Experimental Studies in Face Transplantation: Primate Model

  • Eduardo D. Rodriguez
  • Gerhard S. Mundinger
  • Rolf N. Barth
  • Helen G. Hui-Chou
  • Steven T. Shipley
  • Luke S. Jones
  • Stephen T. Bartlett


In offering optimal reconstruction for severe facial disfigurement, the advent of human face transplantation constitutes a landmark achievement in medicine and stands as a historical testament to the creativity, intelligence, ingenuity, and boldness of the human species. Facial allotransplantation has been modeled in rodents, canines, swine, and lagomorphs. However, human and rodent immune systems are dissimilar to a degree that precludes translation of tolerance induction protocols to humans. Nonhuman primates have long been used as translational models of human immunology and transplant immunobiology due to recent evolutionary divergence and shared major histocompatibility complex (MHC) II polymorphisms. We have developed a reproducible heterotopic model of nonhuman primate facial CTA permissive of long-term rejection-free survival. The purpose of this chapter is to share our experience in the development and maturation of this model, from surgical technique and immunosuppressive strategies, to experimental results and future directions.


Graft Versus Host Disease Mixed Lymphocyte Reaction Acute Rejection Episode Recipient Vessel Composite Tissue 
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.



composite tissue allotransplantation


Epstein–Barr virus


graft versus host disease


immunohistochemical staining




major histocompatibility complex


mixed lymphocyte reaction


mycophenolate mofetil


posttransplant lymphoproliferative disorder


short-tandem repeat


vascularized bone marrow



The authors would like to acknowledge Arthur Nam, Aruna Panda, Debra Kukuruga, Cinthia Drachenberg, Amir H. Dorafshar, and Theresa Alexander for their dedicated work on this project.


