Rapamycin in transplantation: A review of the evidence
2001; Elsevier BV; Volume: 59; Issue: 1 Linguagem: Inglês
10.1046/j.1523-1755.2001.00460.x
ISSN1523-1755
AutoresRichard N. Saunders, M.S. Metcalfe, Michael L. Nicholson,
Tópico(s)Transplantation: Methods and Outcomes
ResumoRapamycin in transplantation: A review of the evidence. The calcineurin inhibitors have been the mainstays of immunosuppression for solid organ transplantation over the last two decades, but nephrotoxicity limits their therapeutic benefit. Rapamycin is a new drug with both immunosuppressant and antiproliferative properties that has a unique mechanism of action distinct from that of the calcineurin inhibitors. It has a role as a maintenance immunosuppressant either alone or in combination with a calcineurin inhibitor and can also be used to treat refractory acute rejection. Theoretical evidence suggests that it may limit the development and progression of chronic rejection in transplant recipients, but this has yet to be confirmed. This review examines the current in vitro animal and human work underlying the use of rapamycin and, in addition, comments on the pharmacokinetics and side-effect profile of this promising new agent. Rapamycin in transplantation: A review of the evidence. The calcineurin inhibitors have been the mainstays of immunosuppression for solid organ transplantation over the last two decades, but nephrotoxicity limits their therapeutic benefit. Rapamycin is a new drug with both immunosuppressant and antiproliferative properties that has a unique mechanism of action distinct from that of the calcineurin inhibitors. It has a role as a maintenance immunosuppressant either alone or in combination with a calcineurin inhibitor and can also be used to treat refractory acute rejection. Theoretical evidence suggests that it may limit the development and progression of chronic rejection in transplant recipients, but this has yet to be confirmed. This review examines the current in vitro animal and human work underlying the use of rapamycin and, in addition, comments on the pharmacokinetics and side-effect profile of this promising new agent. Rapamycin (Rapa, Rapamune, Sirolimus; Wyeth-Ayerst Pharmaceuticals, Philadelphia, PA, USA) is a macrocyclic fermentation product of Streptomyces hygroscopicus, an actinomycete, originally isolated from a soil sample in Rapa Nui (Easter Island, 1975)1.Vezina C. Kudelski A. Sehgal S.N. Rapamycin, a new antifungal antibiotic. Taxonomy of the producing Streptomycete and isolation of the active principle.J Antibiot (Tokyo). 1975; 28: 721-726Crossref PubMed Scopus (1209) Google Scholar,2.Sehgal S.N. Baker H. Vezina C. Rapamycin, a new antifungal antibiotic. Fermentation, isolation and characterization.J Antibiot (Tokyo). 1975; 28: 727-732Crossref PubMed Scopus (766) Google ScholarRapa was initially investigated as an antifungal and antitumor agent. However, its lymphopenic properties heralded its role as an immunosuppressant. There is currently much interest in Rapa because of its unique mechanism of action, lack of end-organ toxicity, and its ability to synergize with other immunosuppressants, yet avoid overlapping side effects. This review discusses the current evidence on which the use of Rapa in transplantation is based. The mainstays of modern immunosuppression, Cyclosporin (CsA) and Tacrolimus (FK506), bind to the intracellular cytosolic immunophilins cyclophilin and FK binding protein 12 (FKBP12), respectively, inhibiting calcineurin phosphatase. This prevents transcription of cytokines [for example, interleukin-2 (IL-2)] and progression of the T-cell cycle from G0 to G13.Manez R. Jain A. Marino I.R. et al.Comparative evaluation of tacrolimus and cyclosporin as immunosuppressive agents.Transplant Rev. 1995; 9: 63Abstract Full Text PDF Scopus (31) Google Scholar. Rapa has a similar molecular structure to FK506 and also binds to FKBP124.Sehgal S.N. Rapamune (Sirolimus, Rapamycin): An overview and mechanism of action.Ther Drug Monit. 