Skip to main content
NCBI home page
Annals of Surgery logoLink to Annals of Surgery
. 1994 Jan;219(1):88–93. doi: 10.1097/00000658-199401000-00014

Efficacy of rapamycin and FK 506 in prolonging rat hind limb allograft survival.

M J Fealy 1, W S Umansky 1, K D Bickel 1, J J Nino 1, R E Morris 1, B H Press 1
PMCID: PMC1243095  PMID: 7507657

Abstract

OBJECTIVE: Graft rejection and the toxicity of current immunosuppressive regimens preclude the application of microsurgical advances to transplantation of limbs or other nonessential parts. If limb transplantation is to become a clinical reality, newer, safer, more effective immunosuppressive agents are needed. SUMMARY BACKGROUND DATA: Rapamycin (RPM) and FK 506 are fungal macrolide antibiotics with effective immunosuppressive properties demonstrated in several animal models. RPM is more potent and effective than is FK 506 in rat cardiac allografts and has demonstrated synergy with cyclosporine (CsA) in limb allograft models. METHODS: An orthotopic rat hind limb allograft model (Brown-Norway [RT-1n] to Lewis [RT-1(1)] rats was used. RPM (doses, 3.0, 4.5, and 6.0 mg/kg/day) was administered intraperitoneally on postoperative days 1 to 14. FK 506 (6 mg/kg/day) was administered orally on postoperative 1 to 14 and 1 to 90 and at rejection onset (10 mg/kg/day for salvage). CsA with RPM (postoperative days 1 to 14) was used to assess synergy, with CsA alone serving as the control. Other controls included untreated and placebo-treated allografted animals. The permutation test and Mann-Whitney test were applied to the data. RESULTS: The mean survival times were assessed as follows: (1) control (placebo, untreated), 5 days; (2) RPM groups, 9.5, 10.6, and 8.7 days; (3) 14-day FK 506, 28 days; (4) 90-day FK 506, > 90 days; (5) CsA, 17.3 days; and (6) CsA with RPM, 19.3 days. FK 506 significantly prolonged graft survival compared with RPM (Permutation Test, p < 0.001 and Mann-Whitney Test, p < 0.05). FK 506 salvage reversed early rejection. High-dose RPM produced significant toxicity. Synergy between CsA and RPM was not demonstrated. CONCLUSIONS: FK 506 prolongs allograft survival, reverses early rejection, and prevents rejection without clinical toxicity when given continually. RPM does not prevent rejection in this model and produces significant toxicity at high doses. FK 506 may be a first step in making limb transplantation a clinical reality in reconstructive surgery.

