Turkiye Klinikleri Journal of Medical Sciences

.: REVIEW
Importance of Non-HLA Antibodies in Solid Organ Transplantations
Solid Organ Transplantasyonunda Non-HLA Antikorlarının Önemi
Burcu ÇERÇİa,b, Mustafa SOYÖZa,b, Tülay KILIÇASLAN AYNAa,b, İbrahim PİRİMa,b
aDepartment of Medical Biology and Genetics, İzmir Katip Çelebi University Faculty of Medicine,
bTissue Typing Laboratory, Health Sciences University Tepecik Training and Research Hospital, İzmir, TURKEY
Turkiye Klinikleri J Med Sci. 2019;39(3):336-44
doi: 10.5336/medsci.2019-65080
Article Language: EN
Full Text
ABSTRACT
The development of surgical techniques and the use of immunosuppressive agents can increase the lifespan of the graft in organ transplants. Nonetheless, donor specific and non-specific antibodies produced prior to transplantation cause both acute and chronic rejection and, consequently, graft damage. Non-HLA antibodies have started to attract attention as a result of the observation of rejections in patients whose cross match test results were negative and didn't have antibodies produced against donor specific and HLA panel. It has been determined that non-HLA antibodies cause both acute and chronic rejections, and may have different effects on the organ they target. These antibodies were first identified in 1995. Vascular receptors, adhesion molecules and intermediate filaments are among the targets of non-HLA antibodies. Many studies are available in literature investigating angiotensin type 1 receptor (AT1R), endothelin type A receptor (ETAR), collagen-V (Kol-V), K-alpha 1 tubulin (KA1T), perlecan (LG3) C-terminal fragment, associated with MHC class I polypeptide A and B. In addition, more non-HLA antibody targets can be identified and organ transplantation and graft survival studies can be developed. In this review, antigenic targets, treatment strategies and detection methods of non-HLA antibodies will be discussed.

Keywords: Transplantation; rejection; antibodies
ÖZET
Cerrahi tekniklerin gelişmesi ve immünsupresif ajanların kullanımı, organ nakillerinde greftin yaşam ömrünü arttırılabilmektedir. Buna rağmen nakil öncesinde oluşmuş donöre özgü ve özgü olmayan antikorlar nakil sonrasında hem akut hem de kronik redde ve dolayısıyla greft hasarına sebep olmaktadır. Hem donöre özgü hem de belirli bir insan lökosit antijen (HLA) paneline karşı üretilen antikorları olmayan ve çapraz uyum testleri de negatif olarak belirlenen hastalarda da organ redlerinin gözlenmesi sonucunda, HLA dışı antikorları ilgi çekmeye başlamıştır. HLA-dışı antikorların hem akut hem de kronik redlere sebep olduğu, hedef aldıkları organa göre farklı etkilerinin olabileceği belirlenmiştir. Bu antikorlar ilk olarak 1995 yılında tespit edilmiştir. Vasküler reseptörler, adezyon moleküleri ve ara filamentler HLA dışı antikorlarının hedefleri arasındadır. Angiotensin tip 1 reseptörü (AT1R), endotelin tip A reseptörü (ETAR), kollajen-V (Kol-V), K-alfa 1 tubulin (KA1T), perlekan (LG3) C terminal fragmanı, MHC sınıf I polipeptidi ile ilişkili A ve B antijenlerine karşı tanımlanan antikorlarla ilgili birçok çalışma bulunmaktadır. Ayrıca daha fazla HLA dışı antikor hedefleri belirlenerek, organ nakli ve greft sağkalım çalışmaları geliştirilebilir. Bu derlemede, HLA dışı antikorların antijenik hedefleri, tedavi stratejileri ve tespit yöntemleri tartışılacaktır.

