Locoregional Immunosuppression in Composite Tissue Allografting

  • Scott A. Gruber

Unlike visceral solid-organ transplants, composite tissue allografts (CTAs) are modules composed of various tissues, each with differing antigenicity, and therefore differing potential for rejection. Skin and muscle (and perhaps synovium) are the most antigenic and appear to be most susceptible to rejection, while bone, tendon, cartilage, and neurovascular tissue appear to be less immunogenic and evoke rejection responses of lower magnitude. Although CTAs have tremendous potential clinical application for functional and structural reconstruction of major congenital and acquired peripheral tissue defects, these transplants have remained one of the last frontiers in clinical organ transplantation because of concerns expressed beginning 15–20 years ago regarding their risk/benefit ratio. Even now, with the performance of unilateral hand, bilateral hand, or digit transplantation in a total of 18 patients from 1998 to 2004, there still remains much concern with regard to the risks of long-term immunosuppression and the potential for development of chronic rejection. The following two questions address the key issues involved. (1) Can rejection of these highly antigenic tissues be prevented using currently available immunosuppressive regimens with acceptable drugspecific and generalized toxicity? (2) Will function be restored to a significant degree so as to justify the surgical and immunosuppressive risks involved?


Graft Survival Skin Allograft Fluocinolone Acetonide Cortisone Acetate 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.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    W. P. Lee, M. J. Yaremchuk, Y. C. Pan, M. A. Randolph, C. M. Tan, A. J. Weiland, Relative antigenicity of components of a vascularized limb allograft, Plast Reconstr Surg 87, 401–411 (1991).PubMedCrossRefGoogle Scholar
  2. 2.
    J. P. Paskert, M. J. Yaremchuk, M. A. Randolph, A. J. Weiland, The role of cyclosporin in prolonging survival in vascularized bone allografts, Plast Reconstr Surg 80, 240–247 (1987).PubMedCrossRefGoogle Scholar
  3. 3.
    Rehabilitation Research and Development Service: Composite Tissue Transplantation Workshop. Department of Veteran Affairs, (1991).Google Scholar
  4. 4.
    M. Lanzetta P. Petruzzo, R. Margreiter, et al., The international registry on hand and composite tissue transplantation, Transplantation 79, 1210–1214 (2005).PubMedCrossRefGoogle Scholar
  5. 5.
    F. Petit, A. B. Minns, J. M. Dubernard, S. Hettiaratchy, W. P. Lee, Composite tissue allotransplantation and reconstructive surgery: first clinical applications, Ann Surg 237, 19–25 (2003).PubMedCrossRefGoogle Scholar
  6. 6.
    P. Petruzzo, L. Badet, M. Lanzetta, J. M. Dubernard, Concerns on clinical application of composite tissue allotransplantation, Acta Chir Belg 104, 266–271 (2004).PubMedGoogle Scholar
  7. 7.
    S. Hettiaratchy, M. A. Randolph, F. Petit, W. P. Lee, P. E. Butler, Composite tissue allotransplantation – a new era in plastic surgery? Br J Plast Surg 57, 381–391 (2004).PubMedCrossRefGoogle Scholar
  8. 8.
    S. A. Gruber, S. Katz, B. Kaplan, et al., Initial results of solitary pancreas transplants performed without regard to donor/recipient HLA mismatching, Transplantation 70, 388–391 (2000).PubMedCrossRefGoogle Scholar
  9. 9.
    S. Schneeberger, A. Kreczy, G. Brandacher, W. Steurer, R. Margreiter, Steroid- and ATG-resistant rejection after double forearm transplantation responds to Campath-1H, Am J Transplant 4, 1372–1374 (2004).PubMedCrossRefGoogle Scholar
  10. 10.
    S. Schneeberger, S. Lucchina, M. Lanzetta, et al., Cytomegalovirus-related complications in human hand transplantation, Transplantation 80, 441–447 (2005).PubMedCrossRefGoogle Scholar
