Nerve Allograft Transplantation: A Review

 

 Buy Article Permissions and Reprints

ABSTRACT

Peripheral nerves that are interrupted by trauma or surgical resection require reapproximation of their ends. When primary repair cannot be performed without undue tension, nerve grafting is required. Nerve repair with autograft is limited when there is insufficient amount of autologous nerves available for large nerve defects. This encouraged the search for alternative means of reconstruction in extensive nerve injuries. The cadaveric nerve allograft provides an unlimited graft source without the morbidities associated with autograft reconstruction; but these grafts are rapidly rejected unless appropriate recipient immunosuppression is achieved. An optimal treatment method for nerve allograft transplantation must minimize or prevent rejection while permitting nerve regeneration at the same time. In this report, the literature of nerve allograft transplantation experimental studies, strategies to prevent nerve allograft rejection, and reported clinical experiences are reviewed.

REFERENCES

• 1 Sunderland S. Nerve Injuries and Their Repair: A Critical Appraisal. New York, NY; Churchill Livingstone 1991: 467-497
  Google Scholar
• 2 Cruikshank W. Experiments on the nerves particularly on their reproductions; and the spinal marrow of living animals.  Philos Trans R Soc Lond. 1795;  85 177-189
  PubMedGoogle Scholar
• 3 Albert E. Einige Operationen an Nerven.  Wien Med Presse. 1885;  26 1285-1288
  PubMedGoogle Scholar
• 4 Seddon HJ Peripheral Nerve Injuries. London, UK; HMSO 1961: 389
  Google Scholar
• 5 Marmor L. The repair of peripheral nerves by irradiated homografts.  Clin Orthop Relat Res. 1964;  34 161-169
  PubMedGoogle Scholar
• 6 Campbell J B, Bassett A L, Boehler J. Frozen-irradiated homografts shielded with microfilter sheaths in peripheral nerve surgery.  J Trauma. 1963;  3 303-311
  PubMedGoogle Scholar
• 7 Mackinnon S E, Doolabh V B, Novak C B, Trulock E P. Clinical outcome following nerve allograft transplantation.  Plast Reconstr Surg. 2001;  107 1419-1429
  CrossrefPubMedGoogle Scholar
• 8 Merriam-Webster's Medical Dictionary .Available at http://www.m-w.com/medical/
• 9 Mackinnon S E, Dellon A L. Nerve repair and nerve grafts. In: Mackinnon SE, Dellon AL Surgery of the Peripheral Nerve. New York, NY; Thieme Medical Publishers 1988: 89-129
  Google Scholar
• 10 Seddon H J. Peripheral nerve injuries in Great Britain during World War II; a review.  Arch Neurol Psychiatry. 1950;  63 171-173
  PubMedGoogle Scholar
• 11 Mackinnon S E. New directions in peripheral nerve surgery.  Ann Plast Surg. 1989;  22 257-273
  CrossrefPubMedGoogle Scholar
• 12 Trumble T E. Peripheral nerve injury: pathophysiology and repair. In: Feliciano DV, Moore EE, Mattox KL Trauma. 4th ed. New York, NY; McGraw-Hill 1999: 2048-2053
  Google Scholar
• 13 Townsend P L. Microsurgical techniques in reconstructive surgery. In: Keen G, Farndon JR Operative Surgery and Management. 3rd ed. Oxford, UK; Butterworth-Heinemann 1994: 434-435
  Google Scholar
• 14 Lundborg G, Rosén B, Dahlin L, Danielsen N, Holmberg J. Tubular versus conventional repair of median and ulnar nerves in the human forearm: early results from a prospective, randomized, clinical study.  J Hand Surg [Am]. 1997;  22 99-106
  PubMedGoogle Scholar
• 15 Siemionow M, Tetik C, Ozer K, Ayhan S, Siemionow K, Browne E. Epineural sleeve neurorrhaphy: surgical technique and functional results-a preliminary report.  Ann Plast Surg. 2002;  48 281-285