Anahtar Kelimeler: Transplantasyon; organ reddi; antikorlar
REFERENCES:
  1. Michielsen LA, van Zuilen AD, Krebber MM, Verhaar MC, Otten HG. Clinical value of non-HLA antibodies in kidney transplantation: still an enigma? Transplant Rev (Orlando). 2016;30(4):195-202. [Crossref]  [PubMed] 
  2. Wiwattanathum P, Ingsathit A, Thammanichanond D, Worawichawong S. Successful treatment of anti-angiotensin II type 1 receptor antibody-associated rejection in kidney transplantation: a case report. Transplant Proc. 2018;50(3):877-80. [Crossref]  [PubMed] 
  3. Valenzuela NM, Reed EF. Antibodies in transplantation: the effects of HLA and non-HLA antibody binding and mechanisms of injury. In: Zachary AA, Leffell MS, eds. Transplantation Immunology Methods and Protocols. 2nd ed. New York: Humana Press; 2013. p.41-71. [Crossref]  [PubMed]  [PMC] 
  4. Sigdel TK, Sarwal MM. Moving beyond HLA: a review of nHLA antibodies in organ transplantation. Hum Immunol. 2013;74(11):1486-90. [Crossref]  [PubMed]  [PMC] 
  5. Terasaki PI, Ozawa M, Castro R. Four-year follow-up of a prospective trial of HLA and MICA antibodies on kidney graft survival. Am J Transplant. 2007;7(2):408-15. [Crossref]  [PubMed] 
  6. Reinsmoen NL, Lai CH, Heidecke H, Haas M, Cao K, Ong G, et al. Anti-angiotensin type 1 receptor antibodies associated with antibody mediated rejection in donor HLA antibody negative patients. Transplantation. 2010;90(12): 1473-7. [Crossref]  [PubMed] 
  7. Dragun D, Catar R, Philippe A. Non-HLA antibodies against endothelial targets bridging allo-and autoimmunity. Kidney Int. 2016;90(2): 280-8. [Crossref]  [PubMed] 
  8. Banasik M, Jabłecki J, Boratyńska M, Kamińska D, Kościelska-Kasprzak K, Bartoszek D, et al. Humoral immunity in hand transplantation: anti-HLA and non-HLA response. Hum Immunol. 2014;75(8):859-62. [Crossref]  [PubMed] 
  9. Zhang Q, Reed EF. The importance of non-HLA antibodies in transplantation. Nat Rev Nephrol. 2016;12(8):484-95. [Crossref]  [PubMed]  [PMC] 
  10. Brasile L, Rodman E, Shield CF 3rd, Clarke J, Cerilli J. The association of antivascular endothelial cell antibody with hyperacute rejection: a case report. Surgery. 1986;99(5): 637-40.
  11. Zhang Z, Li M, Lu R, Alioua A, Stefani E, Toro L. The angiotensin II type 1 receptor (AT1R) closely ınteracts with large conductance voltage- and Ca2+-activated K+ (BK) channels and inhibits their activity ındependent of G-protein activation. J Biol Chem. 2014;289(37): 25678-89. [Crossref]  [PubMed]  [PMC] 
  12. Lim MA, Palmer M, Trofe-Clark J, Bloom RD, Jackson A, Philogene MC, et al. Histopathologic changes in anti-angiotensin II type 1 receptor antibody-positive kidney transplant recipients with acute rejection and no donor specific HLA antibodies. Hum Immunol. 2017;78(4):350-6. [Crossref]  [PubMed] 
  13. Lee J, Park Y, Kim BS, Lee JG, Kim HJ, Kim YS, et al. Clinical implications of angiotensin II type 1 receptor antibodies in antibody-mediated rejection without detectable donor-specific HLA antibodies after renal transplantation. Transplant Proc. 2015;47(3):649-52. [Crossref]  [PubMed] 
  14. Banasik M, Boratńyska M, Kościelska-Kasprzak K, Kamińska D, Zmonarski S, Mazanowska O, et al. Non-HLA antibodies: angiotensin II type 1 receptor (Anti-AT1R) and endothelin-1 type a receptor (anti-ETAR) are associated with renal allograft injury and graft loss. Transplant Proc. 2014;26(21): 2618-21. [Crossref]  [PubMed] 
  15. Dragun D, Catar R, Philippe A. Non-HLA antibodies in solid organ transplantation: recent concepts and clinical relevance. Curr Opin Organ Transplant. 2013;18(4):430-5. [Crossref]  [PubMed] 
  16. Alberts B, Johnson A, Lewis J, Morgan D, Raff M, Roberts K, et al. The innate and adaptive immune systems. Molecular Biology of the Cell. 6th ed. New York: Garland Science, Taylor & Francis Group; 2015. p.1297-347. [Crossref] 
  17. Yoshida S, Haque A, Mizobuchi T, Iwata T, Chiyo M, Webb TJ, et al. Anti-type V collagen lymphocytes that express IL-17 and IL-23 induce rejection pathology in fresh and well-healed lung transplants. Am J Transplant. 2006;6(4):724-35. [Crossref]  [PubMed] 
