Skip to main content

Advertisement

SpringerLink
Log in

Monitoring alloimmune response in kidney transplantation

  • Review
  • Published:
Journal of Nephrology Aims and scope Submit manuscript

Abstract

Currently, immunosuppressive therapy in kidney transplant recipients is generally performed by protocols and adjusted according to functional or histological evaluation of the allograft and/or signs of drug toxicity or infection. As a result, a large fraction of patients are likely to receive too much or too little immunosuppression, exposing them to higher rates of infection, malignancy and drug toxicity, or increased risk of acute and chronic graft injury from rejection, respectively. Developing reliable biomarkers is crucial for individualizing therapy aimed at extending allograft survival. Emerging data indicate that many assays, likely used in panels rather than single assays, have potential to be diagnostic and predictive of short and also long-term outcome. While numerous cross-sectional studies have found associations between the results of these assays and the presence of clinically relevant post-transplantation outcomes, data from prospective studies are still scanty, thereby preventing widespread implementation in the clinic. Of note, some prospective, randomized, multicenter biomarker-driven studies are currently on-going aiming at confirming such preliminary data. These works as well as other future studies are highly warranted to test the hypothesis that tailoring immunosuppression on the basis of results offered by these biomarkers leads to better outcomes than current standard clinical practice.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Varagunam M, Yaqoob MM, Dohler B, Opelz G (2009) C3 polymorphisms and allograft outcome in renal transplantation. N Engl J Med 360:874–880. doi:10.1056/NEJMoa0801861

    Article  CAS  PubMed  Google Scholar 

  2. Alakulppi NS, Kyllonen LE, Jantti VT, Matinlauri IH, Partanen J, Salmela KT et al (2004) Cytokine gene polymorphisms and risks of acute rejection and delayed graft function after kidney transplantation. Transplantation 78:1422–1428

    Article  CAS  PubMed  Google Scholar 

  3. Lechler RI, Lombardi G, Batchelor JR, Reinsmoen N, Bach FH (1990) The molecular basis of alloreactivity. Immunol Today 11:83–88

    Article  CAS  PubMed  Google Scholar 

  4. Shoskes DA, Wood KJ (1994) Indirect presentation of MHC antigens in transplantation. Immunol Today 15:32–38. doi:10.1016/0167-5699(94)90023-X

    Article  CAS  PubMed  Google Scholar 

  5. Lechler RI, Batchelor JR (1982) Immunogenicity of retransplanted rat kidney allografts. Effect of inducing chimerism in the first recipient and quantitative studies on immunosuppression of the second recipient. J Exp Med 156:1835–1841

    Article  CAS  PubMed  Google Scholar 

  6. Lechler RI, Batchelor JR (1982) Restoration of immunogenicity to passenger cell-depleted kidney allografts by the addition of donor strain dendritic cells. J Exp Med 155:31–41

    Article  CAS  PubMed  Google Scholar 

  7. van Besouw NM, Zuijderwijk JM, Vaessen LM, Balk AH, Maat AP, van der Meide PH et al (2005) The direct and indirect allogeneic presentation pathway during acute rejection after human cardiac transplantation. Clin Exp Immunol 141:534–540. doi:10.1111/j.1365-2249.2005.02871.x

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Baker RJ, Hernandez-Fuentes MP, Brookes PA, Chaudhry AN, Lechler R (2001) Comparison of the direct and indirect pathways of allorecognition in chronic allograft failure. Transplant Proc 33:449

    Article  CAS  PubMed  Google Scholar 

  9. Vella JP, Vos L, Carpenter CB, Sayegh MH (1997) Role of indirect allorecognition in experimental late acute rejection. Transplantation 64:1823–1828

    Article  CAS  PubMed  Google Scholar 

  10. Sayegh MH, Carpenter CB (1996) Role of indirect allorecognition in allograft rejection. Int Rev Immunol 13:221–229

    Article  CAS  PubMed  Google Scholar 

  11. Bestard O, Nickel P, Cruzado JM, Schoenemann C, Boenisch O, Sefrin A et al (2008) Circulating alloreactive T cells correlate with graft function in longstanding renal transplant recipients. J Am Soc Nephrol JASN 19:1419–1429. doi:10.1681/ASN.2007050539

    Article  PubMed  Google Scholar 

  12. Herrera OB, Golshayan D, Tibbott R, Salcido Ochoa F, James MJ, Marelli-Berg FM et al (2004) A novel pathway of alloantigen presentation by dendritic cells. J Immunol 173:4828–4837

    Article  CAS  PubMed  Google Scholar 

  13. Thomas FT, Lee HM, Lower RR, Thomas JM (1979) Immunological monitoring as a guide to the management of transplant recipients. Surg Clin North Am 59:253–281