  11. 11.
    S. A. Gruber, Locoregional immunosuppression of organ transplants, Immunol Rev 129, 5–30 (1992).PubMedCrossRefGoogle Scholar
  12. 12.
    R. E. Billingham, P. L. Krohn, P. B. Medawar, Effect of locally applied cortisone acetate on survival of skin homografts in rabbits, Br Med J 1, 1049–1053 (1951).CrossRefGoogle Scholar
  13. 13.
    A. B. Retik, J. M. Dubernard, W. J. Hester, J. E. Murray, A study of the effects of intra-arterial immunosuppressive drug therapy on canine renal allografts, Surgery 60, 1242–1250 (1966).PubMedGoogle Scholar
  14. 14.
    J. J. Terz, R. Crampton, D. Miller, W. Lawrence, Regional infusion chemotherapy for prolongation of kidney allografts, J Surg Res 9, 13–18 (1969).PubMedCrossRefGoogle Scholar
  15. 15.
    S. L. Kountz, R. B. Cohn, Initial treatment of renal allografts with large intrarenal doses of immunosuppressive drugs, Lancet 1, 338–340 (1969).PubMedCrossRefGoogle Scholar
  16. 16.
    N. F. Gergely, J. C. Coles, Prolongation of heterotopic cardiac allografts in dogs by topical radiation, Transplantation 9, 193–202 (1970).PubMedCrossRefGoogle Scholar
  17. 17.
    E. C. Halperin, F. L. Delmonico, P. W. Nelson, W. U. Shipley, A. B. Cosimi, The use of local allograft irradiation following renal transplantation, J Radiat Oncol Biol Phys 10, 987–990 (1984).Google Scholar
  18. 18.
    W. W. Eckman, C. S. Patlak, J. D. Fenstermacher, A critical evaluation of the principles governing the advantages of intraarterial infusions, J Pharmacokinet Biopharm 2, 257–285 (1974).PubMedCrossRefGoogle Scholar
  19. 19.
    T. J. M. Ruers, W. A. Buurman, J. F. M. Smits, et al., Local treatment of renal allografts, a promising way to reduce the dosage of immunosuppressive drugs, Transplantation 41, 156–161 (1986).PubMedCrossRefGoogle Scholar
  20. 20.
    S. A. Gruber, Local immunosuppressive therapy in organ transplantation, Transplant Proc 26, 3214–3216 (1994).PubMedGoogle Scholar
  21. 21.
    K. Yano, Y. Fukuda, R. Sumimoto, K. Sunimoto, H. Ito, K. Dohi, Suppression of liver allograft rejection by administration of 15-deoxyspergualin, Transpl Int 7, 149–156 (1994).PubMedGoogle Scholar
  22. 22.
    S. A. Gruber, W. J. M. Hrushesky, R. J. Cipolle, et al., Local immunosuppression with reduced systemic toxicity in a canine renal allograft model, Transplantation 48, 936–943 (1989).PubMedCrossRefGoogle Scholar
  23. 23.
    S. A. Gruber, G. R. Erdmann, B. A. Burke, et al., Mizoribine pharmacokinetics and pharmacodynamics in a canine renal allograft model of local immunosuppression, Transplantation 53, 12–19 (1992).PubMedCrossRefGoogle Scholar
  24. 24.
    S. Ko, Y. Nakajima, H. Kanehiro, et al., The significance of local immunosuppression in canine liver transplantation, Transplantation 57, 1818–1821 (1994).PubMedGoogle Scholar
  25. 25.
    N. Yoshimura, T. Hamashima, Y. Nakamura, Y. Sudo, H. Yura, T. Oka, Effect of local immunosuppressive therapy with FK 506 on renal allograft survival in the mongrel dog, Transplant Proc 30, 3110–3111 (1998).PubMedCrossRefGoogle Scholar
  26. 26.
    T. Weber, T. Kalbhenn, G. Herrmann, E. Hanisch, Local immunosuppression with budesonide after liver transplantation in the rat: a preliminary histomorphological analysis, Transplantation 64, 705–708 (1997).PubMedCrossRefGoogle Scholar
  27. 27.
    N. Ozcay, J. Fryer, D. Grant, D. Freeman, B. Garcia, R. Zhong, Budesonide, a locally acting steroid, prevents graft rejection in a rat model of intestinal transplantation, Transplantation 63, 1220–1225 (1997).PubMedCrossRefGoogle Scholar
  28. 28.
    S. A. Gruber (ed), Local Immunosuppression of Organ Transplants. Austin: R. G. Landes Company (Medical Intelligence Unit Series) (1996).Google Scholar
