Immunological Monitoring



Facial transplants involve vascularized allografts which are prone to various types of antibody- and cell-mediated rejection. The requirement for multiple non-immunological layers of donor suitability in this context dictates careful assessment of which immunological criteria to consider. Although the clinical practice of facial transplants is fairly recent, experience from other organ and tissue transplants has shown that pre-transplant immunological risk assessment and post-transplant monitoring are critical to maximize graft survival. The real challenge is to correlate short- and long-term outcomes of this procedure with individual tests to determine their clinical relevance in this unique setting. An overview of the landscape of modern immunological testing methods will be presented with emphasis on the clinical applicability of these methods. Both routine and novel testing methods will be reviewed. Relevant studies to assess the clinical significance of different methods in other solid organ and hematopoietic stem cell transplants in humans and from animal models of composite tissue allografts (CTA) will be highlighted.


Peripherally Insert Central Catheter Hyperacute Rejection Panel Reactive Antibody Face Transplant Kidney Allograft Rejection 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



antibody-mediated rejection


adenosine tri-phosphate


cytotoxic crossmatch


composite tissue allotransplantation


donor-specific HLA antibodies


enzyme-linked Immunosorbent Assay


enzyme-linked immunospot


flow cytometric crossmatch


graft-versus-host disease


human leukocyte antigen


human progenitor cells


major histocompatibility complex class I related chain A


not published


peripheral blood lymphocytes


polymerase chain reactions




peripherally inserted central catheter


panel reactive antibodies


sequence-specific oligonucleotide probes


sequence-specific primer


tumor necrosis factor



I would like to thank Drs. Robin Avery, Bijan Eghtesad, Titte Srinivas, and Maria Siemionow from the Cleveland Clinic Transplant Center, Drs. Howard Gebel and Robert Bray from the Department of Pathology at Emory University, and Garnett Smith from the Cleveland Clinic Lerner College of Medicine for providing clinical follow-up data and insightful discussion.