Full text

PDF
88

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Andersson J., Nagy S., Groth C. G., Andersson U. The effects of FK 506 on cytokine production are dependent on the mode of cell activation. Transplant Proc. 1991 Dec;23(6):2916–2919. [PubMed] [Google Scholar]
  2. Arai K., Hotokebuchi T., Miyahara H., Arita C., Mohtai M., Sugioka Y., Kaibara N. Limb allografts in rats immunosuppressed with FK506. I. Reversal of rejection and indefinite survival. Transplantation. 1989 Nov;48(5):782–786. doi: 10.1097/00007890-198911000-00011. [DOI] [PubMed] [Google Scholar]
  3. Arai K., Hotokebuchi T., Miyahara H., Arita C., Mohtai M., Sugioka Y., Kaibara N. Prolonged limb allograft survival with short-term treatment with FK-506 in rats. Transplant Proc. 1989 Feb;21(1 Pt 3):3191–3193. [PubMed] [Google Scholar]
  4. Calne R. Y., White D. J. The use of cyclosporin A in clinical organ grafting. Ann Surg. 1982 Sep;196(3):330–337. doi: 10.1097/00000658-198209000-00012. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Fritz W. D., Swartz W. M., Rose S., Futrell J. W., Klein E. Limb allografts in rats immunosuppressed with cyclosporin A. Ann Surg. 1984 Feb;199(2):211–215. doi: 10.1097/00000658-198402000-00014. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Goldwyn R. M., Beach P. M., Feldman D., Wilson R. E. Canine limb homotransplantation. Plast Reconstr Surg. 1966 Mar;37(3):184–195. doi: 10.1097/00006534-196603000-00002. [DOI] [PubMed] [Google Scholar]
  7. Jamieson S. W., Burton N. A., Bieber C. P., Reitz B. A., Oyer P. E., Stinson E. B., Shumway N. E. Cardiac-allograft survival in primates treated with cyclosporin A. Lancet. 1979 Mar 10;1(8115):545–545. doi: 10.1016/s0140-6736(79)90959-0. [DOI] [PubMed] [Google Scholar]
  8. Jamieson S. W., Burton N. A., Bieber C. P., Reitz B. A., Oyer P. E., Stinson E. B., Shumway N. E. Survival of cardiac allografts in rats treated with cyclosporin A. Surg Forum. 1979;30:289–291. [PubMed] [Google Scholar]
  9. Kim S. K., Aziz S., Oyer P., Hentz V. R. Use of cyclosporin A in allotransplantation of rat limbs. Ann Plast Surg. 1984 Mar;12(3):249–255. doi: 10.1097/00000637-198403000-00006. [DOI] [PubMed] [Google Scholar]
  10. Kuroki H., Ikuta Y., Akiyama M. Experimental studies of vascularized allogeneic limb transplantation in the rat using a new immunosuppressive agent, FK-506: morphological and immunological analysis. Transplant Proc. 1989 Feb;21(1 Pt 3):3187–3190. [PubMed] [Google Scholar]
  11. Lance E. M., Inglis A. E., Figarola F., Veith F. J. Transplantation of the canine hind limb. Surgical technique and methods of immunosuppression for allotransplantation. A preliminary report. J Bone Joint Surg Am. 1971 Sep;53(6):1137–1149. [PubMed] [Google Scholar]
  12. Morris R. E., Meiser B. M., Wu J., Shorthouse R., Wang J. Use of rapamycin for the suppression of alloimmune reactions in vivo: schedule dependence, tolerance induction, synergy with cyclosporine and FK 506, and effect on host-versus-graft and graft-versus-host reactions. Transplant Proc. 1991 Feb;23(1 Pt 1):521–524. [PubMed] [Google Scholar]
  13. Morris R. E., Wu J., Shorthouse R. A study of the contrasting effects of cyclosporine, FK 506, and rapamycin on the suppression of allograft rejection. Transplant Proc. 1990 Aug;22(4):1638–1641. [PubMed] [Google Scholar]
  14. Press B. H., Sibley R. K., Shons A. R. Limb allotransplantation in the rat: extended survival and return of nerve function with continuous cyclosporin/prednisone immunosuppression. Ann Plast Surg. 1986 Apr;16(4):313–321. [PubMed] [Google Scholar]
  15. Reitz B. A., Wallwork J. L., Hunt S. A., Pennock J. L., Billingham M. E., Oyer P. E., Stinson E. B., Shumway N. E. Heart-lung transplantation: successful therapy for patients with pulmonary vascular disease. N Engl J Med. 1982 Mar 11;306(10):557–564. doi: 10.1056/NEJM198203113061001. [DOI] [PubMed] [Google Scholar]
  16. Stark G. B., Swartz W. M., Narayanan K., Møller A. R. Hand transplantation in baboons. Transplant Proc. 1987 Oct;19(5):3968–3971. [PubMed] [Google Scholar]
  17. Stepkowski S. M., Chen H., Daloze P., Kahan B. D. Rapamycin, a potent immunosuppressive drug for vascularized heart, kidney, and small bowel transplantation in the rat. Transplantation. 1991 Jan;51(1):22–26. doi: 10.1097/00007890-199101000-00002. [DOI] [PubMed] [Google Scholar]
  18. Stevens H. P., Hovius S. E., Heeney J. L., van Nierop P. W., Jonker M. Immunologic aspects and complications of composite tissue allografting for upper extremity reconstruction: a study in the rhesus monkey. Transplant Proc. 1991 Feb;23(1 Pt 1):623–625. [PubMed] [Google Scholar]
  19. Zeevi A., Woan M., Yao G. Z., Venkataramanan R., Todo S., Starzl T. E., Duquesnoy R. J. Comparative in vitro studies on the immunosuppressive activities of mycophenolic acid, bredinin, FK 506, cyclosporine, and rapamycin. Transplant Proc. 1991 Dec;23(6):2928–2930. [PMC free article] [PubMed] [Google Scholar]

Articles from Annals of Surgery are provided here courtesy of Lippincott, Williams, and Wilkins

RESOURCES