  CrossrefPubMedGoogle Scholar
• 16 Snyder C C, Webster H D, Pickens J E, Hines W A, Warden G. Intraneural neurorraphy: a preliminary clinical and histological evaluation.  Ann Surg. 1968;  167 691-696
  PubMedGoogle Scholar
• 17 Tetik C, Ozer K, Ayhan S, Siemionow K, Browne E, Siemionow M. Conventional versus epineural sleeve neurorrhaphy technique: functional and histomorphometric analysis.  Ann Plast Surg. 2002;  49 397-403
  CrossrefPubMedGoogle Scholar
• 18 Hentz V R, Rosen J M, Xiao S J, McGill K C, Abraham G. The nerve gap dilemma: a comparison of nerves repaired end to end under tension with nerve grafts in a primate model.  J Hand Surg [Am]. 1993;  18 417-425
  PubMedGoogle Scholar
• 19 Birch R, Raji A R. Repair of median and ulnar nerves. Primary suture is best.  J Bone Joint Surg Br. 1991;  73 154-157
  PubMedGoogle Scholar
• 20 Kline D G, Hackett E R, Davis G D, Myers M B. Effect of mobilization on the blood supply and regeneration of injured nerves.  J Surg Res. 1972;  12 254-266
  CrossrefPubMedGoogle Scholar
• 21 Lundborg G, Rydevik B. Effects of stretching the tibial nerve of the rabbit. A preliminary study of the intraneural circulation and the barrier function of the perineurium.  J Bone Joint Surg Br. 1973;  55 390-401
  PubMedGoogle Scholar
• 22 Millesi H, Meissl G, Berger A. The interfascicular nerve-grafting of the median and ulnar nerves.  J Bone Joint Surg Am. 1972;  54 727-750
  PubMedGoogle Scholar
• 23 Trumble T E, Shon F G. The physiology of nerve transplantation.  Hand Clin. 2000;  16 105-122
  PubMedGoogle Scholar
• 24 Siemionow M, Zielinski M, Meirer R. The single-fascicle method of nerve grafting.  Ann Plast Surg. 2004;  52 72-79
  CrossrefPubMedGoogle Scholar
• 25 Lee S K, Wolfe S W. Peripheral nerve injury and repair.  J Am Acad Orthop Surg. 2000;  8 243-252
  CrossrefPubMedGoogle Scholar
• 26 Hudson T W, Liu S Y, Schmidt C E. Engineering an improved acellular nerve graft via optimized chemical processing.  Tissue Eng. 2004;  10 1346-1358
  CrossrefPubMedGoogle Scholar
• 27 Hudson T W, Zawko S, Deister C et al.. Optimized acellular nerve graft is immunologically tolerated and supports regeneration.  Tissue Eng. 2004;  10 1641-1651
  CrossrefPubMedGoogle Scholar
• 28 Keilhoff G, Pratsch F, Wolf G, Fansa H. Bridging extra large defects of peripheral nerves: possibilities and limitations of alternative biological grafts from acellular muscle and Schwann cells.  Tissue Eng. 2005;  11 1004-1014
  CrossrefPubMedGoogle Scholar
• 29 Rovak J M, Mungara A K, Aydin M A, Cederna P S. Effects of vascular endothelial growth factor on nerve regeneration in acellular nerve grafts.  J Reconstr Microsurg. 2004;  20 53-58
  Article in Thieme ConnectPubMedGoogle Scholar
• 30 Hess J R, Brenner M J, Fox I K et al.. Use of cold-preserved allografts seeded with autologous Schwann cells in the treatment of a long-gap peripheral nerve injury.  Plast Reconstr Surg. 2007;  119 246-259
  CrossrefPubMedGoogle Scholar
• 31 Auba C, Hontanilla B, Arcocha J, Gorria O. Peripheral nerve regeneration through allografts compared with autografts in FK506-treated monkeys.  J Neurosurg. 2006;  105 602-609
  PubMedGoogle Scholar
• 32 Tung T H, Doolabh V B, Mackinnon S B, Mohanakumar T, Hicks M E. Survival of long nerve allografts following donor antigen pretreatment: a pilot study.  J Reconstr Microsurg. 2006;  22 443-449