    Article  CAS  PubMed  Google Scholar 

  14. Ghobrial II, Morris AG, Booth LJ (1994) Clinical significance of in vitro donor-specific hyporesponsiveness in renal allograft recipients as demonstrated by the MLR. Transpl Int 7:420–427

    Article  CAS  PubMed  Google Scholar 

  15. Hernandez-Fuentes MP, Warrens AN, Lechler RI (2003) Immunologic monitoring. Immunol Rev 196:247–264

    Article  CAS  PubMed  Google Scholar 

  16. Page AJ, Ford ML, Kirk AD (2009) Memory T-cell-specific therapeutics in organ transplantation. Curr Opin Organ Transplant 14:643–649. doi:10.1097/MOT.0b013e328332bd4a

    Article  PubMed  PubMed Central  Google Scholar 

  17. Woodland DL, Kohlmeier JE (2009) Migration, maintenance and recall of memory T cells in peripheral tissues. Nat Rev Immunol 9:153–161. doi:10.1038/nri2496

    Article  CAS  PubMed  Google Scholar 

  18. Pearl JP, Parris J, Hale DA, Hoffmann SC, Bernstein WB, McCoy KL et al (2005) Immunocompetent T-cells with a memory-like phenotype are the dominant cell type following antibody-mediated T-cell depletion. Am J Transplant 5:465–474. doi:10.1111/j.1600-6143.2005.00759.x

    Article  CAS  PubMed  Google Scholar 

  19. Mashishi T, Gray CM (2002) The ELISPOT assay: an easily transferable method for measuring cellular responses and identifying T cell epitopes. Clin Chem Lab Med 40:903–910. doi:10.1515/CCLM.2002.159

    Article  CAS  PubMed  Google Scholar 

  20. Hricik DE, Rodriguez V, Riley J, Bryan K, Tary-Lehmann M, Greenspan N et al (2003) Enzyme linked immunosorbent spot (ELISPOT) assay for interferon-gamma independently predicts renal function in kidney transplant recipients. Am J Transplant 3:878–884

    Article  CAS  PubMed  Google Scholar 

  21. Nather BJ, Nickel P, Bold G, Presber F, Schonemann C, Pratschke J et al (2006) Modified ELISPOT technique–highly significant inverse correlation of post-Tx donor-reactive IFNgamma-producing cell frequencies with 6 and 12 months graft function in kidney transplant recipients. Transpl Immunol 16:232–237. doi:10.1016/j.trim.2006.09.026

    Article  PubMed  CAS  Google Scholar 

  22. Heeger PS, Greenspan NS, Kuhlenschmidt S, Dejelo C, Hricik DE, Schulak JA et al (1999) Pretransplant frequency of donor-specific, IFN-gamma-producing lymphocytes is a manifestation of immunologic memory and correlates with the risk of posttransplant rejection episodes. J Immunol 163:2267–2275

    CAS  PubMed  Google Scholar 

  23. Augustine JJ, Siu DS, Clemente MJ, Schulak JA, Heeger PS, Hricik DE (2005) Pre-transplant IFN-gamma ELISPOTs are associated with post-transplant renal function in African American renal transplant recipients. Am J Transplant 5:1971–1975. doi:10.1111/j.1600-6143.2005.00958.x

    Article  PubMed  Google Scholar 

  24. Augustine JJ, Poggio ED, Clemente M, Aeder MI, Bodziak KA, Schulak JA et al (2007) Hemodialysis vintage, black ethnicity, and pretransplantation antidonor cellular immunity in kidney transplant recipients. J Am Soc Nephrol JASN 18:1602–1606. doi:10.1681/ASN.2006101105

    Article  PubMed  Google Scholar 

  25. Nickel P, Presber F, Bold G, Biti D, Schonemann C, Tullius SG et al (2004) Enzyme-linked immunosorbent spot assay for donor-reactive interferon-gamma-producing cells identifies T-cell presensitization and correlates with graft function at 6 and 12 months in renal-transplant recipients. Transplantation 78:1640–1646

    Article  CAS  PubMed  Google Scholar 

  26. Kim SH, Oh EJ, Kim MJ, Park YJ, Han K, Yang HJ et al (2007) Pretransplant donor-specific interferon-gamma ELISPOT assay predicts acute rejection episodes in renal transplant recipients. Transplant Proc 39:3057–3060. doi:10.1016/j.transproceed.2007.06.080

