Hand Allotransplantation

ABSTRACT

In the past decade, more than 100 different composite tissue allotransplantation (CTA) procedures have been performed around the world including more than 50 hand and 8 facial transplants with encouraging graft survival and excellent functional outcomes. Broader clinical application of CTA, however, continues to be hampered by requirement for long-term, high-dose, multidrug maintenance immunosuppression to prevent graft rejection mediated particularly by composite tissue allograft's highly immunogenic skin component. Medication toxicity could result in severe adverse events including metabolic and infectious complications or malignancy. Notably, unlike in solid organs, clinical success is dictated not only by graft acceptance and survival but also by nerve regeneration, which determines ultimate functional outcomes. Novel strategies such as cellular and biologic therapies that integrate the concepts of immune regulation with those of nerve regeneration have shown promising results in small and large animal models. Clinical translation of these insights to reconstructive transplantation and CTA could further minimize the need of immunosuppression and optimize functional outcomes. This will enable wider application of such treatment options for patients in need of complex reconstructive surgery for congenital deformities or devastating injuries that are not amenable to standard methods of repair.

KEYWORDS

Transplantation - composite tissue - hand - immunosuppression - nerve regeneration

REFERENCES

• 1 Black K S, Hewitt C W, Fraser L A et al.. Cosmas and Damian in the laboratory.  N Engl J Med. 1982;  306 368-369
• 2 Gilbert R. Transplant is successful with a cadaver forearm.  Med Trib Med News. 1964;  5 20-22
• 3 Tobin G R, Breidenbach III W C, Ildstad S T, Marvin M M, Buell J F, Ravindra K V. The history of human composite tissue allotransplantation.  Transplant Proc. 2009;  41 466-471
• 4 Benhaim P, Anthony J P, Lin L Y, McCalmont T H, Mathes S J. A long-term study of allogeneic rat hindlimb transplants immunosuppressed with RS-61443.  Transplantation. 1993;  56 911-917
• 5 Dubernard J M, Owen E, Herzberg G et al.. Human hand allograft: report on first 6 months.  Lancet. 1999;  353 1315-1320
• 6 Jones J W, Gruber S A, Barker J H, Breidenbach W C. Louisville Hand Transplant Team . Successful hand transplantation. One-year follow-up.  N Engl J Med. 2000;  343 468-473
• 7 Margreiter R, Brandacher G, Ninkovic M, Steurer W, Kreczy A, Schneeberger S. A double-hand transplant can be worth the effort!.  Transplantation. 2002;  74 85-90
• 8 Petruzzo P, Lanzetta M, Dubernard J M et al.. The international registry on hand and composite tissue transplantation.  Transplantation. 2008;  86 487-492
• 9 Ravindra K V, Buell J F, Kaufman C L et al.. Hand transplantation in the United States: experience with 3 patients.  Surgery. 2008;  144 638-643 discussion 643-644
• 10 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
• 11 Giraux P, Sirigu A, Schneider F, Dubernard J M. Cortical reorganization in motor cortex after graft of both hands.  Nat Neurosci. 2001;  4 691-692
• 12 Murray J E. Organ transplantation (skin, kidney, heart) and the plastic surgeon.  Plast Reconstr Surg. 1971;  47 425-431
• 13 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
• 14 Schneeberger S, Gorantla V S, Hautz T, Pulikkottil B, Margreiter R, Lee W P. Immunosuppression and rejection in human hand transplantation.  Transplant Proc. 2009;  41 472-475