  Article in Thieme ConnectPubMedGoogle Scholar
• 33 Brown D L, Bishop D K, Wood S Y, Cederna P S. Short-term anti-CD40 ligand costimulatory blockade induces tolerance to peripheral nerve allografts, resulting in improved skeletal muscle function.  Plast Reconstr Surg. 2006;  117 2250-2258
  CrossrefPubMedGoogle Scholar
• 34 Midha R, Mackinnon S E, Becker L E. The fate of Schwann cells in peripheral nerve allograft.  J Neuropathol Exp Neurol. 1994;  53 316-322
  PubMedGoogle Scholar
• 35 Hettiaratchy S, Melendy E, Randolph M A et al.. Tolerance to composite tissue allograft across a major histocompatibility barrier in miniature swine.  Transplantation. 2004;  77 514-521
  CrossrefPubMedGoogle Scholar
• 36 Gulati A K. Immune response and neurotrophic factor interactions in peripheral nerve transplants.  Acta Haematol. 1998;  99 171-174
  CrossrefPubMedGoogle Scholar
• 37 Bain J R. Peripheral nerve and neuromuscular allotransplantation: current status.  Microsurgery. 2000;  20 384-388
  CrossrefPubMedGoogle Scholar
• 38 Zalewski A A, Gulati A K. Evaluation of histocompatibility as a factor in the repair of nerve with a frozen nerve allograft.  J Neurosurg. 1982;  56 550-554
  PubMedGoogle Scholar
• 39 Atchabahian A, Mackinnon S E, Hunter D A. Cold preservation of nerve grafts decreases expression of ICAM-1 and class II MHC antigens.  J Reconstr Microsurg. 1999;  15 307-311
  Article in Thieme ConnectPubMedGoogle Scholar
• 40 Levi A D, Evans P J, Mackinnon S E, Bunge R P. Cold storage of peripheral nerves: an in vitro assay of cell viability and function.  Glia. 1994;  10 121-131
  CrossrefPubMedGoogle Scholar
• 41 Evans P J, Mackinnon S E, Levi A D et al.. Cold preserved nerve allograft: changes in basement membrane, viability, immunogenicity, and regeneration.  Muscle Nerve. 1998;  21 1507-1522
  CrossrefPubMedGoogle Scholar
• 42 Strasberg S R, Mackinnon S E, Hare G M, Narini P P, Hertl M C, Hay J B. Reduction in peripheral nerve allograft antigenicity with warm and cold temperature preservation.  Plast Reconstr Surg. 1996;  97 152-160
  PubMedGoogle Scholar
• 43 Evans P J, Mackinnon S E, Best T J et al.. Regeneration across preserved peripheral nerve grafts.  Muscle Nerve. 1995;  18 1128-1138
  CrossrefPubMedGoogle Scholar
• 44 Mackinnon S E, Hudson A R, Falk R E, Kline D, Hunter D. Peripheral nerve allograft: an immunological assessment of pretreatment methods.  Neurosurgery. 1984;  14 167-171
  PubMedGoogle Scholar
• 45 Pollard J D, McLeod J G. Fresh and predegenerate nerve allograft and isografts in trembler mice.  Muscle Nerve. 1981;  4 274-281
  PubMedGoogle Scholar
• 46 Trumble T E. Peripheral nerve transplantation: the effects of predegenerated grafts and immunosuppression.  J Neural Transplant Plast. 1992;  3 39-49
  CrossrefPubMedGoogle Scholar
• 47 Kripke M L. Immunological unresponsiveness induced by ultraviolet radiation.  Immunol Rev. 1984;  80 87-102
  CrossrefPubMedGoogle Scholar
• 48 Krutmann J, Khan I U, Wallis R S et al.. Cell membrane is a major locus for ultraviolet B-induced alterations in accessory cells.  J Clin Invest. 1990;  85 1529-1536
  PubMedGoogle Scholar
• 49 Genden E M, Mackinnon S E, Yu S, Hunter D A, Flye M W. Pretreatment with portal venous ultraviolet B-irradiated donor alloantigen promotes donor-specific tolerance to rat nerve allograft.  Laryngoscope. 2001;  111 439-447
  PubMedGoogle Scholar
• 50 Evans P J, MacKinnon S E, Midha R et al.. Regeneration across cold preserved peripheral nerve allograft.  Microsurgery. 1999;  19 115-127