  1. 1.
    Breidenbach WC, Ravindra K, Blair B, et al. Update on the Louiville Hand Transplant Experience. American Society for Reconstructive Microsurgery 2010 Annual Scientific Meetings 2010.Google Scholar
  2. 2.
    Elster EA, Blair PJ, Kirk AD. Potential of costimulation-based therapies for composite tissue allotransplantation. Microsurgery. 2000;20:430-434.PubMedCrossRefGoogle Scholar
  3. 3.
    Hui-Chou HG, Mundinger GS, Jones LS, et al. Vascularized bone marrow permits long-term rejection free survival of facial composite tissue allografts in non-human primates. Am J Transplant. 2010;10:91.Google Scholar
  4. 4.
    Siemionow M, Nasir S. Impact of donor bone marrow on survival of composite tissue allografts. Ann Plast Surg. 2008;60:455-462.PubMedCrossRefGoogle Scholar
  5. 5.
    Yen EF, Hardinger K, Brennan DC, et al. Cost-effectiveness of extending Medicare coverage of immunosuppressive medications to the life of a kidney transplant. Am J Transplant. 2004;4:1703-1708.PubMedCrossRefGoogle Scholar
  6. 6.
    Matas AJ, Humar A, Gillingham KJ, et al. Five preventable causes of kidney graft loss in the 1990s: a single-center analysis. Kidney Int. 2002;62:704-714.PubMedCrossRefGoogle Scholar
  7. 7.
    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
  8. 8.
    Barth RN, Nam AJ, Stanwix MG, et al. Prolonged survival of composite facial allografts in non-human primates associated with posttransplant lymphoproliferative disorder. Transplantation. 2009;88:1242-1250.PubMedCrossRefGoogle Scholar
  9. 9.
    Siemionow M, Klimczak A. Advances in the development of experimental composite tissue transplantation models. Transpl Int. 2010;23:2-13.PubMedCrossRefGoogle Scholar
  10. 10.
    Landin L, Cavadas PC, Gonzalez E, et al. Functional outcome after facial allograft transplantation in rats. J Plast Reconstr Aesthet Surg. 2008;61:1034-1043.PubMedCrossRefGoogle Scholar
  11. 11.
    Siemionow M, Agaoglu G. Face transplantation. In: Hewitt C, Lee W, Gordon C, eds. Transplantation of Composite Tissue Allografts. New York: Springer; 2008:344-354.CrossRefGoogle Scholar
  12. 12.
    Zor F, Bozkurt M, Nair D, Siemionow M. A new composite midface allotransplantation model with sensory and motor reinnervation. Transpl Int. 2010;23:649-656.PubMedCrossRefGoogle Scholar
  13. 13.
    Kulahci Y, Siemionow M. A new composite hemiface/mandible/tongue transplantation model in rats. Ann Plast Surg. 2010;64:114-121.PubMedCrossRefGoogle Scholar
  14. 14.
    Landin L, Cavadas PC, Gonzalez E, et al. Sensorimotor recovery after partial facial (mystacial pad) transplantation in rats. Ann Plast Surg. 2009;63:428-435.PubMedCrossRefGoogle Scholar
  15. 15.
    Washington KM, Solari MG, Sacks JM, et al. A model for functional recovery and cortical reintegration after hemifacial composite tissue allotransplantation. Plast Reconstr Surg. 2009;123:26S-33S.PubMedCrossRefGoogle Scholar
  16. 16.
    Yazici I, Unal S, Siemionow M. Composite hemiface/calvaria transplantation model in rats. Plast Reconstr Surg. 2006;118:1321-1327.PubMedCrossRefGoogle Scholar
  17. 17.
    Ulusal AE, Ulusal BG, Hung LM, et al. Establishing a composite auricle allotransplantation model in rats: introduction to transplantation of facial subunits. Plast Reconstr Surg. 2005;116:811-817.PubMedCrossRefGoogle Scholar
  18. 18.
    Shengwu Z, Qingfeng L, Hao J, et al. Developing a canine model of composite facial/scalp allograft transplantation. Ann Plast Surg. 2007;59:185-194.PubMedCrossRefGoogle Scholar
  19. 19.
    Kuo YR, Shih HS, Lin CC, et al. Swine hemi-facial composite tissue allotransplantation: a model to study immune rejection. J Surg Res. 2009;153:268-273.PubMedCrossRefGoogle Scholar
  20. 20.
    Xudong Z, Shuzhong G, Yan H, et al. A hemifacial transplantation model in rabbits. Ann Plast Surg. 2006;56:665-669.PubMedCrossRefGoogle Scholar
  21. 21.
    Rab M, Haslik W, Grunbeck M, et al. Free functional muscle transplantation for facial reanimation: experimental comparison between the one- and two-stage approach. J Plast Reconstr Aesthet Surg. 2006;59:797-806.PubMedCrossRefGoogle Scholar
  22. 22.
    Siemionow M, Unal S. Strategies for tolerance induction in nonhuman primates. Ann Plast Surg. 2005;55:545-553.PubMedCrossRefGoogle Scholar
  23. 23.
    Geluk A, Elferink DG, Slierendregt BL, et al. Evolutionary conservation of major histocompatibility complex-DR/peptide/T cell interactions in primates. J Exp Med. 1993;177:979-987.PubMedCrossRefGoogle Scholar
  24. 24.
    Daniel RK, Egerszegi EP, Samulack DD, et al. Tissue transplants in primates for upper extremity reconstruction: a preliminary report. J Hand Surg Am. 1986;11:1-8.PubMedGoogle Scholar
  25. 25.
    Stevens HP, Hovius SE, Heeney JL, et al. Immunologic aspects and complications of composite tissue allografting for upper extremity reconstruction: a study in the rhesus monkey. Transplant Proc. 1991;23:623-625.PubMedGoogle Scholar
  26. 26.
    Cendales LC, Xu H, Bacher J, et al. Composite tissue allotransplantation: development of a preclinical model in nonhuman primates. Transplantation. 2005;80:1447-1454.PubMedCrossRefGoogle Scholar
  27. 27.
    Stark GB, Swartz WM, Narayanan K, et al. Hand transplantation in baboons. Transplant Proc. 1987;19:3968-3971.PubMedGoogle Scholar
  28. 28.
    Stevens HP, Hovius SE, Vuzevski VD, et al. Immunological aspects of allogeneic partial hand transplantation in the rhesus monkey. Transplant Proc. 1990;22:2006-2008.PubMedGoogle Scholar
  29. 29.
    Gold ME, Randzio J, Kniha H, et al. Transplantation of vascularized composite mandibular allografts in young cynomolgus monkeys. Ann Plast Surg. 1991;26:125-132.PubMedCrossRefGoogle Scholar
  30. 30.
    Silverman RP, Banks ND, Detolla LJ, et al. A heterotopic primate model for facial composite tissue transplantation. Ann Plast Surg. 2008;60:209-216.PubMedCrossRefGoogle Scholar
  31. 31.
    Barth RN, Bluebond-Langner R, Nam A, et al. Facial subunit composite tissue allografts in nonhuman primates: I. Technical and immunosuppressive requirements for prolonged graft survival. Plast Reconstr Surg. 2009;123:493-501.PubMedCrossRefGoogle Scholar
  32. 32.
    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
  33. 33.
    Unadkat JV, Schneeberger S, Horibe EH, et al. Composite tissue vasculopathy and degeneration following multiple episodes of acute rejection in reconstructive transplantation. Am J Transplant. 2009;10:251-261.PubMedCrossRefGoogle Scholar
  34. 34.
    Mundinger GS, Munivenkatappa R, Hui-Chou HG, et al. Chronic rejection in a non-human primate model of facial composite tissue allotransplantation: clinical, pathological, and immunohistochemical characterization. 23rd Annual International Congress of the Transplantation Society 2010:#2633.Google Scholar
  35. 35.
    Unadkat JV, Haribe EK, Schneeberger S, et al. Systemic analysis of chronic rejection in composite tissue allotransplantation. 7th International Symposium on Composite Tissue Transplantation. Seefeld/Tyrol, Austria 2007.Google Scholar
  36. 36.
    Vanhove B, Laflamme G, Coulon F, et al. Selective blockade of CD28 and not CTLA-4 with a single-chain Fv-alpha1-antitrypsin fusion antibody. Blood. 2003;102:564-570.PubMedCrossRefGoogle Scholar
  37. 37.
    Poirier N, Azimzadeh AM, Zhang T, et al. Inducing CTLA-4-dependent immune regulation by selective CD28 blockade promotes regulatory T cells in organ transplantation. Sci Transl Med. 2010;2:17ra10.PubMedGoogle Scholar
  38. 38.
    Mundinger GS, Jones LS, Hui-Chou HG, et al. Costimulatory blockade does not promote survival of skin component in non-human-primate composite tissue allografts. 23rd Annual International Congress of the Transplantation Society 2010:#2606.Google Scholar
  39. 39.
    Mathes DW, Randolph MA, Solari MG, et al. Split tolerance to a composite tissue allograft in a swine model. Transplantation. 2003;75:25-31.PubMedCrossRefGoogle Scholar

Copyright information

© Springer London 2011

Authors and Affiliations

  • Eduardo D. Rodriguez
    • 1
  • Gerhard S. Mundinger
  • Rolf N. Barth
  • Helen G. Hui-Chou
  • Steven T. Shipley
  • Luke S. Jones
  • Stephen T. Bartlett
  1. 1.Division of Plastic and Reconstructive Surgery, R Adams Cowley Shock Trauma CenterJohns Hopkins Hospital/University of Maryland School of MedicineBaltimoreUSA

Personalised recommendations