  18. Wu P, Ren Y, Ma Y, Wang Y, Jiang H, Chaudhari S, et al. Negative regulation of Smad1 pathway and collagen IV expression by store-operated Ca2+ entry in glomerular mesangial cells. Am J Physiol Renal Physiol. 2017; 312(6):F1090-F100. [Crossref]  [PubMed]  [PMC] 
  19. Angaswamy N, Klein C, Tiriveedhi V, Gaut J, Anwar S, Rossi A, et al. Immune responses to collagen-IV and fibronectin in renal transplant recipients with transplant glomerulopathy. Am J Transplant. 2014;14(3):685-93. [Crossref]  [PubMed] 
  20. Hachem RR, Tiriveedhi V, Patterson GA, Aloush A, Trulock EP, Mohanakumar T. Antibodies to K- a 1 tubulin and collagen v are associated with chronic rejection after lung transplantation. Am J Transplant. 2012;12(8):2164-71. [Crossref]  [PubMed]  [PMC] 
  21. Golocheikine A, Nath DS, Basha HI, Saini D, Phelan D, Aloush A, et al. Increased erythrocyte c4d ıs associated with known alloantibody and autoantibody markers of antibody mediated rejection in human lung transplant recipients. J Heart Lung Transplant. 2010;29(4):410-6. [Crossref]  [PubMed]  [PMC] 
  22. Delville M, Charreau B, Rabant M, Legendre C, Anglicheau D. Pathogenesis of non-HLA antibodies in solid organ transplantation: where do we stand? Hum Immunol. 2016; 77(11):1055-62. [Crossref]  [PubMed] 
  23. Sigdel TK, Sarwal MM. Moving beyond HLA: a review of nHLA antibodies in organ transplantation. Hum Immunol. 2013;74(11):1486-90. [Crossref]  [PubMed]  [PMC] 
  24. Gubbiotti MA, Neill T, Iozzo RV. A current view of perlecan in physiology and pathology: a mosaic of functions. Matrix Biol. 2016;57-58:285-98. [Crossref]  [PubMed]  [PMC] 
  25. Katta K, Boersema M, Adepu S, Rienstra H, Celie JWAM, Mencke R, et al. Renal heparan sulfate proteoglycans modulate fibroblast growth factor 2 signaling in experimental chronic transplant dysfunction. Am J Pathol. 2013;183(5):1571-84. [Crossref]  [PubMed] 
  26. Celie JW, Rutjes NW, Keuning ED, Soininen R, Heljasvaara R, Pihlajaniemi T, et al. Subendothelial heparan sulfate proteoglycans become major L-selectin and monocyte chemoattractant protein-1 ligands upon renal ischemia/reperfusion. Am J Pathol. 2007;170(6):1865-78. [Crossref]  [PubMed]  [PMC] 
  27. Hönger G, Cardinal H, Dieudé M, Buser A, Hösli I, Dragun D, et al. Human pregnancy and generation of anti-angiotensin receptor and anti-perlecan antibodies. Transpl Int. 2014;27(5):467-74. [Crossref]  [PubMed] 
  28. Pilon EA, Dieudé M, Qi S, Hamelin K, Pomerleau L, Beillevaire D, et al. The perlecan fragment LG3 regulates homing of mesenchymal stem cells and neointima formation during vascular rejection. Am J Transplant. 2015;15(5):1205-18. [Crossref]  [PubMed] 
  29. Riesco L, Irure J, Rodrigo E, Guiral S, Ruiz JC, Gómez J, et al. Anti-perlecan antibodies and acute humoral rejection in hypersensitized patients without forbidden HLA specificities after kidney transplantation. Transpl Immunol. 2019;52:53-6. [Crossref]  [PubMed] 
  30. Cardinal H, Dieudé M, Brassard N, Qi S, Patey N, Soulez M, et al. Antiperlecan antibodies are novel accelerators of immune-mediated vascular injury. Am J Transplant. 2013;13(4):861-74. [Crossref]  [PubMed] 
  31. Padet L, Dieudé M, Karakeussian-Rimbaud A, Yang, B, Turgeon J, Cailhier JF, et al. New insights into immune mechanisms of antiperlecan/LG3 antibody production: importance of T cells and innate B1 cells. Am J Transplant. 2019;19(3):699-712. [Crossref]  [PubMed]  [PMC] 
  32. Sumitran-Holgersson S. Relevance of MICA and other non-HLA antibodies in clinical transplantation. Curr Opin Immunol. 2008;20(5): 607-13. [Crossref]  [PubMed] 
  33. Panigrahi A, Gupta N, Siddiqui JA, Margoob A, Bhowmik D, Guleria S, et al. Post transplant development of MICA and anti-HLA antibodies is associated with acute rejection episodes and renal allograft loss. Hum Immunol. 2007;68(5):362-7. [Crossref]  [PubMed] 
  34. Zwirner NW, Marcos CY, Mirbaha F, Zou Y, Stastny P. Identification of MICA as a new polymorphic alloantigen recognized by antibodies in sera of organ transplant recipients. Hum Immunol. 2000;61(9):917-24. [Crossref] 