  CrossrefPubMedGoogle Scholar
• 51 Strasberg S R, Hertl M C, Mackinnon S E et al.. Peripheral nerve allograft preservation improves regeneration and decreases systemic cyclosporin A requirements.  Exp Neurol. 1996;  139 306-316
  CrossrefPubMedGoogle Scholar
• 52 Mackinnon S E, Hudson A R, Falk R E, Hunter D A. The nerve allograft response-an experimental model in the rat.  Ann Plast Surg. 1985;  14 334-339
  PubMedGoogle Scholar
• 53 Mackinnon S E, Hudson A R, Bain J R, Falk R E, Hunter D A. The peripheral nerve allograft: an assessment of regeneration in the immunosuppressed host.  Plast Reconstr Surg. 1987;  79 436-446
  PubMedGoogle Scholar
• 54 Zalewski A A, Gulati A K. Survival of nerve and Schwann cells in allograft after cyclosporin A treatment.  Exp Neurol. 1980;  70 219-225
  CrossrefPubMedGoogle Scholar
• 55 Zalewski A A, Gulati A K. Failure of cyclosporin-A to induce immunological unresponsiveness to nerve allograft.  Exp Neurol. 1984;  83 659-663
  CrossrefPubMedGoogle Scholar
• 56 Bain J R, Mackinnon S E, Hudson A R, Falk R E, Falk J A, Hunter D A. The peripheral nerve allograft: an assessment of regeneration across nerve allograft in rats immunosuppressed with cyclosporin A.  Plast Reconstr Surg. 1988;  82 1052-1066
  PubMedGoogle Scholar
• 57 Ishida O, Daves J, Tsai T M, Breidenbach W C, Firrell J. Regeneration following rejection of peripheral nerve allograft of rats on withdrawal of cyclosporine.  Plast Reconstr Surg. 1993;  92 916-926
  PubMedGoogle Scholar
• 58 Meirer R, Babuccu O, Unsal M et al.. Effect of chronic cyclosporine administration on peripheral nerve regeneration: a dose-response study.  Ann Plast Surg. 2002;  49 96-103
  CrossrefPubMedGoogle Scholar
• 59 Buttemeyer R, Rao U, Jones N F. Peripheral nerve allograft transplantation with FK506: functional, histological, and immunological results before and after discontinuation of immunosuppression.  Ann Plast Surg. 1995;  35 396-401
  PubMedGoogle Scholar
• 60 Gold B G. FK506 and the role of the immunophilin FKBP-52 in nerve regeneration.  Drug Metab Rev. 1999;  31 649-663
  CrossrefPubMedGoogle Scholar
• 61 Myckatyn T M, Mackinnon S E. A review of research endeavors to optimize peripheral nerve reconstruction.  Neurol Res. 2004;  26 124-138
  CrossrefPubMedGoogle Scholar
• 62 Steiner J P, Connolly M A, Valentine H L et al.. Neurotrophic actions of nonimmunosuppressive analogues of immunosuppressive drugs FK506, rapamycin and cyclosporine.  Nat Med. 1997;  3 421-428
  CrossrefPubMedGoogle Scholar
• 63 Atchabahian A, Mackinnon S E, Doolabh V B, Yu S, Hunter D A, Flye M W. Indefinite survival of peripheral nerve allograft after temporary cyclosporine A immunosuppression.  Restor Neurol Neurosci. 1998;  13 129-139
  PubMedGoogle Scholar
• 64 Lechler R I, Sykes M, Thomson A W, Turka L A. Organ transplantation-how much of the promise has been realized?.  Nat Med. 2005;  11 605-613
  PubMedGoogle Scholar
• 65 Mackinnon S E, Hudson A R. Clinical application of peripheral nerve transplantation.  Plast Reconstr Surg. 1997;  90 695-699
  PubMedGoogle Scholar
• 66 Morris P J, Russell N K. Alemtuzumab (Campath-1H): a systemic review in organ transplantation.  Transplantation. 2006;  81 1361-1367
  CrossrefPubMedGoogle Scholar
• 67 Scharpf J, Strome M, Siemionow M. Immunomodulation with anti-alphabeta T-cell receptor monoclonal antibodies in combination with cyclosporine A improves regeneration in nerve allograft.  Microsurgery. 2006;  26 599-607