    Article  CAS  PubMed  Google Scholar 

  27. Koscielska-Kasprzak K, Drulis-Fajdasz D, Kaminska D, Mazanowska O, Krajewska M, Gdowska W et al (2009) Pretransplantation cellular alloreactivity is predictive of acute graft rejection and 1-year graft function in kidney transplant recipients. Transplant Proc 41:3006–3008. doi:10.1016/j.transproceed.2009.07.086

    Article  CAS  PubMed  Google Scholar 

  28. Bestard O, Cruzado JM, Mestre M, Caldes A, Bas J, Carrera M et al (2007) Achieving donor-specific hyporesponsiveness is associated with FOXP3+ regulatory T cell recruitment in human renal allograft infiltrates. J Immunol 179:4901–4909

    Article  CAS  PubMed  Google Scholar 

  29. Augustine JJ, Poggio ED, Heeger PS, Hricik DE (2008) Preferential benefit of antibody induction therapy in kidney recipients with high pretransplant frequencies of donor-reactive interferon-gamma enzyme-linked immunosorbent spots. Transplantation 86:529–534. doi:10.1097/TP.0b013e31818046db

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Cherkassky L, Lanning M, Lalli PN, Czerr J, Siegel H, Danziger-Isakov L et al (2011) Evaluation of alloreactivity in kidney transplant recipients treated with antithymocyte globulin versus IL-2 receptor blocker. Am J Transplant 11:1388–1396. doi:10.1111/j.1600-6143.2011.03540.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Crespo E, Lucia M, Cruzado JM, Luque S, Melilli E, Manonelles A et al (2015) Pre-transplant donor-specific T-cell alloreactivity is strongly associated with early acute cellular rejection in kidney transplant recipients not receiving T-cell depleting induction therapy. PLoS One 10:e0117618. doi:10.1371/journal.pone.0117618

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Hricik DE, Augustine J, Nickerson P, Formica RN, Poggio ED, Rush D et al (2015) Interferon gamma ELISPOT testing as a risk-stratifying Biomarker for kidney transplant injury: results from the CTOT-01 multicenter study. Am J Transplant 15:3166–3173. doi:10.1111/ajt.13401

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Bestard O, Cruzado JM, Lucia M, Crespo E, Casis L, Sawitzki B et al (2013) Prospective assessment of antidonor cellular alloreactivity is a tool for guidance of immunosuppression in kidney transplantation. Kidney Int 84:1226–1236. doi:10.1038/ki.2013.236

    Article  CAS  PubMed  Google Scholar 

  34. Andree H, Nickel P, Nasiadko C, Hammer MH, Schonemann C, Pruss A et al (2006) Identification of dialysis patients with panel-reactive memory T cells before kidney transplantation using an allogeneic cell bank. J Am Soc Nephrol JASN 17:573–580. doi:10.1681/ASN.2005030299

    Article  CAS  PubMed  Google Scholar 

  35. Poggio ED, Clemente M, Hricik DE, Heeger PS (2006) Panel of reactive T cells as a measurement of primed cellular alloimmunity in kidney transplant candidates. J Am Soc Nephrol JASN 17:564–572. doi:10.1681/ASN.2005030293

    Article  CAS  PubMed  Google Scholar 

  36. Poggio ED, Augustine JJ, Clemente M, Danzig JM, Volokh N, Zand MS et al (2007) Pretransplant cellular alloimmunity as assessed by a panel of reactive T cells assay correlates with acute renal graft rejection. Transplantation 83:847–852. doi:10.1097/01.tp.0000258730.75137.39

    Article  PubMed  Google Scholar 

  37. Pawlik A, Florczak M, Masiuk M, Dutkiewicz G, Machalinski B, Rozanski J et al (2003) The expansion of CD4+CD28−T cells in patients with chronic kidney graft rejection. Transplant Proc 35:2902–2904

    Article  CAS  PubMed  Google Scholar 

  38. Brzezinska A, Magalska A, Szybinska A, Sikora E (2004) Proliferation and apoptosis of human CD8(+)CD28(+) and CD8(+)CD28(−) lymphocytes during aging. Exp Gerontol 39:539–544. doi:10.1016/j.exger.2003.09.026

    Article  PubMed  Google Scholar 

  39. Scheuring UJ, Sabzevari H, Theofilopoulos AN (2002) Proliferative arrest and cell cycle regulation in CD8(+)CD28(−) versus CD8(+)CD28(+) T cells. Hum Immunol 63:1000–1009

    Article  CAS  PubMed  Google Scholar 

  40. Tortorella C, Pisconti A, Piazzolla G, Antonaci S (2002) APC-dependent impairment of T cell proliferation in aging: role of CD28- and IL-12/IL-15-mediated signaling. Mech Ageing Dev 123:1389–1402