1995; 17: 660-665Crossref PubMed Scopus (253) Google Scholar. However, the Rapa-FKBP12 complex has no effect on calcineurin phosphatase. Instead, it binds to one or more proteins known as “targets of rapamycin” (TOR)5.Morris R.E. New small molecule immunosuppressants for transplantation: Review of essential concepts.J Heart Lung Transplant. 1993; 12: S275-S286PubMed Google Scholar. These effector proteins were originally demonstrated as TOR1 and TOR2 in yeast6.Cardenas M.E. Lorenz M. Hemenway C. Heitmen J. Yeast as model T cells.Drug Des Discov. 1994; 2: 103-126Crossref Scopus (31) Google Scholar, but a mammalian homologue has now been identified7.Chiu M.I. Katz H. Berlin V. RAPT1, a mammalian homologue of yeast TOR interacts with the FKBP12-Rapamycin complex.Proc Natl Acad Sci USA. 1994; 91: 12574-12578Crossref PubMed Scopus (386) Google Scholar. This has been given a number of acronyms, including mTOR, FRAP, SEP, and RAFT17.Chiu M.I. Katz H. Berlin V. RAPT1, a mammalian homologue of yeast TOR interacts with the FKBP12-Rapamycin complex.Proc Natl Acad Sci USA. 1994; 91: 12574-12578Crossref PubMed Scopus (386) Google Scholar, 8.Chen Y. Chen H. Rhoad A.O. et al.A putative Sirolimus (Rapamycin) effector protein.Biochem Biophys Res Commun. 1994; 203: 1-7Crossref PubMed Scopus (55) Google Scholar, 9.Brown E.J. Albers M.W. Shin T.B. et al.Purification and molecular cloning of FRAP a direct target of G1 arrest complex FKBP12-Rapamycin.Nature. 1994; 369: 756-761Crossref PubMed Scopus (1568) Google Scholar, 10.Sabers C.J. Martin M.M. Brunn et al, G.J. Isolation of protein target of FKBP12-Rapamycin complex in mammalian cells.J Biol Chem. 1994; 270: 815-822Crossref Scopus (656) Google Scholar, but “mammalian target of rapamycin” (mTOR) is most commonly used. Both cytokines, such as IL-2 and the CD28/B7 costimulatory pathway activate mTOR, resulting in downstream events critical for cell cycle regulation Figure 1. This process is complex and the underlying metabolic pathway has not been fully characterized11.Sonenberg N. Gingras A.C. The mRNA 5′ cap-binding protein eIF-4E and control of cell growth.Curr Opin Cell Biol. 1998; 10: 268-275Crossref PubMed Scopus (493) Google Scholar, 12.Beretta L. Gingras A.C. Svitkin Y.V. et al.Rapamycin blocks the phosphorylation of 4E-BP1 and inhibits cap-dependent initiation of translation.Embo J. 1996; 15: 658-664Crossref PubMed Scopus (582) Google Scholar, 13.Sabatini D.M. Pierchala B.A. Barrow R.K. et al.The Rapamycin and FKBP12 target (RAFT) displays phospatidylinositol 4-kinase activity.J Biol Chem. 1995; 270: 20875-20878Crossref PubMed Scopus (64) Google Scholar, 14.Jeffries H.B.J. Fumagalli S. Dennis P.B. et al.Rapamycin suppresses 5′TOP mRNA translation through inhibition of p70s6k.Embo J. 1997; 12: 3693-3704Crossref Scopus (793) Google Scholar, 15.Chung J. Kuo C.J. Crabtree G.R. et al.Rapamycin-FKBP12 specifically blocks growth-dependent activation of and signalling by the 70kd S6 protein kinases.Cell. 1992; 69: 1227-1236Abstract Full Text PDF PubMed Scopus (987) Google Scholar. However, the Rapa-FKBP12 complex binds mTOR and subsequently inhibits both DNA and protein synthesis, resulting in arrest of the cell cycle in late G1 as it progresses to the S phase16.Terada N. Lucas J.J. Szepesi A. et al.Rapamycin blocks cell cycle progression of activated T cells prior to events characteristic of the middle to late G1 phase of the cell cycle.J Cell Physiol. 