• 15 Lee W P, Yaremchuk M J, Pan Y C, Randolph M A, Tan C M, Weiland A J. Relative antigenicity of components of a vascularized limb allograft.  Plast Reconstr Surg. 1991;  87 401-411
• 16 Mathes D W, Randolph M A, Solari M G et al.. Split tolerance to a composite tissue allograft in a swine model.  Transplantation. 2003;  75 25-31
• 17 Brouha P C, Perez-Abadia G, Francois C G et al.. Lymphadenectomy prior to rat hind limb allotransplantation prevents graft-versus-host disease in chimeric hosts.  Transpl Int. 2004;  17 341-350
• 18 Starzl T E, Murase N, Abu-Elmagd K et al.. Tolerogenic immunosuppression for organ transplantation.  Lancet. 2003;  361 1502-1510
• 19 Margreiter R, Klempnauer J, Neuhaus P, Muehlbacher F, Boesmueller C, Calne R Y. Alemtuzumab (Campath-1H) and tacrolimus monotherapy after renal transplantation: results of a prospective randomized trial.  Am J Transplant. 2008;  8 1480-1485
• 20 Tzakis A G, Kato T, Nishida S et al.. Alemtuzumab (Campath-1H) combined with tacrolimus in intestinal and multivisceral transplantation.  Transplantation. 2003;  75 1512-1517
• 21 Ravindra K V, Wu S, Bozulic L, Xu H, Breidenbach W C, Ildstad S T. Composite tissue transplantation: a rapidly advancing field.  Transplant Proc. 2008;  40 1237-1248
• 22 Taieb A, Clavijo-Alvarez J A, Hamad G G, Lee W P. Immunologic approaches to composite tissue allograft.  J Hand Surg [Am]. 2007;  32 1072-1085
• 23 Siemionow M, Nasir S. Impact of donor bone marrow on survival of composite tissue allografts.  Ann Plast Surg. 2008;  60 455-462
• 24 Kawai T, Cosimi A B, Spitzer T R et al.. HLA-mismatched renal transplantation without maintenance immunosuppression.  N Engl J Med. 2008;  358 353-361
• 25 Starzl T E, Demetris A J, Trucco M et al.. Cell migration and chimerism after whole-organ transplantation: the basis of graft acceptance.  Hepatology. 1993;  17 1127-1152
• 26 Wekerle T, Sykes M. Mixed chimerism and transplantation tolerance.  Annu Rev Med. 2001;  52 353-370
• 27 Klimczak A, Unal S, Jankowska A, Coburn C, Siemionow M. Donor-origin cell engraftment after intraosseous or intravenous bone marrow transplantation in a rat model.  Bone Marrow Transplant. 2007;  40 373-380
• 28 Wekerle T, Blaha P, Koporc Z, Bigenzahn S, Pusch M, Muehlbacher F. Mechanisms of tolerance induction through the transplantation of donor hematopoietic stem cells: central versus peripheral tolerance.  Transplantation. 2003;  75(9, Suppl) 21S-25S
• 29 Foster R D, Fan L, Neipp M et al.. Donor-specific tolerance induction in composite tissue allografts.  Am J Surg. 1998;  176 418-421
• 30 Prabhune K A, Gorantla V S, Maldonado C, Perez-Abadia G, Barker J H, Ildstad S T. Mixed allogeneic chimerism and tolerance to composite tissue allografts.  Microsurgery. 2000;  20 441-447
• 31 Wood K J. Passenger leukocytes and microchimerism: what role in tolerance induction?.  Transplantation. 2003;  75(9, Suppl) 17S-20S
• 32 Sykes M. Mixed chimerism and transplant tolerance.  Immunity. 2001;  14 417-424
• 33 Ramsamooj R, Llull R, Black K S, Hewitt C W. Composite tissue allografts in rats: IV. Graft-versus-host disease in recipients of vascularized bone marrow transplants.  Plast Reconstr Surg. 1999;  104 1365-1371
• 34 Ciancio G, Miller J, Garcia-Morales R O et al.. Six-year clinical effect of donor bone marrow infusions in renal transplant patients.  Transplantation. 2001;  71 827-835
• 35 Starzl T E. Immunosuppressive therapy and tolerance of organ allografts.  N Engl J Med. 2008;  358 407-411