    Article  CAS  PubMed  Google Scholar 

  41. Traitanon O, Gorbachev A, Bechtel JJ, Keslar KS, Baldwin WM 3rd, Poggio ED et al (2014) IL-15 induces alloreactive CD28(−) memory CD8 T cell proliferation and CTLA4-Ig resistant memory CD8 T cell activation. Am J Transplant 14:1277–1289. doi:10.1111/ajt.12719

    Article  CAS  PubMed  Google Scholar 

  42. Conlon TM, Saeb-Parsy K, Cole JL, Motallebzadeh R, Qureshi MS, Rehakova S et al (2012) Germinal center alloantibody responses are mediated exclusively by indirect-pathway CD4 T follicular helper cells. J Immunol 188:2643–2652. doi:10.4049/jimmunol.1102830

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Steele DJ, Laufer TM, Smiley ST, Ando Y, Grusby MJ, Glimcher LH et al (1996) Two levels of help for B cell alloantibody production. J Exp Med 183:699–703

    Article  CAS  PubMed  Google Scholar 

  44. Poggio ED, Clemente M, Riley J, Roddy M, Greenspan NS, Dejelo C et al (2004) Alloreactivity in renal transplant recipients with and without chronic allograft nephropathy. J Am Soc Nephrol JASN 15:1952–1960

    Article  PubMed  Google Scholar 

  45. Illigens BM, Yamada A, Anosova N, Dong VM, Sayegh MH, Benichou G (2009) Dual effects of the alloresponse by Th1 and Th2 cells on acute and chronic rejection of allotransplants. Eur J Immunol 39:3000–3009. doi:10.1002/eji.200838980

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Reznik SI, Jaramillo A, SivaSai KS, Womer KL, Sayegh MH, Trulock EP et al (2001) Indirect allorecognition of mismatched donor HLA class II peptides in lung transplant recipients with bronchiolitis obliterans syndrome. Am J Transplant 1:228–235

    Article  CAS  PubMed  Google Scholar 

  47. Stegmann S, Muller A, Zavazava N (2000) Synthetic HLA-A2 derived peptides are recognized and presented in renal graft recipients. Hum Immunol 61:1363–1369

    Article  CAS  PubMed  Google Scholar 

  48. Benichou G, Valujskikh A, Heeger PS (1999) Contributions of direct and indirect T cell alloreactivity during allograft rejection in mice. J Immunol 162:352–358

    CAS  PubMed  Google Scholar 

  49. Ciubotariu R, Liu Z, Colovai AI, Ho E, Itescu S, Ravalli S et al (1998) Persistent allopeptide reactivity and epitope spreading in chronic rejection of organ allografts. J Clin Invest 101:398–405. doi:10.1172/JCI1117

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Smith HJ, Hanvesakul R, Bentall A, Shabir S, Morgan MD, Briggs D et al (2011) T Lymphocyte responses to nonpolymorphic HLA-derived peptides are associated with chronic renal allograft dysfunction. Transplantation 91:279–286. doi:10.1097/TP.0b013e318203862d

    Article  CAS  PubMed  Google Scholar 

  51. Boisgerault F, Anosova NG, Tam RC, Illigens BM, Fedoseyeva EV, Benichou G (2000) Induction of T-cell response to cryptic MHC determinants during allograft rejection. Hum Immunol 61:1352–1362

    Article  CAS  PubMed  Google Scholar 

  52. Lovegrove E, Pettigrew GJ, Bolton EM, Bradley JA (2001) Epitope mapping of the indirect T cell response to allogeneic class I MHC: sequences shared by donor and recipient MHC may prime T cells that provide help for alloantibody production. J Immunol 167:4338–4344

    Article  CAS  PubMed  Google Scholar 

  53. Maynard CL, Harrington LE, Janowski KM, Oliver JR, Zindl CL, Rudensky AY et al (2007) Regulatory T cells expressing interleukin 10 develop from Foxp3+ and Foxp3- precursor cells in the absence of interleukin 10. Nat Immunol 8:931–941. doi:10.1038/ni1504

    Article  CAS  PubMed  Google Scholar 

  54. Collison LW, Workman CJ, Kuo TT, Boyd K, Wang Y, Vignali KM et al (2007) The inhibitory cytokine IL-35 contributes to regulatory T-cell function. Nature 450:566–569. doi:10.1038/nature06306

    Article  CAS  PubMed  Google Scholar 

  55. Joffre O, Santolaria T, Calise D, Al Saati T, Hudrisier D, Romagnoli P et al (2008) Prevention of acute and chronic allograft rejection with CD4+CD25+Foxp3+ regulatory T lymphocytes. Nat Med 14:88–92. doi:10.1038/nm1688