  35. Li L, Chen A, Chaudhuri A, Kambham N, Sigdel T, Chen R, et al. Compartmental localization and clinical relevance of MICA antibodies after renal transplantation. Transplantation. 2010;89(3):312-9. [Crossref]  [PubMed]  [PMC] 
  36. Mizutani K, Terasaki PI, Shih RN, Pei R, Ozawa M, Lee J. Frequency of MIC antibody in rejected renal transplant patients without HLA antibody. Hum Immunol. 2006;67(3):223-9. [Crossref]  [PubMed] 
  37. Terasaki PI, Ozawa M, Castro R. Four-year follow-up of a prospective trial of HLA and MICA antibodies on kidney graft survival. Am J Transplant. 2007;7(2):408-15. [Crossref]  [PubMed] 
  38. Rose ML. Role of anti-vimentin antibodies in allograft rejection. Hum Immunol. 2013;74(11):1459-62. [Crossref]  [PubMed]  [PMC] 
  39. Mor-Vaknin N, Punturieri A, Sitwala K, Markovitz DM. Vimentin is secreted by activated macrophages. Nat Cell Biol. 2003;5(1):59-63. [Crossref]  [PubMed] 
  40. Carter V, Shenton BK, Jaques B, Turner D, Talbot D, Gupta A, et al. Vimentin antibodies: a non-HLA antibody as a potential risk factor in renal transplantation. Transplant Proc. 2005;37(2):654-7. [Crossref]  [PubMed] 
  41. Lopez-Soler RI, Borgia JA, Kanangat S, Fhied CL, Conti DJ, Constantino D, et al. Anti-vimentin antibodies present at the time of transplantation may predict early development of interstitial fibrosis/tubular atrophy. Transplant Proc. 2016;48(6):2023-33. [Crossref]  [PubMed] 
  42. Gunasekaran M, Maw TT, Santos RD, Shenoy S, Wellen J, Mohanakumar T. Immunoglobulin isotype switching of antibodies to vimentin is associated with development of transplant glomerulopathy following human renal transplantation. Transplant Immunol. 2017;45:42-7. [Crossref]  [PubMed] 
  43. Carter V, Howell WM. Vimentin antibody production in transplant patients and immunomodulatory effects of vimentin in-vitro. Hum Immunol. 2013;74(11):1463-9. [Crossref]  [PubMed] 
  44. O'Donohoe TJ, Schrale RG, Ketheesan N. The role of anti-myosin antibodies in perpetuating cardiac damage following myocardial infarction. Int J Cardiol. 2016;209:226-33. [Crossref]  [PubMed] 
  45. O'Donohoe TJ, Schrale RG, Sikder S, Surve N, Rudd D, Ketheesan N. Significance of anti-myosin antibody formation in patients with myocardial infarction: a prospective observational study. Heart Lung Circ. 2019;28(4):583-90. [Crossref]  [PubMed] 
  46. Nath DS, Ilias Basha H, Tiriveedhi V, Alur C, Phelan D, Ewald GA, et al. Characterization of immune responses to cardiac self- antigens myosin and vimentin in human cardiac allograft recipients with antibody-mediated rejection and cardiac allograft vasculopathy. J Heart Lung Transplant. 2010;29(11):1277-85. [Crossref]  [PubMed]  [PMC] 
  47. Morgun A, Shulzhenko N, Unterkircher CS, Diniz RV, Pereira AB, Silva MS, et al. Pre-and post-trasnplant anti myosin and anti-heat shock protein antibodies and cardiac transplant. J Heart Lung Transplant. 2004; 2498(3):204-9. [Crossref] 
  48. Dzierzak-Mietla M, Markiewicz M, Siekiera U, Mizia S, Koclega A, Zielinska P, et al. Occurrence and impact of minor histocompatibility antigens' disparities on outcomes of hematopoietic stem cell transplantation from HLA-matched sibling donors. Bone Marrow Res. 2012;2012:257086. [Crossref]  [PubMed]  [PMC] 
  49. Miklos DB, Kim HT, Miller KH, Guo L, Zorn E, Lee SJ, et al. Antibody responses to H-Y minor histocompatibility antigens correlate with chronic graft-versus-host disease and disease remission. Blood. 2005;105(7):2973-8. [Crossref]  [PubMed]  [PMC] 
  50. Dierselhuis M, Goulmy E. The relevance of minor histocompatibility antigens in solid organ transplantation. Curr Opin Organ Transplant. 2009;14(4):419-25. [Crossref]  [PubMed] 
  51. Tait BD, Süsal C, Gebel HM, Nickerson PW, Zachary AA, Claas FH, et al. Consensus guidelines on the testing and clinical management issues associated with HLA and non-HLA antibodies in transplantation. Transplantation. 2013;95(1):19-47. [Crossref]  [PubMed] 