  1. 1.
    Carter V. My approach to cardiothoracic transplantation and the role of the histocompatibility and immunogenetics laboratory in a rapidly developing field. J Clin Pathol. 2010;63:189-193.PubMedCrossRefGoogle Scholar
  2. 2.
    Sage D. My approach to the immunogenetics of haematopoietic stem cell transplant matching. J Clin Pathol. 2010;63:194-198.PubMedCrossRefGoogle Scholar
  3. 3.
    Siemionow M, Klimczak A. Advances in the development of experimental composite tissue transplantation models. Transpl Int. 2010;23:2-13.PubMedCrossRefGoogle Scholar
  4. 4.
    Baxter-Lowe LA, Hurley CK. Advancement and clinical implications of HLA typing in allogeneic hematopoietic stem cell transplantation. Cancer Treat Res. 2009;144:1-24.CrossRefGoogle Scholar
  5. 5.
    Gordon CR, Siemionow M, Papay F, et al. The world’s experience with facial transplantation: what have we learned thus far? Ann Plast Surg. 2009;63:572-578.PubMedCrossRefGoogle Scholar
  6. 6.
    Jones JW, Gruber SA, Barker JH, Breidenbach WC. Successful hand transplantation. One-year follow-up. Louisville Hand transplant team. N Engl J Med. 2000;343(7):468-473.PubMedCrossRefGoogle Scholar
  7. 7.
    Gordon CR, Siemionow M. Requirements for the development of a hand transplantation program. Ann Plast Surg. 2009;63:262-273.PubMedCrossRefGoogle Scholar
  8. 8.
    Opelz G. New immunosuppressants and HLA matching. Transplant Proc. 2001;33(1-2):467-468.PubMedCrossRefGoogle Scholar
  9. 9.
    Lee SJ, Klein J, Haagenson M, et al. High-resolution donor-recipient HLA matching contributes to the success of unrelated donor marrow transplantation. Blood. 2007;110:4576-4583.PubMedCrossRefGoogle Scholar
  10. 10.
    Kamani N, Spellman S, Hurley CK, et al. State of the art review: HLA matching and outcome of unrelated donor umbilical cord blood transplants. Biol Blood Marrow Transplant. 2008;14:1-6.PubMedCrossRefGoogle Scholar
  11. 11.
    Kissmeyer-Nielsen F, Olsen S, Petersen VP, Fjeldborg O. Hyperacute rejection of kidney allografts, associated with pre-existing humoral antibodies against donor cells. Lancet. 1966;2:662-665.PubMedCrossRefGoogle Scholar
  12. 12.
    Ciurea SO, de Lima M, Cano P, et al. High risk of graft failure in patients with anti-HLA antibodies undergoing haploidentical stem-cell transplantation. Transplantation. 2009;88:1019-1024.PubMedCrossRefGoogle Scholar
  13. 13.
    Spellman S, Bray R, Rosen-Bronson S, et al. The detection of donor-directed, HLA-specific alloantibodies in recipients of unrelated hematopoietic cell transplantation is predictive of graft failure. Blood. 2010;115:2704-2708.PubMedCrossRefGoogle Scholar
  14. 14.
    Gebel HM, Moussa O, Eckels DD, Bray RA. Donor-reactive HLA antibodies in renal allograft recipients: considerations, complications, and conundrums. Hum Immunol. 2009;70:610-617.PubMedCrossRefGoogle Scholar
  15. 15.
    El-Awar N, Lee J, Terasaki PI. HLA antibody identification with single antigen beads compared to conventional methods. Hum Immunol. 2005;66(9):989-997.PubMedCrossRefGoogle Scholar
  16. 16.
    Cecka JM. Calculated PRA (CPRA): the new measure of sensitization for transplant candidates. Am J Transplant. 2010;10:26-29.PubMedCrossRefGoogle Scholar
  17. 17.
    Wahrmann M, Bartel G, Exner M, et al. Clinical relevance of preformed C4d-fixing and non-C4d-fixing HLA single antigen reactivity in renal allograft recipients. Transpl Int. 2009;22:982-989.PubMedCrossRefGoogle Scholar
  18. 18.
    Rose ML, Smith JD. Clinical relevance of complement-fixing antibodies in cardiac transplantation. Hum Immunol. 2009;70:605-609.PubMedCrossRefGoogle Scholar
  19. 19.
    Baldwin WM III, Qian Z, Wasowska B, Sanfilippo F. Complement causes allograft injury by cell activation rather than lysis. Transplantation. 1999;67:1498-1499.PubMedCrossRefGoogle Scholar
  20. 20.
    Solez K, Colvin RB, Racusen LC, et al. Banff 07 classification of renal allograft pathology: updates and future directions. Am J Transplant. 2008;8:753-760.PubMedCrossRefGoogle Scholar
  21. 21.
    Smith JD, Hamour IM, Banner NR, Rose ML. C4d fixing, luminex binding antibodies – a new tool for prediction of graft failure after heart transplantation. Am J Transplant. 2007;7:2809-2815.PubMedCrossRefGoogle Scholar
  22. 22.