    Article  CAS  PubMed  Google Scholar 

  56. Louis S, Braudeau C, Giral M, Dupont A, Moizant F, Robillard N et al (2006) Contrasting CD25hiCD4+ T cells/FOXP3 patterns in chronic rejection and operational drug-free tolerance. Transplantation 81:398–407. doi:10.1097/01.tp.0000203166.44968.86

    Article  PubMed  Google Scholar 

  57. Perrella O, Sbreglia C, Arenga G, Perrella A, Ferrara A, D’Antonio A et al (2006) Acute rejection after liver transplantation: is there a specific immunological pattern? Transplant Proc 38:3594–3596. doi:10.1016/j.transproceed.2006.10.102

    Article  CAS  PubMed  Google Scholar 

  58. Demirkiran A, Kok A, Kwekkeboom J, Kusters JG, Metselaar HJ, Tilanus HW et al (2006) Low circulating regulatory T-cell levels after acute rejection in liver transplantation. Liver Transpl 12:277–284. doi:10.1002/lt.20612

    Article  PubMed  Google Scholar 

  59. Ashton-Chess J, Dugast E, Colvin RB, Giral M, Foucher Y, Moreau A et al (2009) Regulatory, effector, and cytotoxic T cell profiles in long-term kidney transplant patients. J Am Soc Nephrol JASN 20:1113–1122. doi:10.1681/ASN.2008050450

    Article  PubMed  Google Scholar 

  60. Dijke IE, Korevaar SS, Caliskan K, Balk AH, Maat AP, Weimar W et al (2009) Inadequate immune regulatory function of CD4+CD25bright+FoxP3+T cells in heart transplant patients who experience acute cellular rejection. Transplantation 87:1191–1200. doi:10.1097/TP.0b013e31819ec2fb

    Article  PubMed  Google Scholar 

  61. Akl A, Jones ND, Rogers N, Bakr MA, Mostafa A, El Shehawy M et al (2008) An investigation to assess the potential of CD25highCD4+ T cells to regulate responses to donor alloantigens in clinically stable renal transplant recipients. Transpl Int 21:65–73. doi:10.1111/j.1432-2277.2007.00560.x

    PubMed  Google Scholar 

  62. Koshiba T, Li Y, Takemura M, Wu Y, Sakaguchi S, Minato N et al (2007) Clinical, immunological, and pathological aspects of operational tolerance after pediatric living-donor liver transplantation. Transpl Immunol 17:94–97. doi:10.1016/j.trim.2006.10.004

    Article  CAS  PubMed  Google Scholar 

  63. Martinez-Llordella M, Puig-Pey I, Orlando G, Ramoni M, Tisone G, Rimola A et al (2007) Multiparameter immune profiling of operational tolerance in liver transplantation. Am J Transplant 7:309–319. doi:10.1111/j.1600-6143.2006.01621.x

    Article  CAS  PubMed  Google Scholar 

  64. Martinez-Llordella M, Lozano JJ, Puig-Pey I, Orlando G, Tisone G, Lerut J et al (2008) Using transcriptional profiling to develop a diagnostic test of operational tolerance in liver transplant recipients. J Clin Invest 118:2845–2857. doi:10.1172/JCI35342

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Braudeau C, Racape M, Giral M, Louis S, Moreau A, Berthelot L et al (2007) Variation in numbers of CD4+CD25highFOXP3+ T cells with normal immuno-regulatory properties in long-term graft outcome. Transpl Int 20:845–855. doi:10.1111/j.1432-2277.2007.00537.x

    Article  CAS  PubMed  Google Scholar 

  66. Kreijveld E, Koenen HJ, van Cranenbroek B, van Rijssen E, Joosten I, Hilbrands LB (2008) Immunological monitoring of renal transplant recipients to predict acute allograft rejection following the discontinuation of tacrolimus. PLoS One 3:e2711. doi:10.1371/journal.pone.0002711

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  67. Akimova T, Kamath BM, Goebel JW, Meyers KE, Rand EB, Hawkins A et al (2012) Differing effects of rapamycin or calcineurin inhibitor on T-regulatory cells in pediatric liver and kidney transplant recipients. Am J Transplant 12:3449–3461. doi:10.1111/j.1600-6143.2012.04269.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Canavan JB, Afzali B, Scotta C, Fazekasova H, Edozie FC, Macdonald TT et al (2012) A rapid diagnostic test for human regulatory T-cell function to enable regulatory T-cell therapy. Blood 119:e57–e66. doi:10.1182/blood-2011-09-380048