1993; 268: 22825-22829Google Scholar. The immunosuppressive properties of Rapa result from inhibition of leukocyte activity. It blocks T-cell proliferation induced by cytokines (IL-1, -2, -3, -4, -6, -7, -12, and -15), alloantigens, and mitogens in a dose-dependent manner17.Sehgal S.N. Rapamune: Mechanism of action immunosuppressive effect results from blockade of signal transduction and inhibition of cell cycle progression.Clin Biochem. 1998; 31: 335-340Crossref PubMed Scopus (601) Google Scholar, 18.Bertagnolli M.M. Yang L. Herrmann S.H. et al.Evidence that Rapamycin inhibits interleukin-12 induced proliferation of activated T lymphocytes.Transplantation. 1994; 58: 1091-1096Crossref PubMed Scopus (30) Google Scholar, 19.Sehgal S.N. Bansbach C.C. An in vitro immunological profile of Rapamycin.Ann NY Acad Sci. 1993; 685: 58-67Crossref PubMed Scopus (35) Google Scholar. However, Rapa does not appear to alter IL-2 induced T-cell apoptosis (Abstract 73; Transplantation Society XVII, World Congress, Montreal, Canada, 1998). Natural killer, cytokine-activated killer, and antibody-dependent cell cytotoxicity functions of human leukocytes are suppressed by Rapa at concentrations 10- to 100-fold greater than those needed to block T-cell proliferation20.Sehgal S.N. Molnar-Kimber K. Ocain T. et al.Rapamycin: A novel immunosuppressive macrolide.Med Res Rev. 1994; 14: 1-22Crossref PubMed Scopus (167) Google Scholar. Rapa acts on B cells independently of its effects on T helper cells, causing an inhibition of antigen and cytokine driven B-cell proliferation21.Aaguaard-Tillery K.M. Jelinek D. Inhibition of human B lymphocyte cell cycle progression and differentiation by Rapamycin.Cell Immunol. 1994; 152: 493-507Crossref Scopus (102) Google Scholar. In addition, it has been shown to inhibit cytokine-dependent (IL-2 and IL-6) differentiation into antibody-producing cells, thus decreasing immunoglobulin synthesis22.Kim H.S. Raskova J. Degiannis D. et al.Effects of cyclosporin and Rapamycin on immunoglobulin production by preactivated human B cells.Clin Exp Immunol. 1994; 96: 508-512Crossref PubMed Scopus (33) Google Scholar. In contrast to the calcineurin inhibitors, it has been claimed that Rapa has limited effects on cytokine expression in vitro. It does not inhibit the transcription of IL-2, -3, -4 or tumor necrosis factor-α (TNF-α) in mitogen-activated T cells17.Sehgal S.N. Rapamune: Mechanism of action immunosuppressive effect results from blockade of signal transduction and inhibition of cell cycle progression.Clin Biochem. 1998; 31: 335-340Crossref PubMed Scopus (601) Google Scholar and has been shown to have variable effects on interferon-γ (IFN-γ) transcription dependent on the stimulus23.Dumont F.J. Kastner C.A. Transforming growth factor beta 1 inhibits interleukin-1 induced but enhances ionomycin induced interferon-γ production in a T cell lymphoma: Comparison with the effects of Rapamycin.J Cell Physiol. 1994; 160: 141-153Crossref PubMed Scopus (16) Google Scholar. However, work comparing the expression of TH1 and TH2 cytokines using reverse transcription-polymerase chain reaction (RT-PCR) in concavalin A-stimulated spleen cells suggested that Rapa inhibited the expression of IL-2, IFN-γ, IL-4, and IL-10 more than nonimmunosuppressed controls24.Zheng X.X. Strom T.B. Steele A.W. Quantitative comparison of Rapamycin and cyclosporin, effects on cytokine gene expression studied by reverse transcriptase-competitive polymerase chain reaction.Transplantation. 