  52. Zitzner JR, Shah S, Jie C, Wegner W, Tambur AR, Friedewald JJ. A prospective study evaluating the role of donor-specific anti-endothelial crossmatch (XM-ONE assay) in predicting living donor kidney transplant outcome. Hum Immunol. 2013;74(11):1431-6. [Crossref]  [PubMed] 
  53. Dib H, Tamby MC, Bussone G, Regent A, Berezné A, Lafine C, et al. Targets of anti-endothelial cell antibodies in pulmonary hypertension and scleroderma. Eur Respir J. 2012;39(6):1405-14. [Crossref]  [PubMed] 
  54. Barber LD, Whitelegg A, Madrigal JA, Banner NR, Rose ML. Detection of vimentin- specific autoreactive CD8+ T cells in cardiac transplant patients. Transplantation. 2004;77(10): 1604-9. [Crossref]  [PubMed] 
  55. Nath DS, Tiriveedhi V, Basha HI, Phelan D, Moazami N, Ewald GA, et al. A role for antibodies to human leukocyte antigens, collagen-V, and K-alpha1-tubulin in antibodymediated rejection and cardiac allograft vasculopathy. Transplantation. 2011;91(9):1036-43. [Crossref]  [PubMed]  [PMC] 
  56. Saini D, Weber J, Ramachandran S, Phelan D, Tiriveedhi V, Liu M, et al. Alloimmunity-induced autoimmunity as a potential mechanism in the pathogenesis of chronic rejection of human lung allografts. J Heart Lung Transplant. 2011;30(6):624-31. [Crossref]  [PubMed]  [PMC] 
  57. Fhied C, Kanangat S, Borgia JA. Development of a bead-based immunoassay to routinely measure vimentin autoantibodies in the clinical setting. J Immunol Methods. 2014;407:9-14. [Crossref]  [PubMed] 
  58. Riesco L, Irure J, Rodrigo E, Guiral S, Ruiz JC, Gómez J, et al. Anti-perlecan antibodies and acute humoral rejection in hypersensitized patients without forbidden HLA specificities after kidney transplantation. Transpl Immunol. 2019;52:53-6. [Crossref]  [PubMed] 
  59. Dragun D, Catar R, Kusch A, Heidecke H, Philippe A. Non-HLA-antibodies targeting angiotensin type 1 receptor and antibody mediated rejection. Hum Immunol. 2012;73(12): 1282-6. [Crossref]  [PubMed] 
  60. Lemy A, Andrien M, Wissing KM, Ryhahi K, Vandersarren A, Racapé J, et al. Major histocompatibility complex class 1 chain-related antigen a antibodies: Sensitizing events and impact on renal graft outcomes. Transplantation. 2010;90(2):168-74. [Crossref]  [PubMed] 
  61. Pearl MH, Leuchter RK, Reed EF, Zhang Q, Ettenger RB, Tsai EW. Accelerated rejection, thrombosis, and graft failure with angiotensin II type 1 receptor antibodies. Pediatr Nephrol. 2015;30(8):1371-4. [Crossref]  [PubMed] 
  62. Guzzo I, Morolli F, Camassei FD, Piazza A, Poggi E, Dello Strologo L. Acute kidney transplant rejection mediated by angiotensin II type 1 receptor antibodies in a pediatric hyperimmune patient. Pediatr Nephrol. 2017;32(1): 185-8. [Crossref]  [PubMed] 
  63. Kelsch R, Everding AS, Kuwertz-Bröking E, Brand E, Spriewald BM, Sibrowski W, et al. Accelerated kidney transplant rejection and hypertensive encephalopathy in a pediatric patient associated with antibodies against angiotensin type 1 receptor and HLA class II. Transplantation. 2011;92(10):e57-9. [Crossref]  [PubMed] 
  64. Jobert A, Rao N, Deayton S, Bennett GD, Brealey J, Nolan J, et al. Angiotensin II type 1 receptor antibody precipitating acute vascular rejection in kidney transplantation. Nephrology (Carlton). 2015;20 Suppl 1:10-2. [Crossref]  [PubMed] 
  65. Lee J, Kim BS, Park Y, Lee JG, Lim BJ, Jeong HJ, et al. The effect of Bortezomib on antibody-mediated rejection after kidney transplantation. Yonsei Med J. 2015;56(6):1638-42. [Crossref]  [PubMed]  [PMC] 
  66. Narayan S, Tsai EW, Zhang Q, Wallace WD, Reed EF, Ettenger RB. Acute rejection associated with donor-specific anti-MICA antibody in a highly sensitized pediatric renal transplant recipient. Pediatr Transplant. 2011;15(1):E1-7. [Crossref]  [PubMed]  [PMC] 
  67. Scornik JC, Guerra G, Schold JD, Srinivas TR, Dragun D, Meier-Kriesche HU. Value of posttransplant antibody tests in the evaluation of patients with renal graft dysfunction. Am J Transplant. 2007;7(7):1808-14. [Crossref]  [PubMed] 
  68. Rose ML, Smith J, Dureau G, Keogh A, Kobashigowa J. Mycophenolate mofetil decreases antibody production after cardiac transplantation. J Heart Lung Transplant. 2002;21(2):282-5. [Crossref] 