    Cendales LC, Kanitakis J, Schneeberger S, et al. The Banff 2007 working classification of skin-containing composite tissue allograft pathology. Am J Transplant. 2008;8:1396-1400.PubMedCrossRefGoogle Scholar
  23. 23.
    Patel R, Terasaki PI. Significance of the positive crossmatch test in kidney transplantation. N Engl J Med. 1969;280:735-739.PubMedCrossRefGoogle Scholar
  24. 24.
    Ilham MA, Winkler S, Coates E, Rizzello A, Rees TJ, Asderakis A. Clinical significance of a positive flow crossmatch on the outcomes of cadaveric renal transplants. Transplant Proc. 2008;40:1839-1843.PubMedCrossRefGoogle Scholar
  25. 25.
    Graff RJ, Xiao H, Schnitzler MA, et al. The role of positive flow cytometry crossmatch in late renal allograft loss. Hum Immunol. 2009;70:502-505.PubMedCrossRefGoogle Scholar
  26. 26.
    Zheng XF, Pei GX, Qiu YR, Zhu LJ, Gu LQ. Serial monitoring of immunological parameters following human hand transplant. Clin Transplant. 2004;18:119-123.PubMedCrossRefGoogle Scholar
  27. 27.
    Brandacher G, Ninkovic M, Piza-Katzer H, et al. The Innsbruck hand transplant program: update at 8 years after the first transplant. Transplant Proc. 2009;41:491-494.PubMedCrossRefGoogle Scholar
  28. 28.
    Gebel HM, Lebeck LK. Crossmatch procedures used in organ transplantation. Clin Lab Med. 1991;11:603-620.PubMedGoogle Scholar
  29. 29.
    Gebel HM, Bray RA, Nickerson P. Pre-transplant assessment of donor-reactive, HLA-specific antibodies in renal transplantation: contraindication vs. risk. Am J Transplant. 2003;3:1488-1500.PubMedCrossRefGoogle Scholar
  30. 30.
    Saw CL, Bray RA, Gebel HM. Cytotoxicity and antibody binding by flow cytometry: a single assay to simultaneously assess two parameters. Cytom B Clin Cytom. 2008;74:287-294.CrossRefGoogle Scholar
  31. 31.
    Billen EV, Voorter CE, Christiaans MH, van den Berg-Loonen EM. Luminex donor-specific crossmatches. Tissue Antigens. 2008;71:507-513.PubMedCrossRefGoogle Scholar
  32. 32.
    Delmonico FL, Fuller A, Cosimi AB, et al. New approaches to donor crossmatching and successful transplantation of highly sensitized patients. Transplantation. 1983;36:629-633.PubMedCrossRefGoogle Scholar
  33. 33.
    Appel JZ 3rd, Hartwig MG, Cantu E 3rd, Palmer SM, Reinsmoen NL, Davis RD. Role of flow cytometry to define unacceptable HLA antigens in lung transplant recipients with HLA-specific antibodies. Transplantation. 2006;81:1049-1057.PubMedCrossRefGoogle Scholar
  34. 34.
    Amico P, Honger G, Steiger J, Schaub S. Utility of the virtual crossmatch in solid organ transplantation. Curr Opin Organ Transplant. 2009;14:656-661.PubMedCrossRefGoogle Scholar
  35. 35.
    Gutman JA, McKinney SK, Pereira S, et al. Prospective monitoring for alloimmunization in cord blood transplantation: “virtual crossmatch” can be used to demonstrate donor-directed antibodies. Transplantation. 2009;87:415-418.PubMedCrossRefGoogle Scholar
  36. 36.
    Einecke G, Sis B, Reeve J, et al. Antibody-mediated microcirculation injury is the major cause of late kidney transplant failure. Am J Transplant. 2009;9:2520-2531.PubMedCrossRefGoogle Scholar
  37. 37.
    Morales-Buenrostro LE, Castro R, Terasaki PI. A single human leukocyte antigen-antibody test after heart or lung transplantation is predictive of survival. Transplantation. 2008;85:478-481.PubMedCrossRefGoogle Scholar
  38. 38.
    Girnita AL, McCurry KR, Zeevi A. Increased lung allograft failure in patients with HLA-specific antibody. Clin Transpl. 2007:231-239.Google Scholar
  39. 39.
    Worthington JE, Martin S, Al-Husseini DM, Dyer PA, Johnson RW. Posttransplantation production of donor HLA-specific antibodies as a predictor of renal transplant outcome. Transplantation. 2003;75:1034-1040.PubMedCrossRefGoogle Scholar
  40. 40.
    Siemionow M, Papay F, Alam D, et al. Near-total human face transplantation for a severely disfigured patient in the USA. Lancet. 2009;18(374):203-209.CrossRefGoogle Scholar
  41. 41.
    Ahern AT, Artruc SB, DellaPelle P, et al. Hyperacute rejection of HLA-AB-identical renal allografts associated with B lymphocyte and endothelial reactive antibodies. Transplantation. 1982;33:103-106.PubMedCrossRefGoogle Scholar
  42. 42.
    Opelz G. Non-HLA transplantation immunity revealed by lymphocytotoxic antibodies. Lancet. 2005;365:1570-1576.PubMedCrossRefGoogle Scholar
  43. 43.