1994; 58: 87-92Crossref PubMed Scopus (35) Google Scholar. Indeed, Rapa inhibited IL-10 expression more effectively than CsA (100 vs. 65% inhibition). Rapa's main mode of action is the inhibition of cytokine-activated signal transduction, but clearly, any inhibitory effect on proinflammatory cytokine transcription (however minor) would complement its immunosuppressive efficacy. The underlying mechanism for this is not known but may stem from the inhibition of costimulatory pathway transduction as this has been implicated in the transcriptional activation of several cytokine genes. The concept of inhibiting cytokine transcription and simultaneously blocking cytokine-mediated signal transduction has been investigated in vitro using CsA/Rapa combinations. Rapa augmented the inhibitory effects of CsA on antibody and phytohemaglutinin-stimulated peripheral blood leukocyte activation25.Kahan B.D. Gibbons S. Chou T.C. Synergistic interactions of cyclosporine and Rapamycin to inhibit immune performances of normal human peripheral blood leukocytes in vitro.Transplantation. 1991; 51: 232-239Crossref PubMed Scopus (196) Google Scholar. Furthermore, relatively high doses of Rapa and CsA alone were required to inhibit cell-mediated lympholysis in vitro (IC50 Rapa = 8721 × 10-9 M, CsA = 1052 × 10-9 M). However, the same degree of inhibition was produced by a combination of both at 72 and 144 × 10-9 M, respectively. In a further study, the IC50s required to inhibit the proliferation of an IL-2–dependent cell line for Rapa and CsA alone were 90.9 and 2602 × 10-9 M, respectively, compared with 65 and 260 × 10-9 M when combined23.Dumont F.J. Kastner C.A. Transforming growth factor beta 1 inhibits interleukin-1 induced but enhances ionomycin induced interferon-γ production in a T cell lymphoma: Comparison with the effects of Rapamycin.J Cell Physiol. 1994; 160: 141-153Crossref PubMed Scopus (16) Google Scholar. This work has shown that the combination of Rapa and CsA is highly complimentary. Reduced doses of both drugs achieve a response much greater than one would expect from a purely additive effect, suggesting a synergistic interaction. The pharmacokinetic/pharmacodynamic mechanisms underlying this are not clear. However, this combination ensures that only small amounts of cytokine are produced, causing reduced activation of cytokine receptors and an attenuated downstream signal that is more easily inhibited by Rapa. It was hoped that the combination of FK506 and Rapa would display similar synergism. However, equimolar doses produced an additive effect, and if either was given in 50- to 1000-fold excess, they became antagonistic in vitro26.Vathsala A. Goto S. Yoshimara N. et al.Immunosuppressive antagonism of FK506 and Cyclosporin at low drug doses.Transplantation. 1991; 52: 121-128Crossref PubMed Scopus (30) Google Scholar,27.Dumont F.J. Melino M.R. Staruch M.J. et al.The immunosuppressive macrolides FK506 and Rapamycin act as reciprocal antagonists in murine T cells.J Immunol. 1990; 144: 1418PubMed Google Scholar. The first in vivo studies documenting the immunosuppressive properties of Rapa were published by Calne et al and Morris and Meiser28.Calne R. Collier D. Lim S. et al.Rapamycin for immunosuppression in organ allografting.Lancet. 1989; 2: 227Abstract PubMed Scopus (330) Google Scholar,29.Morris R.E. Meiser B.M. Identification of a new pharmacological action for a old compound.Med Sci Res. 1989; 17: 609-610Google Scholar. Both groups gave Rapa at various doses to rats receiving heterotopic cardiac allografts and noted longer graft and animal survival rates in comparison to nonimmunosuppressed controls. Similar benefits have been demonstrated for skin, renal, small bowel, pancreatic, and pancreaticoduodenal allografts in a number of species, including mice, rats, rabbits, pigs, dogs, and primates, although in dogs and primates fatal gastrointestinal side effects frequently occurred28.Calne R. Collier D. Lim S. et al.Rapamycin for immunosuppression in organ allografting.Lancet. 