  29. 29.
    R. J. Keenan, A. Iacono, J. H. Dauber, et al., Treatment of refractory acute allograft rejection with aerosolized cyclosporine in lung transplant recipients, J Thorac Cardiovasc Surg 113, 335–340 (1997).PubMedCrossRefGoogle Scholar
  30. 30.
    A. T. Iacono, R. J. Keenan, S. R. Duncan, et al., Aerosolized cyclosporine in lung recipients with refractory chronic rejection, Am J Respir Crit Care Med 153, 1451–1455 (1996).PubMedGoogle Scholar
  31. 31.
    J. M. Collins, Pharmacologic rationale for regional drug delivery, J Clin Oncol 2, 498–504 (1984).PubMedGoogle Scholar
  32. 32.
    C.-S. Lai, T. A. Wesseler Jr., J. W. Alexander, G. F. Babcock, Long-term survival of skin allografts in rats treated with topical cyclosporine, Transplantation 44, 83–87 (1987).PubMedCrossRefGoogle Scholar
  33. 33.
    K. S. Black, C. W. Hewitt, C. L. C. Chau, L. Pizzo, Transdermal application of cyclosporine prolongs skin allograft survival, Transplant Proc 20, 660–662 (1988).PubMedGoogle Scholar
  34. 34.
    K. S. Black, D. K. Nguyen, C. M. Proctor, et al., Site-specific suppression of cell-mediated immunity by cyclosporine, J Invest Dermatol 94, 644–648 (1990).PubMedCrossRefGoogle Scholar
  35. 35.
    K. S. Black, M. P. Patel, A. P. Patel, et al., Mechanisms of site-specific immunosuppression, Transplant Proc 23, 120–121 (1991).PubMedGoogle Scholar
  36. 36.
    X.-F. Zhao, J. W. Alexander, T. Schroeder, G. F. Babcock, The synergistic effect of low-dose cyclosporine and fluocinolone acetonide on the survival of rat allogeneic skin grafts, Transplantation 46, 490–492 (1988).PubMedCrossRefGoogle Scholar
  37. 37.
    S. Inceoglu, M. Siemionow, L. Chick, C. M. Craven, G. D. Lister, The effect of combined immunosuppression with systemic low-dose cyclosporin and topical fluocinolone acetonide on the survival of rat hind-limb allografts, Ann Plast Surg 33, 57–65 (1994).PubMedCrossRefGoogle Scholar
  38. 38.
    R. Llull, T. P. Lee, A. N. Vu, K. S. Black, C. W. Hewitt, Site-specific immune suppression with topical cyclosporine. Synergism with combined topical corticosteroid added during the maintenance phase, Transplantation 59, 1483–1485 (1995).PubMedCrossRefGoogle Scholar
  39. 39.
    K. Yuzawa, H. Taniguchi, K. Seino, M. Otsuka, K. Fukao, Topical immunosuppression in skin grafting with FK 506 ointment, Transplant Proc 28, 1387–1389 (1996).PubMedGoogle Scholar
  40. 40.
    T. Fujita, S. Takahashi, A. Yagihashi, K. Jimbow, N. Sato, Prolonged survival of rat skin allograft by treatment with FK506 ointment, Transplantation 64, 922–925 (1997).PubMedCrossRefGoogle Scholar
  41. 41.
    M. V. Shirbacheh, X. Ren, J. W. Jones, et al., Pharmacokinetic advantage of intraarterial cyclosporine delivery to the vascularly-isolated rabbit forelimb. I. Model development, J Pharmacol Exp Ther 289, 1185–1190 (1999).PubMedGoogle Scholar
  42. 42.
    M. V. Shirbacheh, T. A. Harralson, J. W. Jones, et al., Pharmacokinetic advantage of intraarterial cyclosporine delivery to the vascularly-isolated rabbit forelimb. II. Dose-dependence, J Pharmacol Exp Ther 289, 1191–1195 (1999).PubMedGoogle Scholar
  43. 43.
    M. V. Shirbacheh, T. A. Harralson, J. W. Jones, et al, Pharmacokinetics of intraarterial delivery of tacrolimus to the vascularly-isolated rabbit forelimb, J Pharmacol Exp Ther 289, 1196–1201 (1999).PubMedGoogle Scholar
  44. 44.
    S. A. Gruber, The case for local immunosuppression, Transplantation 54, 1–11 (1992).PubMedCrossRefGoogle Scholar

Copyright information

© Springer 2008

Authors and Affiliations

  • Scott A. Gruber
    • 1
  1. 1.Wayne State University School of MedicineHarper University HospitalDetroit

Personalised recommendations