• 36 Chong A K, Chang J. Tissue engineering for the hand surgeon: a clinical perspective.  J Hand Surg [Am]. 2006;  31 349-358
• 37 Tanaka K, Fujita N, Higashi Y, Ogawa N. Neuroprotective and antioxidant properties of FKBP-binding immunophilin ligands are independent on the FKBP12 pathway in human cells.  Neurosci Lett. 2002;  330 147-150
• 38 Moore A M, Ray W Z, Chenard K E, Tung T, Mackinnon S E. Nerve allotransplantation as it pertains to composite tissue transplantation.  Hand (N Y). 2009;  4 239-244
• 39 Tung T H, Liu D Z, Mackinnon S E. Nerve transfer for elbow flexion in radiation-induced brachial plexopathy: a case report.  Hand (N Y). 2009;  4 123-128
• 40 Ogden M A, Feng F Y, Myckatyn T M et al.. Safe injection of cultured schwann cells into peripheral nerve allografts.  Microsurgery. 2000;  20 314-323
• 41 Mosahebi A, Fuller P, Wiberg M, Terenghi G. Effect of allogeneic Schwann cell transplantation on peripheral nerve regeneration.  Exp Neurol. 2002;  173 213-223
• 42 Walsh S, Midha R. Practical considerations concerning the use of stem cells for peripheral nerve repair.  Neurosurg Focus. 2009;  26 E2
• 43 Kuo Y R, Goto S, Shih H S et al.. Mesenchymal stem cells prolong composite tissue allotransplant survival in a swine model.  Transplantation. 2009;  87 1769-1777
• 44 Popp F C, Renner P, Eggenhofer E et al.. Mesenchymal stem cells as immunomodulators after liver transplantation.  Liver Transpl. 2009;  15 1192-1198
• 45 Uccelli A, Moretta L, Pistoia V. Mesenchymal stem cells in health and disease.  Nat Rev Immunol. 2008;  8 726-736
• 46 Le Blanc K, Ringdén O. Immunobiology of human mesenchymal stem cells and future use in hematopoietic stem cell transplantation.  Biol Blood Marrow Transplant. 2005;  11 321-334
• 47 Meisel R, Zibert A, Laryea M, Göbel U, Däubener W, Dilloo D. Human bone marrow stromal cells inhibit allogeneic T-cell responses by indoleamine 2,3-dioxygenase-mediated tryptophan degradation.  Blood. 2004;  103 4619-4621
• 48 Dezawa M, Takahashi I, Esaki M, Takano M, Sawada H. Sciatic nerve regeneration in rats induced by transplantation of in vitro differentiated bone-marrow stromal cells.  Eur J Neurosci. 2001;  14 1771-1776
• 49 Wang J, Ding F, Gu Y, Liu J, Gu X. Bone marrow mesenchymal stem cells promote cell proliferation and neurotrophic function of Schwann cells in vitro and in vivo.  Brain Res. 2009;  1262 7-15
• 50 Crop M, Baan C, Weimar W, Hoogduijn M. Potential of mesenchymal stem cells as immune therapy in solid-organ transplantation.  Transpl Int. 2009;  22 365-376
• 51 Le Blanc K, Tammik C, Rosendahl K, Zetterberg E, Ringdén O. HLA expression and immunologic properties of differentiated and undifferentiated mesenchymal stem cells.  Exp Hematol. 2003;  31 890-896
• 52 Ge W, Jiang J, Baroja M L et al.. Infusion of mesenchymal stem cells and rapamycin synergize to attenuate alloimmune responses and promote cardiac allograft tolerance.  Am J Transplant. 2009;  9 1760-1772
• 53 Bartholomew A, Sturgeon C, Siatskas M et al.. Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo.  Exp Hematol. 2002;  30 42-48
• 54 Aksu A E, Horibe E, Sacks J et al.. Co-infusion of donor bone marrow with host mesenchymal stem cells treats GVHD and promotes vascularized skin allograft survival in rats.  Clin Immunol. 2008;  127 348-358
• 55 Li Y, Chen J, Chen X G et al.. Human marrow stromal cell therapy for stroke in rat: neurotrophins and functional recovery.  Neurology. 2002;  59 514-523
• 56 Jones B J, McTaggart S J. Immunosuppression by mesenchymal stromal cells: from culture to clinic.  Exp Hematol. 2008;  36 733-741