1989; 2: 227Abstract PubMed Scopus (330) Google Scholar, 29.Morris R.E. Meiser B.M. Identification of a new pharmacological action for a old compound.Med Sci Res. 1989; 17: 609-610Google Scholar, 30.Eng C.P. Gullo-Brown J.G. Chang J.Y. et al.Inhibition of skin graft rejection in mice by Rapamycin: A novel immunosuppressive macrolide.Transplant Proc. 1991; 23: 868-869PubMed Google Scholar, 31.Ochiai T. Gunji Y. Nagata M. et al.Effects of Rapamycin in experimental organ allografting.Transplantation. 1993; 56: 15-19Crossref PubMed Scopus (61) Google Scholar, 32.Schmidbauer G. Hancock W.W. Wasowska B. et al.Rapamycin abrogates accelerated rejection in sensitized rats by selectively suppressing intragraft cell activation, adhesion binding properties and modulating serum alloantibody responses.Transplant Proc. 1995; 27: 427-429PubMed Google Scholar, 33.Stepkowski S.M. Kahan B.D. Rapamycin and cyclosporin synergistically prolong heart and kidney allograft survival.Transplant Proc. 1991; 23: 3262-3264PubMed Google Scholar, 34.Stepkowski S.M. Chen H. Daloze P. et al.Rapamycin, a potent immunosuppressive drug for vascularized heart, kidney and small bowel transplantation in the rat.Transplantation. 1991; 51: 22Crossref PubMed Scopus (153) Google Scholar, 35.Vu M.D. Qi S. Xu D. et al.Synergistic effects of Mycophenolate mofetil and Sirolimus in prevention of acute heart, pancreas and kidney allograft rejection and in reversal of ongoing heart allograft rejection in the rat.Transplantation. 1998; 66: 1575-1580Crossref PubMed Scopus (60) Google Scholar, 36.Chen H. Wu J. Xu D. et al.The effect of Rapamycin on orthoptic small bowel transplantation in the rat.Transplant Proc. 1992; 24: 1157PubMed Google Scholar, 37.Kahan B.D. Chang J.Y. Sehgal S.N. Preclinical evaluation of a new potent immunosuppressive agent, Rapamycin.Transplantation. 1991; 52: 185-191Crossref PubMed Scopus (147) Google Scholar, 38.Fryer J. Yatscoff R.W. Pascoe E.A. et al.The relationship of blood concentrations of Rapamycin and cyclosporin to suppression of allograft rejection in a rabbit heterotopic heart allograft model.Transplantation. 1993; 55: 340-345Crossref PubMed Scopus (79) Google Scholar, 39.Knight R. Ferraresso M. Serino F. et al.Low dose Rapamycin potentiates the effects of subtherapeutic doses of cyclosporin to prolong renal allograft survival in the mongrel canine model.Transplantation. 1993; 55: 947-949Crossref PubMed Google Scholar, 40.St J Collier D. Calne R. Thiru S. et al.Rapamycin in experimental renal allografts in dogs and pigs.Transplant Proc. 1990; 22: 1674-1675PubMed Google Scholar, 41.Almond P.S. Moss A. Nakhleh R. et al.Rapamycin: Immunosuppression, hyporesponsiveness and side effects in a porcine renal allograft model.Transplantation. 1993; 56: 275-281Crossref PubMed Scopus (31) Google Scholar, 42.Granger D.K. Cromwell J.W. Chen S. et al.Prolongation of renal allograft survival in a large animal model by oral Rapamycin monotherapy.Transplantation. 1995; 59: 183-186Crossref PubMed Scopus (76) Google Scholar, 43.St J Collier D. Calne R.Y. Pollard S.G. et al.Rapamycin in experimental renal allografts in primates.Transplant Proc. 1991; 23: 2246-2247PubMed Google Scholar. It is difficult to compare the immunosuppressive efficacy of Rapa between studies as various doses, routes of administration, and allograft models have been used Table 1. However Rapa is 20 to 100 times more potent than CsA and acted in a dose-dependent manner to prevent acute allograft rejection. In studies that measured trough levels, a range of 5 to 10 ng/mL provided effective immunosuppression in small animals, but larger animals required levels> 10 ng/mL. Subsequently, Rapa (0.8 mg/kg/day intravenously) was investigated as a potential treatment for ongoing acute rejection and was found to prolong the survival of presensitized rat skin and cardiac allograft recipients 44a.Chen H.F. Luo H. Daloze P. et al.Long term in vivo effects of Rapamycin on humoral and cellular immune responses in the rat.Immunobiology. 