    Article  CAS  PubMed  Google Scholar 

  69. Vallotton L, Hadaya K, Venetz JP, Buehler LH, Ciuffreda D, Nseir G et al (2011) Monitoring of CD4+CD25highIL-7Ralphahigh activated T cells in kidney transplant recipients. Clin J Am Soc Nephrol 6:2025–2033. doi:10.2215/CJN.09611010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Hope CM, Grace BS, Pilkington KR, Coates PT, Bergmann IP, Carroll RP (2014) The immune phenotype may relate to cancer development in kidney transplant recipients. Kidney Int 86:175–183. doi:10.1038/ki.2013.538

    Article  CAS  PubMed  Google Scholar 

  71. Ruggenenti P, Perico N, Gotti E, Cravedi P, D’Agati V, Gagliardini E et al (2007) Sirolimus versus cyclosporine therapy increases circulating regulatory T cells, but does not protect renal transplant patients given alemtuzumab induction from chronic allograft injury. Transplantation 84:956–964. doi:10.1097/01.tp.0000284808.28353.2c

    Article  CAS  PubMed  Google Scholar 

  72. Mathew T, Kreis H, Friend P (2004) Two-year incidence of malignancy in sirolimus-treated renal transplant recipients: results from five multicenter studies. Clin Transplant 18:446–449. doi:10.1111/j.1399-0012.2004.00188.x

    Article  PubMed  Google Scholar 

  73. Kissmeyer-Nielsen F, Olsen S, Petersen VP, Fjeldborg O (1966) Hyperacute rejection of kidney allografts, associated with pre-existing humoral antibodies against donor cells. Lancet 2:662–665

    Article  CAS  PubMed  Google Scholar 

  74. Patel R, Terasaki PI (1969) Significance of the positive crossmatch test in kidney transplantation. N Engl J Med 280:735–739. doi:10.1056/NEJM196904032801401

    Article  CAS  PubMed  Google Scholar 

  75. Konvalinka A, Tinckam K (2015) Utility of HLA Antibody Testing in Kidney Transplantation. J Am Soc Nephrol JASN 26:1489–1502. doi:10.1681/ASN.2014080837

    Article  CAS  PubMed  Google Scholar 

  76. Lanzavecchia A, Bernasconi N, Traggiai E, Ruprecht CR, Corti D, Sallusto F (2006) Understanding and making use of human memory B cells. Immunol Rev 211:303–309. doi:10.1111/j.0105-2896.2006.00403.x

    Article  CAS  PubMed  Google Scholar 

  77. Crotty S, Aubert RD, Glidewell J, Ahmed R (2004) Tracking human antigen-specific memory B cells: a sensitive and generalized ELISPOT system. J Immunol Methods 286:111–122. doi:10.1016/j.jim.2003.12.015

    Article  CAS  PubMed  Google Scholar 

  78. Shlomchik MJ, Weisel F (2012) Germinal centers. Immunol Rev 247:5–10. doi:10.1111/j.1600-065X.2012.01125.x

    Article  PubMed  Google Scholar 

  79. Anderson SM, Tomayko MM, Ahuja A, Haberman AM, Shlomchik MJ (2007) New markers for murine memory B cells that define mutated and unmutated subsets. J Exp Med 204:2103–2114. doi:10.1084/jem.20062571

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Crotty S, Felgner P, Davies H, Glidewell J, Villarreal L, Ahmed R (2003) Cutting edge: long-term B cell memory in humans after smallpox vaccination. J Immunol 171:4969–4973

    Article  CAS  PubMed  Google Scholar 

  81. Pinna D, Corti D, Jarrossay D, Sallusto F, Lanzavecchia A (2009) Clonal dissection of the human memory B-cell repertoire following infection and vaccination. Eur J Immunol 39:1260–1270. doi:10.1002/eji.200839129

    Article  CAS  PubMed  Google Scholar 

  82. Billen EV, Christiaans MH, Lee J, van den Berg-Loonen EM (2009) Donor-directed HLA antibodies before and after transplantectomy detected by the luminex single antigen assay. Transplantation 87:563–569. doi:10.1097/TP.0b013e3181949e37

    Article  CAS  PubMed  Google Scholar 

  83. Magee JC, Barr ML, Basadonna GP, Johnson MR, Mahadevan S, McBride MA et al (2007) Repeat organ transplantation in the US, 1996–2005. Am J Transplant 7:1424–1433. doi:10.1111/j.1600-6143.2007.01786.x

    Article  CAS  PubMed  Google Scholar 

  84. Racusen LC, Haas M (2006) Antibody-mediated rejection in renal allografts: lessons from pathology. Clin J Am Soc Nephrol 1:415–420. doi:10.2215/CJN.01881105