    Angaswamy N, Saini D, Ramachandran S, et al. Development of antibodies to human leukocyte antigen precedes development of antibodies to major histocompatibility class I-related chain A and are significantly associated with development of chronic rejection after human lung transplantation. Hum Immunol. 2010;71:560-565.PubMedCrossRefGoogle Scholar
  44. 44.
    Nath DS, Basha HI, Mohanakumar T. Antihuman leukocyte antigen antibody-induced autoimmunity: role in chronic rejection. Curr Opin Organ Transplant. 2010;15:16-20.PubMedCrossRefGoogle Scholar
  45. 45.
    Sumitran-Karuppan S, Tyden G, Reinholt F, Berg U, Moller E. Hyperacute rejections of two consecutive renal allografts and early loss of the third transplant caused by non-HLA antibodies specific for endothelial cells. Transpl Immunol. 1997;5:321-327.PubMedCrossRefGoogle Scholar
  46. 46.
    Magro CM, Klinger DM, Adams PW, et al. Evidence that humoral allograft rejection in lung transplant patients is not histocompatibility antigen-related. Am J Transplant. 2003;3:1264-1272.PubMedCrossRefGoogle Scholar
  47. 47.
    Kowalski R, Post D, Schneider MC, et al. Immune cell function testing: an adjunct to therapeutic drug monitoring in transplant patient management. Clin Transplant. 2003;17:77-88.PubMedCrossRefGoogle Scholar
  48. 48.
    Serban G, Whittaker V, Fan J, et al. Significance of immune cell function monitoring in renal transplantation after thymoglobulin induction therapy. Hum Immunol. 2009;70:882-890.PubMedCrossRefGoogle Scholar
  49. 49.
    Smith CA, Gruss HJ, Davis T, et al. CD30 antigen, a marker for Hodgkin’s lymphoma, is a receptor whose ligand defines an emerging family of cytokines with homology to TNF. Cell. 1993;73:1349-1360.PubMedCrossRefGoogle Scholar
  50. 50.
    Pelzl S, Opelz G, Daniel V, Wiesel M, Susal C. Evaluation of posttransplantation soluble CD30 for diagnosis of acute renal allograft rejection. Transplantation. 2003;75:421-423.PubMedCrossRefGoogle Scholar
  51. 51.
    Wang D, Wu GJ, Wu WZ, et al. Pre- and post-transplant monitoring of soluble CD30 levels as predictor of acute renal allograft rejection. Transpl Immunol. 2007;17:278-282.PubMedCrossRefGoogle Scholar
  52. 52.
    Gebauer BS, Hricik DE, Atallah A, et al. Evolution of the enzyme-linked immunosorbent spot assay for post-transplant alloreactivity as a potentially useful immune monitoring tool. Am J Transplant. 2002;2:857-866.PubMedCrossRefGoogle Scholar
  53. 53.
    Dubernard JM, Lengele B, Morelon E, et al. Outcomes 18 months after the first human partial face transplantation. N Engl J Med. 2007;357:2451-2460.PubMedCrossRefGoogle Scholar
  54. 54.
    Gordon CR, Tai CY, Suzuki H, et al. Review of vascularized bone marrow transplantation: current status and future clinical applications. Microsurgery. 2007;27:348-353.PubMedCrossRefGoogle Scholar
  55. 55.
    Alizadeh M, Bernard M, Danic B, et al. Quantitative assessment of hematopoietic chimerism after bone marrow transplantation by real-time quantitative polymerase chain reaction. Blood. 2002;99:4618-4625.PubMedCrossRefGoogle Scholar
  56. 56.
    Kawai T, Cosimi AB, Spitzer TR, et al. HLA-mismatched renal transplantation without maintenance immunosuppression. N Engl J Med. 2008;358:353-361.PubMedCrossRefGoogle Scholar
  57. 57.
    Smith DM, Agura E, Netto G, et al. Liver transplant-associated graft-versus-host disease. Transplantation. 2003;75:118-126.PubMedCrossRefGoogle Scholar
  58. 58.
    Domiati-Saad R, Klintmalm GB, Netto G, Agura ED, Chinnakotla S, Smith DM. Acute graft versus host disease after liver transplantation: patterns of lymphocyte chimerism. Am J Transplant. 2005;5:2968-2973.PubMedCrossRefGoogle Scholar
  59. 59.
    Stotler CJ, Eghtesad B, Hsi E, Silver B. Rapid resolution of GVHD after orthotopic liver transplantation in a patient treated with alefacept. Blood. 2009;113(21):5365-5366.PubMedCrossRefGoogle Scholar
  60. 60.
    Dai Y, Sui W, Lan H, Yan Q, Huang H, Huang Y. Comprehensive analysis of microRNA expression patterns in renal biopsies of lupus nephritis patients. Rheumatol Int. 2009;29:749-754.PubMedCrossRefGoogle Scholar

Copyright information

© Springer London 2011

Authors and Affiliations

  1. 1.Allogen Laboratories, Transplant Center, Department of Surgery, Cleveland Clinic, Cleveland Clinic Lerner College of MedicineCase Western Reserve UniversityClevelandUSA

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