1993; 188: 303-315Crossref PubMed Scopus (24) Google Scholar, 44b.Chen H.F. Wu J.P. Luo H.Y. et al.Reversal of ongoing heart, kidney, and pancreas rejection and suppression of accelerated heart allograft rejection in the rat by Rapamycin.Transplantation. 1993; 56: 661-666Crossref PubMed Scopus (51) Google Scholar. This dose-dependent effect (Rapa 0.08 to 0.8 mg/kg) was confirmed in cardiac, renal, and pancreas allografts with acute rejection46.Wang M. Stepkowski S.M. Ferraresso M. et al.Evidence that Rapamycin rescue therapy delays rejection of major and minor histocompatible heart allografts in rats.Transplantation. 1992; 54: 704-709Crossref PubMed Scopus (18) Google Scholar,47.Longoria J.L. Roberts R.F. Marboe C.C. et al.Sirolimus potentiates cyclosporin in prevention of acute lung rejection.J Thorac Cardiovasc Surg. 1999; 117: 715-718Abstract Full Text Full Text PDF Scopus (27) Google Scholar.Table 1Summary of the immunosuppressive efficacy of rapamycin alone at preventing graft loss secondary to the development of acute rejection in animal allograftsSpeciesType of allograft [Reference]Rapamycin dose mg/kg/dayRoute of administrationMaximum duration of treatment days post-op unless statedMean number of days graft survival > controlsMouseSkin30.Eng C.P. Gullo-Brown J.G. Chang J.Y. et al.Inhibition of skin graft rejection in mice by Rapamycin: A novel immunosuppressive macrolide.Transplant Proc. 1991; 23: 868-869PubMed Google Scholar0.25–4IP64–5Heart29.Morris R.E. Meiser B.M. Identification of a new pharmacological action for a old compound.Med Sci Res. 1989; 17: 609-610Google Scholar 0.75–3.0/6.0IP/PO1415–136/5RatSkin31.Ochiai T. Gunji Y. Nagata M. et al.Effects of Rapamycin in experimental organ allografting.Transplantation. 1993; 56: 15-19Crossref PubMed Scopus (61) Google Scholar3.0 and 10.0IM86Heart31.Ochiai T. Gunji Y. Nagata M. et al.Effects of Rapamycin in experimental organ allografting.Transplantation. 1993; 56: 15-19Crossref PubMed Scopus (61) Google Scholar0.1–5.0IM119–100+Heart28.Calne R. Collier D. Lim S. et al.Rapamycin for immunosuppression in organ allografting.Lancet. 1989; 2: 227Abstract PubMed Scopus (330) Google Scholar0.5–5IM1010–90Heart33.Stepkowski S.M. Kahan B.D. Rapamycin and cyclosporin synergistically prolong heart and kidney allograft survival.Transplant Proc. 1991; 23: 3262-3264PubMed Google Scholar0.04IV147Heart34.Stepkowski S.M. Chen H. Daloze P. et al.Rapamycin, a potent immunosuppressive drug for vascularized heart, kidney and small bowel transplantation in the rat.Transplantation. 1991; 51: 22Crossref PubMed Scopus (153) Google Scholar0.16–0.8IV1432–41Heart32.Schmidbauer G. Hancock W.W. Wasowska B. et al.Rapamycin abrogates accelerated rejection in sensitized rats by selectively suppressing intragraft cell activation, adhesion binding properties and modulating serum alloantibody responses.Transplant Proc. 1995; 27: 427-429PubMed Google Scholar0.25IP7aPreoperative administration only45Heart35.Vu M.D. Qi S. Xu D. et al.Synergistic effects of Mycophenolate mofetil and Sirolimus in prevention of acute heart, pancreas and kidney allograft rejection and in reversal of ongoing heart allograft rejection in the rat.Transplantation. 1998; 66: 1575-1580Crossref PubMed Scopus (60) Google Scholar0.2–1.2PO3013–55Kidney33.Stepkowski S.M. Kahan B.D. Rapamycin and cyclosporin synergistically prolong heart and kidney allograft survival.Transplant Proc. 1991; 23: 3262-3264PubMed Google Scholar0.01–0.04IV1410–100+Kidney34.Stepkowski S.M. Chen H. Daloze P. et al.Rapamycin, a potent immunosuppressive drug for vascularized heart, kidney and small bowel transplantation in the rat.Transplantation. 