    Article  CAS  PubMed  Google Scholar 

  85. Mulder A, Eijsink C, Kardol MJ, Franke-van Dijk ME, van der Burg SH, Kester M et al (2003) Identification, isolation, and culture of HLA-A2-specific B lymphocytes using MHC class I tetramers. J Immunol 171:6599–6603

    Article  CAS  PubMed  Google Scholar 

  86. Mulder A, Kardol MJ, Arn JS, Eijsink C, Franke ME, Schreuder GM et al (2010) Human monoclonal HLA antibodies reveal interspecies crossreactive swine MHC class I epitopes relevant for xenotransplantation. Mol Immunol 47:809–815. doi:10.1016/j.molimm.2009.10.004

    Article  CAS  PubMed  Google Scholar 

  87. Zachary AA, Kopchaliiska D, Montgomery RA, Leffell MS (2007) HLA-specific B cells: I. A method for their detection, quantification, and isolation using HLA tetramers. Transplantation 83:982–988. doi:10.1097/01.tp.0000259017.32857.99

    Article  PubMed  Google Scholar 

  88. Zachary AA, Kopchaliiska D, Montgomery RA, Melancon JK, Leffell MS (2007) HLA-specific B cells: II. Application to transplantation. Transplantation 83:989–994. doi:10.1097/01.tp.0000259019.68244.d7

    Article  PubMed  Google Scholar 

  89. Kopchaliiska D, Zachary AA, Montgomery RA, Leffell MS (2009) Reconstitution of peripheral allospecific CD19+ B-cell subsets after B-lymphocyte depletion therapy in renal transplant patients. Transplantation 87:1394–1401. doi:10.1097/TP.0b013e3181a27683

    Article  CAS  PubMed  Google Scholar 

  90. Pape KA, Taylor JJ, Maul RW, Gearhart PJ, Jenkins MK (2011) Different B cell populations mediate early and late memory during an endogenous immune response. Science 331:1203–1207. doi:10.1126/science.1201730

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Jahnmatz M, Kesa G, Netterlid E, Buisman AM, Thorstensson R, Ahlborg N (2013) Optimization of a human IgG B-cell ELISpot assay for the analysis of vaccine-induced B-cell responses. J Immunol Methods 391:50–59. doi:10.1016/j.jim.2013.02.009

    Article  CAS  PubMed  Google Scholar 

  92. Buisman AM, de Rond CG, Ozturk K, Ten Hulscher HI, van Binnendijk RS (2009) Long-term presence of memory B-cells specific for different vaccine components. Vaccine 28:179–186. doi:10.1016/j.vaccine.2009.09.102

    Article  CAS  PubMed  Google Scholar 

  93. Han M, Rogers JA, Lavingia B, Stastny P (2009) Peripheral blood B cells producing donor-specific HLA antibodies in vitro. Hum Immunol 70:29–34. doi:10.1016/j.humimm.2008.10.013

    Article  CAS  PubMed  Google Scholar 

  94. Snanoudj R, Claas FH, Heidt S, Legendre C, Chatenoud L, Candon S (2015) Restricted specificity of peripheral alloreactive memory B cells in HLA-sensitized patients awaiting a kidney transplant. Kidney Int 87:1230–1240. doi:10.1038/ki.2014.390

    Article  PubMed  Google Scholar 

  95. Czerkinsky CC, Nilsson LA, Nygren H, Ouchterlony O, Tarkowski A (1983) A solid-phase enzyme-linked immunospot (ELISPOT) assay for enumeration of specific antibody-secreting cells. J Immunol Methods 65:109–121

    Article  CAS  PubMed  Google Scholar 

  96. Bernasconi NL, Traggiai E, Lanzavecchia A (2002) Maintenance of serological memory by polyclonal activation of human memory B cells. Science 298:2199–2202. doi:10.1126/science.1076071

    Article  CAS  PubMed  Google Scholar 

  97. Bauer T, Jilg W (2006) Hepatitis B surface antigen-specific T and B cell memory in individuals who had lost protective antibodies after hepatitis B vaccination. Vaccine 24:572–577. doi:10.1016/j.vaccine.2005.08.058

    Article  CAS  PubMed  Google Scholar 

  98. Lucia M, Crespo E, Melilli E, Cruzado JM, Luque S, Llaudo I et al (2014) Preformed frequencies of cytomegalovirus (CMV)-specific memory T and B cells identify protected CMV-sensitized individuals among seronegative kidney transplant recipients. Clin Infect Dis 59:1537–1545. doi:10.1093/cid/ciu589