  CrossrefPubMedGoogle Scholar
• 68 Larsen C P, Elwood E T, Alexander D Z et al.. Long-term acceptance of skin and cardiac allografts after blocking CD40 and CD28 pathways.  Nature. 1996;  381 434-438
  CrossrefPubMedGoogle Scholar
• 69 Wekerle T, Sayegh M H, Ito H et al.. Anti-CD154 or CTLA4Ig obviates the need for thymic irradiation in a non-myeloablative conditioning regimen for the induction of mixed hematopoietic chimerism and tolerance.  Transplantation. 1999;  68 1348-1355
  CrossrefPubMedGoogle Scholar
• 70 Lin H, Bolling S F, Linsley P S et al.. Long-term acceptance of major histocompatibility complex mismatched cardiac allografts induced by CTLA4Ig plus donor-specific transfusion.  J Exp Med. 1993;  178 1801-1806
  CrossrefPubMedGoogle Scholar
• 71 Larsen C P, Pearson T C, Adams A B et al.. Rational development of LEA29Y (belatacept), a high-affinity variant of CTLA4-Ig with potent immunosuppressive properties.  Am J Transplant. 2005;  5 443-453
  CrossrefPubMedGoogle Scholar
• 72 Vincenti F, Larsen C, Durrbach A et al. Belatacept Study Group. Costimulation blockade with belatacept in renal transplantation.  N Engl J Med. 2005;  353 770-781
  CrossrefPubMedGoogle Scholar
• 73 Larsen C P, Knechtle S J, Adams A, Pearson T, Kirk A D. A new look at blockade of T-cell costimulation: a therapeutic strategy for long-term maintenance immunosuppression.  Am J Transplant. 2006;  6 876-883
  CrossrefPubMedGoogle Scholar
• 74 Dubernard J M, Owen E, Herzberg G et al.. Human hand allograft: report on first 6 months.  Lancet. 1999;  353 1315-1320
  CrossrefPubMedGoogle Scholar
• 75 Lanzetta M, Petruzzo P, Dubernard J M et al.. Second report (1998-2006) of the International Registry of Hand and Composite Tissue Transplantation.  Transpl Immunol. 2007;  18 1-6
  CrossrefPubMedGoogle Scholar
• 76 Heine W, Conant K, Griffin J W, Hoke A. Transplanted neural stem cells promote axonal regeneration through chronically denervated peripheral nerves.  Exp Neurol. 2004;  189 231-240
  CrossrefPubMedGoogle Scholar
• 77 Myckatyn T M, Mackinnon S E, McDonald J W. Stem cell transplantation and other novel techniques for promoting recovery from spinal cord injury.  Transpl Immunol. 2004;  12 343-358
  PubMedGoogle Scholar
• 78 Chen C J, Ou Y C, Liao S L et al.. Transplantation of bone marrow stromal cells for peripheral nerve repair.  Exp Neurol. 2007;  204 443-453
  CrossrefPubMedGoogle Scholar
• 79 Rodriguez F J, Verdu E, Ceballos D, Navarro X. Nerve guides seeded with autologous Schwann cells improve nerve regeneration.  Exp Neurol. 2000;  161 571-584
  CrossrefPubMedGoogle Scholar
• 80 Sen S K, Lowe III J B, Brenner M J, Hunter D A, Mackinnon S E. Assessment of the immune response to dose of nerve allografts.  Plast Reconstr Surg. 2005;  115 823-830
  CrossrefPubMedGoogle Scholar
• 81 Jensen J N, Tung T H, Mackinnon S E, Brenner M J, Hunter D A. Use of anti-CD40 ligand monoclonal antibody as antirejection therapy in a murine peripheral nerve allograft model.  Microsurgery. 2004;  24 309-315
  CrossrefPubMedGoogle Scholar
• 82 Brenner M J, Jensen J N, Lowe III J B et al.. Anti-CD40 ligand antibody permits regeneration through peripheral nerve allografts in a nonhuman primate model.  Plast Reconstr Surg. 2004;  114 1802-1814
  CrossrefPubMedGoogle Scholar

Maria SiemionowM.D. Ph.D. D.Sc. 

Department of Plastic Surgery, A60

The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195