1991; 51: 22Crossref PubMed Scopus (153) Google Scholar0.8IV1488Kidney35.Vu M.D. Qi S. Xu D. et al.Synergistic effects of Mycophenolate mofetil and Sirolimus in prevention of acute heart, pancreas and kidney allograft rejection and in reversal of ongoing heart allograft rejection in the rat.Transplantation. 1998; 66: 1575-1580Crossref PubMed Scopus (60) Google Scholar0.2–0.4PO302–6.5Small bowel34.Stepkowski S.M. Chen H. Daloze P. et al.Rapamycin, a potent immunosuppressive drug for vascularized heart, kidney and small bowel transplantation in the rat.Transplantation. 1991; 51: 22Crossref PubMed Scopus (153) Google Scholar,36.Chen H. Wu J. Xu D. et al.The effect of Rapamycin on orthoptic small bowel transplantation in the rat.Transplant Proc. 1992; 24: 1157PubMed Google Scholar0.8IV1417Pancreas35.Vu M.D. Qi S. Xu D. et al.Synergistic effects of Mycophenolate mofetil and Sirolimus in prevention of acute heart, pancreas and kidney allograft rejection and in reversal of ongoing heart allograft rejection in the rat.Transplantation. 1998; 66: 1575-1580Crossref PubMed Scopus (60) Google Scholar0.2–0.4PO305–8Pancreaticoduodenal37.Kahan B.D. Chang J.Y. Sehgal S.N. Preclinical evaluation of a new potent immunosuppressive agent, Rapamycin.Transplantation. 1991; 52: 185-191Crossref PubMed Scopus (147) Google Scholar0.8IV1448RabbitHeart38.Fryer J. Yatscoff R.W. Pascoe E.A. et al.The relationship of blood concentrations of Rapamycin and cyclosporin to suppression of allograft rejection in a rabbit heterotopic heart allograft model.Transplantation. 1993; 55: 340-345Crossref PubMed Scopus (79) Google Scholar0.05–1.0IV60> controlcMean values not recordedDogKidney31.Ochiai T. Gunji Y. Nagata M. et al.Effects of Rapamycin in experimental organ allografting.Transplantation. 1993; 56: 15-19Crossref PubMed Scopus (61) Google Scholar0.3–1.5IMLifespan2–10 < controlbSevere gastrointestinal side effectsKidney39.Knight R. Ferraresso M. Serino F. et al.Low dose Rapamycin potentiates the effects of subtherapeutic doses of cyclosporin to prolong renal allograft survival in the mongrel canine model.Transplantation. 1993; 55: 947-949Crossref PubMed Google Scholar0.05IV7–2016bSevere gastrointestinal side effectsKidney40.St J Collier D. Calne R. Thiru S. et al.Rapamycin in experimental renal allografts in dogs and pigs.Transplant Proc. 1990; 22: 1674-1675PubMed Google Scholar2.0PODays 3–51bSevere gastrointestinal side effectsPigKidney41.Almond P.S. Moss A. Nakhleh R. et al.Rapamycin: Immunosuppression, hyporesponsiveness and side effects in a porcine renal allograft model.Transplantation. 1993; 56: 275-281Crossref PubMed Scopus (31) Google Scholar0.25IM3053Kidney40.St J Collier D. Calne R. Thiru S. et al.Rapamycin in experimental renal allografts in dogs and pigs.Transplant Proc. 1990; 22: 1674-1675PubMed Google Scholar2IM6465Kidney42.Granger D.K. Cromwell J.W. Chen S. et al.Prolongation of renal allograft survival in a large animal model by oral Rapamycin monotherapy.Transplantation. 1995; 59: 183-186Crossref PubMed Scopus (76) Google Scholar0.1–2.0PO284–24BaboonKidney43.St J Collier D. Calne R.Y. Pollard S.G. et al.Rapamycin in experimental renal allografts in primates.Transplant Proc. 1991; 23: 2246-2247PubMed Google Scholar2–50PO/IM/IV15–200–30bSevere gastrointestinal side effectsAbbreviations are: IP, intraperitoneal; PO, oral; IM, intramuscular; IV, intravenous.a Preoperative administration onlyb Severe gastrointestinal side effectsc Mean values not recorded Open table in a new tab Abbreviations are: IP, intraperitoneal; PO, oral; IM, intramuscular; IV, intravenous. The synergy between Rapa and CsA suggested in vitro was also observed in animal work. Subtherapeutic doses of Rapa (0.01 to 0.04 mg/kg/day) and CsA (0.5 to 2.0 mg/kg/day) prolonged rat cardiac and kidney allograft survival compared with either drug alone or the additive effect of a combination of both33.Stepkowski S.M. Kahan B.D. Rapamycin and cyclosporin synergistically prolong heart and kidney allograft survival.Transplant Proc. 1991; 23: 3262-3264PubMed Google Scholar. Similar results were observed in studies using rat lung48.Qi S. Xu D. Peng J. et al.Synergistic effect of rapamycin and cyclosporin in prevention of acute kidney allograft rejection in the mouse.Microsurgrery. 