.: Up To Date

Login



Contact


Ortadoğu Reklam Tanıtım Yayıncılık Turizm Eğitim İnşaat Sanayi ve Ticaret A.Ş.

.: Address

Turkocagi Caddesi No:30 06520 Balgat / ANKARA
Phone: +90 312 286 56 56
Fax: +90 312 220 04 70
E-mail: info@turkiyeklinikleri.com

.: Manuscript Editing Department

Phone: +90 312 286 56 56/ 2
E-mail: yaziisleri@turkiyeklinikleri.com

.: English Language Redaction

Phone: +90 312 286 56 56/ 145
E-mail: tkyayindestek@turkiyeklinikleri.com

.: Marketing Sales-Project Department

Phone: +90 312 286 56 56/ 142
E-mail: reklam@turkiyeklinikleri.com

.: Subscription and Public Relations Department

Phone: +90 312 286 56 56/ 118
E-mail: abone@turkiyeklinikleri.com

.: Customer Services

Phone: +90 312 286 56 56/ 118
E-mail: satisdestek@turkiyeklinikleri.com

1. TERMS OF USE

1.1. To use the web pages with http://www.turkiyeklinikleri.com domain name or the websites reached through the sub domain names attached to the domain name (They will be collectively referred as "SITE"), please read the conditions below. If you do not accept these terms, please cease to use the "SITE." "SITE" owner reserves the right to change the information on the website, forms, contents, the "SITE," "SITE" terms of use anytime they want.

1.2. The owner of the "SITE" is Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. (From now on it is going to be referred as "Turkiye Klinikleri", shortly) and it resides at Turkocagi cad. No:30, 06520 Balgat Ankara. The services in the "SITE" are provided by "Turkiye Klinikleri."

1.3. Anyone accessing the "SITE" with or without a fee whether they are a natural person or a legal identity is considered to agree these terms of use. In this contract hereby, "Turkiye Klinikleri" may change the stated terms anytime. These changes will be published in the "SITE" periodically and they will be valid when they are published. Any natural person or legal identity benefiting from and reaching to the "SITE" are considered to be agreed to any change on hereby contract terms done by "Turkiye Klinikleri."

1.4. The "Terms of Use" hereby is published in the website with the last change on March 30th 2014 and the "SITE" is activated by enabling the access to everyone. The "Terms of Use" hereby is also a part of the any "USER Contract" was and/or will be done with the users using "Turkiye Klinikleri" services with or without a fee an inseparable.

2. DEFINITIONS

2.1. "SITE": A website offering different kind of services and context with a certain frame determined by "Turkiye Klinikleri" and it is accessible on-line on http://www.turkiyeklinikleri.com domain name and/or subdomains connected to the domain name.

2.2. USER: A natural person or a legal identity accessing to the "SITE" through online settings.

2.3. LINK: A link enabling to access to another website through the "SITE", the files, the context or through another website to the "SITE", the files and the context.

2.4. CONTEXT: Any visual, literary and auditory images published in the "Turkiye Klinikleri", "SITE" and/or any website or any accessible information, file, picture, number/figures, price, etc.

2.5. "USER CONTRACT": An electronically signed contract between a natural or a legal identity benefiting from special services "Turkiye Klinikleri" will provide and "Turkiye Klinikleri".

3. SCOPE OF THE SERVICES

3.1. "Turkiye Klinikleri" is completely free to determine the scope and quality of the services via the "SITE".

