccine in patients receiving hemodialysis. Immunogenicity and efficacy. N Engl J Med. 1984; 311:496–501.

67. Peces R, Laurés AS. Persistence of immunologic memory in long-term hemodialysis patients and healthcare workers given hepatitis B vaccine: role of a booster dose on antibody response. Nephron. 2001; 89:172–176.

68. Hornell TM, Beresford GW, Bushey A, Boss JM, Mellins ED. Regulation of the class II MHC pathway in primary human monocytes by granulocyte-macrophage colony-stimulating factor. J Immunol. 2003; 171:2374–2383.

69. Storozynsky E, Woodward JG, Frelinger JG, Lord EM. Interleukin-3 and granulocyte-macrophage colony-stimulating factor enhance the generation and function of dendritic cells. Immunology. 1999; 97:138–149.

70. Hanada K, Tsunoda R, Hamada H. GM-CSF-induced in vivo expansion of splenic dendritic cells and their strong costimulation activity. J Leukoc Biol. 1996; 60:181–190.

71. Kapoor D, Aggarwal SR, Singh NP, Thakur V, Sarin SK. Granulocyte-macrophage colony-stimulating factor enhances the efficacy of hepatitis B virus vaccine in previously unvaccinated haemodialysis patients. J Viral Hepat. 1999; 6:405–409.

72. Fabrizi F, Ganeshan SV, Dixit V, Martin P. Meta-analysis: the adjuvant role of granulocyte macrophage-colony stimulating factor on immunological response to hepatitis B virus vaccine in end-stage renal disease. Aliment Pharmacol Ther. 2006; 24:789–796.

73. Cruciani M, Mengoli C, Serpelloni G, Mazzi R, Bosco O, Malena M. Granulocyte macrophage colony-stimulating factor as an adjuvant for hepatitis B vaccination: a metaanalysis. Vaccine. 2007; 25:709–718.

74. Alavian SM, Tabatabaei SV. Effects of oral levamisole as an adjuvant to hepatitis B vaccine in adults with end-stage renal disease: a meta-analysis of controlled clinical trials. Clin Ther. 2010; 32:1–10.

75. Fabrizi F, Dixit V, Messa P, Martin P. Meta-analysis: levamisole improves the immune response to hepatitis B vaccine in dialysis patients. Aliment Pharmacol Ther. 2010; 32:756–762.

76. Chen LY, Lin YL, Chiang BL. Levamisole enhances immune response by affecting the activation and maturation of human monocyte-derived dendritic cells. Clin Exp Immunol. 2008; 151:174–1781.

77. Niu X, Yang Y, Wang J. Synergistic and additive effects of cimetidine and levamisole on cellular immune responses to hepatitis B virus DNA vaccine in mice. Scand J Immunol. 2013; 77:84–91.

78. Deniz Ayli M, Ensari C, Ayli M, Mandiroglu F, Mut S. Effect of oral levamisole supplementation to hepatitis B vaccination on the rate of immune response in chronic hemodialysis patients. Nephron. 2000; 84:291–292.

79. Kayataş M. Levamisole treatment enhances protective antibody response to hepatitis B vaccination in hemodialysis patients. Artif Organs. 2002; 26:492–496.

80. Argani H, Akhtarishojaie E. Levamizole enhances immune responsiveness to intra-dermal and intra-muscular hepatitis B vaccination in chronic hemodialysis patients. J Immune Based Ther Vaccines. 2006; 4:3.

81. Fallahzadeh MK, Sajjadi S, Singh N, Khajeh M, Sagheb MM. Effect of levamisole supplementation on tetanus vaccination response rates in haemodialysis patients: a randomized double-blind placebo-controlled trial. Nephrology (Carlton). 2014; 19:27–31.

82. Sali S, Alavian SM, Hajarizadeh B. Effect of levamisole supplementation on hepatitis B virus vaccination response in hemodialysis patients. Nephrology (Carlton). 2008; 13:376–379.

83. Sanadgol H, Khoshnoodi M, Mashhadi MA, Forghani MS. Effect of adding levamisole on seroconversion response to hepatitis B virus vaccination in hemodialysis patients: a single-center experience. Iran J Kidney Dis. 2011; 5:338–341.

84. Garçon N, Chomez P, Van Mechelen M. Glaxo-SmithKline adjuvant systems in vaccines: concepts, achievements and perspectives. Expert Rev Vaccines. 2007; 6:723–739.

85. Ulrich JT, Myers KR. Monophosphoryl lipid A as an adjuvant. Past experiences and new directions. Pharm Biotechnol. 1995; 6:495–524.

86. Evans JT, Cluff CW, Johnson DA, Lacy MJ, Persing DH, Baldridge JR. Enhancement of antigen-specific immunity via the TLR4 ligands MPL adjuvant and Ribi.529. Expert Rev Vaccines. 2003; 2:219–229.

87. Eleftheriadis T, Pissas G, Liakopoulos V, Stefanidis I, Lawson BR. Toll-like receptors and their role in renal pathologies. Inflamm Allergy Drug Targets. 2012; 11:464–477.

88. Tong NK, Beran J, Kee SA, Miguel JL, Sánchez C, Bayas JM, Vilella A, de Juanes JR, Arrazola P, Calbo-Torrecillas F, de Novales EL, Hamtiaux V, Lievens M, Stoffel M. Immunogenicity and safety of an adjuvanted hepatitis B vaccine in pre-hemodialysis and hemodialysis patients. Kidney Int. 2005; 68:2298–2303.

89. Kong NC, Beran J, Kee SA, Miguel JL, Sánchez C, Bayas JM, Vilella A, Calbo-Torrecillas F, López de Novales E, Srinivasa K, Stoffel M, Hoet B. A new adjuvant improves the immune response to hepatitis B vaccine in hemodialysis patients. Kidney Int. 2008; 73:856–862.

90. Surquin M, Tielemans CL, Kulcsár I, Ryba M, Vörös P, Mat O, Treille S, Dhaene M, Stolear JC, Kuriyakose SO, Leyssen MX, Houard SA. Rapid, enhanced, and persistent protection of patients with renal insufficiency by AS02(V)-adjuvanted hepatitis B vaccine. Kidney Int. 2010; 77:247–255.