1999; 19: 344-347Crossref PubMed Scopus (14) Google Scholar and mouse kidney allografts49.Stepkowski S.M. Tian L. Napoli K.L. et al.Synergistic mechanisms by which sirolimus and cyclosporin inhibit rat heart and kidney allograft rejection.Clin Exp Immunol. 1997; 108: 63-68Crossref PubMed Scopus (89) Google Scholar as well as a mongrel canine model39.Knight R. Ferraresso M. Serino F. et al.Low dose Rapamycin potentiates the effects of subtherapeutic doses of cyclosporin to prolong renal allograft survival in the mongrel canine model.Transplantation. 1993; 55: 947-949Crossref PubMed Google Scholar. In the preliminary investigation of Rapa (1991), a Rapa/FK506 combination acted synergistically in prolonging mouse heart tissue allograft survival50.Morris R.E. Meiser B.M. Wu J. et al.Use of rapamycin for the suppression of alloimmune reactions in vivo: Schedule dependence, tolerance induction, synergy with cyclosporin and FK506 and effect on host-versus-graft and graft-versus-host reactions.Transplant Proc. 1991; 23: 521-524PubMed Google Scholar. However, in vitro studies contradicted these findings and discouraged investigators until relatively recently. In 1997, subtherapeutic doses of Rapa (0.02 to 0.04 mg/kg/day intravenously) and FK506 (0.01 to 0.04 mg/kg/day intramuscularly) in rat cardiac allografts not only prevented the development, but also reversed active acute rejection51.Vu M.D. Qi S. Dasheng X. et al.Tacrolimus and Sirolimus in combination are not antagonistic but produce extended graft survival in cardiac transplantation in the rat.Transplantation. 1997; 64: 1853-1856Crossref PubMed Scopus (104) Google Scholar. The therapeutic combination index used confirmed the efficacy of these agents with no evidence of the antagonism observed in vitro. Larger doses of oral Rapa (2 to 4 mg/kg/day) and intramuscular FK506 (2 to 4 mg/kg/day) demonstrated a similar extended survival in a mouse small bowel allograft model52.Chen H. Qi S. Xu D. et al.FK506 and Rapamycinin combination are not antagonistic but produce extended small bowel graft survival in the mouse.Transplant Proc. 1998; 30: 1039-1041Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar. The contradictory findings in vitro and in vivo are difficult to reconcile. However, only a small fraction of FKBP12 needs to be occupied by either Rapa or FK506 in order to achieve maximal immunosuppression53.De Paulis A. Cirillo R. Ciccarelli A. et al.FK506 a potent novel inhibitor of the release of proinflammatory mediators from human FceRI+ cells.J Immunol. 1991; 146: 2374PubMed Google Scholar. FKBP12 is abundant in vivo, and thus, competitive inhibition is unlikely to be a problem54.Sigal N.H. Dumont F.J. Cyclosporin A, FK506 and Rapamycin: Pharmacological probes of lymphocyte signal transduction.Annu Rev Immunol. 1992; 10: 519Crossref PubMed Scopus (637) Google Scholar. In vitro, on the other hand, it is limited, and the opposite applies. In addition, it is possible that these drugs have immunosuppressive mechanisms that are distinct from the FKBP12 complex55.Bierer B.E. Somers P.K. Wandless T.J. et al.Probing immunosuppressant action with nonnatural immun
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