3.2. To benefit the services of "Turkiye Klinikleri" "SITE", the "USER" must deliver the features that will be specified by "Turkiye Klinikleri". "Turkiye Klinikleri" may change this necessity any time single-sided.

3.3. Not for a limited number, the services "Turkiye Klinikleri" will provide through the "SITE" for a certain price or for free are;

- Providing scientific articles, books and informative publications for health industry.

- Providing structural, statistical and editorial support to article preparation stage for scientific journals.

4. GENERAL PROVISIONS

4.1. "Turkiye Klinikleri" is completely free to determine which of the services and contents provided in the "SITE" will be charged.

4.2. People benefiting from the services provided by "Turkiye Klinikleri" and using the website can use the "SITE" only according to the law and only for personal reasons. Users have the criminal and civil liability for every process and action they take in the "SITE". Every USER agrees, declares and undertakes that they will not proceed by any function or action infringement of rights of "Turkiye Klinikleri"s and/or other third parties', they are the exclusive right holder on usage, processing, storage, made public and revealing any written, visual or auditory information reported to Turkiye Klinikleri" and/or "SITE" to the third parties. "USER" agrees and undertakes that s/he will not duplicate, copy, distribute, process, the pictures, text, visual and auditory images, video clips, files, databases, catalogs and lists within the "SITE", s/he will not be using these actions or with other ways to compete with "Turkiye Klinikleri", directly or indirectly.

4.3. The services provided and the context published within the "SITE" by third parties is not under the responsibility of "Turkiye Klinikleri", institutions collaborated with "Turkiye Klinikleri", "Turkiye Klinikleri" employee and directors, "Turkiye Klinikleri" authorized salespeople. Commitment to accuracy and legality of the published information, context, visual and auditory images provided by any third party are under the full responsibility of the third party. "Turkiye Klinikleri" does not promise and guarantee the safety, accuracy and legality of the services and context provided by a third party.

4.4. "USER"s cannot act against "Turkiye Klinikleri", other "USER"s and third parties by using the "SITE". "Turkiye Klinikleri" has no direct and/or indirect responsibility for any damage a third party suffered or will suffer regarding "USER"s actions on the "SITE" against the rules of the hereby "Terms of Use" and the law.

4.5. "USER"s accept and undertake that the information and context they provided to the "SITE" are accurate and legal. "Turkiye Klinikleri" is not liable and responsible for promising and guaranteeing the verification of the information and context transmitted to "Turkiye Klinikleri" by the "USER"s, or uploaded, changed and provided through the "SITE" by them and whether these information are safe, accurate and legal.

4.6. "USER"s agree and undertake that they will not perform any action leading to unfair competition, weakening the personal and commercial credit of "Turkiye Klinikleri" and a third party,  encroaching and attacking on personal rights within the "SITE" in accordance with the Turkish Commercial Code Law.

4.7. "Turkiye Klinikleri" reserves the right to change the services and the context within the "SITE"  anytime. "Turkiye Klinikleri" may use this right without any notification and timelessly. "USER"s have to make the changes and/or corrections "Turkiye Klinikleri" required immediately. Any changes and/or corrections that are required by "Turkiye Klinikleri", may be made by "Turkiye Klinikleri" when needed. Any harm, criminal and civil liability resulted or will result from changes and/or corrections required by "Turkiye Klinikleri" and were not made on time by the "USER"s belongs completely to the users.

4.8. "Turkiye Klinikleri" may give links through the "SITE" to other websites and/or "CONTEXT"s and/or folders that are outside of their control and owned and run by third parties. These links are provided for ease of reference only and do not hold qualification for support the respective web SITE or the admin or declaration or guarantee for the information inside. "Turkiye Klinikleri" does not hold any responsibility over the web-sites connected through the links on the "SITE", folders and context, the services or products on the websites provided through these links or their context.

4.9. "Turkiye Klinikleri" may use the information provided to them by the "USERS" through the "SITE" in line with the terms of the "PRIVACY POLICY" and "USER CONTRACT". It may process the information or classify and save them on a database. "Turkiye Klinikleri" may also use the USER's or visitor's identity, address, e-mail address, phone number, IP number, which sections of the "SITE" they visited, domain type, browser type, date and time information to provide statistical evaluation and customized services.