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Fan X, Ang A, Pollock-Barziv SM, Dipchand AI, Ruiz P, Wilson G et al (2004) Donor-specific B-cell tolerance after ABO-incompatible infant heart transplantation. Nat Med 10:1227–1233. doi:10.1038/nm1126

    Article  CAS  PubMed  Google Scholar 

  100. Perry DK, Pollinger HS, Burns JM, Rea D, Ramos E, Platt JL et al (2008) Two novel assays of alloantibody-secreting cells demonstrating resistance to desensitization with IVIG and rATG. Am J Transplant 8:133–143. doi:10.1111/j.1600-6143.2007.02039.x

    Article  CAS  PubMed  Google Scholar 

  101. Heidt S, Roelen DL, de Vaal YJ, Kester MG, Eijsink C, Thomas S et al (2012) A NOVel ELISPOT assay to quantify HLA-specific B cells in HLA-immunized individuals. Am J Transplant 12:1469–1478. doi:10.1111/j.1600-6143.2011.03982.x

    Article  CAS  PubMed  Google Scholar 

  102. Karahan GE, Eikmans M, Anholts JD, Claas FH, Heidt S (2014) Polyclonal B cell activation for accurate analysis of pre-existing antigen-specific memory B cells. Clin Exp Immunol 177:333–340. doi:10.1111/cei.12305

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Lucia M, Luque S, Crespo E, Melilli E, Cruzado JM, Martorell J et al (2015) Preformed circulating HLA-specific memory B cells predict high risk of humoral rejection in kidney transplantation. Kidney Int 88:874–887. doi:10.1038/ki.2015.205

    Article  CAS  PubMed  Google Scholar 

  104. Lynch RJ, Silva IA, Chen BJ, Punch JD, Cascalho M, Platt JL (2013) Cryptic B cell response to renal transplantation. Am J Transplant 13:1713–1723. doi:10.1111/ajt.12308

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. De Vlaminck I, Valantine HA, Snyder TM, Strehl C, Cohen G, Luikart H et al (2014) Circulating cell-free DNA enables noninvasive diagnosis of heart transplant rejection. Sci Transl Med 6:241ra77. doi:10.1126/scitranslmed.3007803

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  106. De Vlaminck I, Martin L, Kertesz M, Patel K, Kowarsky M, Strehl C et al (2015) Noninvasive monitoring of infection and rejection after lung transplantation. Proc Natl Acad Sci USA 112:13336–13341. doi:10.1073/pnas.1517494112

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  107. Ashoor I, Najafian N, Korin Y, Reed EF, Mohanakumar T, Ikle D et al (2013) Standardization and cross validation of alloreactive IFNgamma ELISPOT assays within the clinical trials in organ transplantation consortium. Am J Transplant 13:1871–1879. doi:10.1111/ajt.12286

    Article  CAS  PubMed  Google Scholar 

  108. Bestard O, Crespo E, Stein M, Lucia M, Roelen DL, de Vaal YJ et al (2013) Cross-validation of IFN-gamma Elispot assay for measuring alloreactive memory/effector T cell responses in renal transplant recipients. Am J Transplant 13:1880–1890. doi:10.1111/ajt.12285

    Article  CAS  PubMed  Google Scholar 

  109. Brodin P, Valentini D, Uhlin M, Mattsson J, Zumla A, Maeurer MJ (2013) Systems level immune response analysis and personalized medicine. Expert Rev Clin Immunol 9:307–317. doi:10.1586/eci.13.9

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was partially supported by a Spanish public Grant (FIS PI13/01263), a European Commission grant from the Biomarker-Driven Immunosuppression Minimization (BIODRIM) Consortium (Bio-Drim, 12CEE014) as well as by the Spanish Red de Investigación Renal (REDinREN, RD12/0021).

Author information

Authors and Affiliations

  1. Kidney Transplant Unit, Nephrology Department, Bellvitge University Hospital, Barcelona University, IDIBELL, Barcelona, Spain

    Oriol Bestard

  2. Renal Division, Department of Medicine, Icahn School of Medicine at Mount Sinai, One Gustave Levy Place, Annenberg Building, New York, NY, 10029, USA

    Paolo Cravedi

Authors
  1. Oriol Bestard
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Paolo Cravedi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Paolo Cravedi.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

This is a review article that does not involve any new studies of human or animal subjects performed by any of the authors.

Informed consent

For this type of study formal consent is not required.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bestard, O., Cravedi, P. Monitoring alloimmune response in kidney transplantation. J Nephrol 30, 187–200 (2017). https://doi.org/10.1007/s40620-016-0320-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40620-016-0320-7

Keywords

Search

Navigation