5. PROPRIETARY RIGHTS

5.1. The information accessed through this "SITE" or provided by the users legally and all the elements (including but not limited to design, text, image, html code and other codes) of the "SITE" (all of them will be called as studies tied to "Turkiye Klinikleri"s copyrights) belongs to "Turkiye Klinikleri". Users do not have the right to resell, process, share, distribute, display or give someone permission to access or to use the "Turkiye Klinikleri" services, "Turkiye Klinikleri" information and the products under copyright protection by "Turkiye Klinikleri". Within hereby "Terms of Use" unless explicitly permitted by "Turkiye Klinikleri" nobody can reproduce, process, distribute or produce or prepare any study from those under "Turkiye Klinikleri" copyright protection.

5.2. Within hereby "Terms of Use", "Turkiye Klinikleri" reserves the rights for "Turkiye Klinikleri" services, "Turkiye Klinikleri" information, the products associated with "Turkiye Klinikleri" copyrights, "Turkiye Klinikleri" trademarks, "Turkiye Klinikleri" trade looks or its all rights for other entity and information it has through this website unless it is explicitly authorized by "Turkiye Klinikleri".

6. CHANGES IN THE TERMS OF USE

"Turkiye Klinikleri" in its sole discretion may change the hereby "Terms of Use" anytime announcing within the "SITE". The changed terms of the hereby "Terms of Use" will become valid when they are announced. Hereby "Terms of Use" cannot be changed by unilateral declarations of users.

7. FORCE MAJEURE

"Turkiye Klinikleri" is not responsible for executing late or never of this hereby "Terms of Use", privacy policy and "USER Contract" in any situation legally taken into account as force majeure. Being late or failure of performance or non-defaulting of this and similar cases like this will not be the case from the viewpoint of "Turkiye Klinikleri", and "Turkiye Klinikleri" will not have any damage liability for these situations. "Force majeure" term will be regarded as outside of the concerned party's reasonable control and any situation that "Turkiye Klinikleri" cannot prevent even though it shows due diligence. Also, force majeure situations include but not limited to natural disasters, rebellion, war, strike, communication problems, infrastructure and internet failure, power cut and bad weather conditions.

8. LAW AND AUTHORISATION TO FOLLOW

Turkish Law will be applied in practicing, interpreting the hereby "Terms of Use" and managing the emerging legal relationships within this "Terms of Use" in case of finding element of foreignness, except for the rules of Turkish conflict of laws. Ankara Courts and Enforcement Offices are entitled in any controversy happened or may happen due to hereby contract.

9. CLOSING AND AGREEMENT

Hereby "Terms of Use" come into force when announced in the "SITE" by "Turkiye Klinikleri". The users are regarded to agree to hereby contract terms by using the "SITE". "Turkiye Klinikleri" may change the contract terms and the changes will be come into force by specifying the version number and the date of change on time it is published in the "SITE".

 

30.03.2014

Privacy Policy

We recommend you to read the terms of use below before you visit our website. In case you agree these terms, following our rules will be to your favor. Please read our Terms of Use thoroughly.

www.turkiyeklinikleri.com website belongs to Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. and is designed in order to inform physicians in the field of health

www.turkiyeklinikleri.com cannot reach to user’s identity, address, service providers or other information. The users may send this information to the website through forms if they would like to. However, www.turkiyeklinikleri.com may collect your hardware and software information. The information consists of your IP address, browser type, operating system, domain name, access time, and related websites. www.turkiyeklinikleri.com cannot sell the provided user information (your name, e-mail address, home and work address, phone number) to the third parties, publish it publicly, or keep it in the website. Gathered information has a directing feature to be a source for the website’s visitor profile, reporting and promotion of the services.

www.turkiyeklinikleri.com uses the taken information:

-To enhance, improve and maintain the quality of the website

-To generate visitor’s profile and statistical data

-To determine the tendency of the visitors on using our website

-To send print publications/correspondences

-To send press releases or notifications through e-mail

-To generate a list for an event or competition

By using www.turkiyeklinikleri.com you are considered to agree that;

-Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. cannot be hold responsible for any user’s illegal and immoral behavior,

-Terms of use may change from time to time,

-It is not responsible for other websites’ contents it cannot control or the harms they may cause although it uses the connection they provided.

Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. may block the website to users in the following events:

-Information with wrong, incomplete, deceiving or immoral expressions is recorded to the website,

-Proclamation, advertisement, announcement, libelous expressions are used against natural person or legal identity,

-During various attacks to the website,

-Disruption of the website because of a virus.

Written, visual and audible materials of the website, including the code and the software are under protection by legal legislation.

Without the written consent of Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. the information on the website cannot be downloaded, changed, reproduced, copied, republished, posted or distributed.

All rights of the software and the design of the website belong to Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc.

Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. will be pleased to hear your comments about our terms of use. Please share the subjects you think may enrich our website or if there is any problem regarding our website.

info@turkiyeklinikleri.com