Published online Sep 14, 2009. doi: 10.3748/wjg.15.4225
Revised: July 30, 2009
Accepted: August 6, 2009
Published online: September 14, 2009
Continued advances in surgical techniques and immunosuppressive therapy have allowed liver transplantation to become an extremely successful treatment option for patients with end-stage liver disease. Beginning with the revolutionary discovery of cyclosporine in the 1970s, immunosuppressive regimens have evolved greatly and current statistics confirm one-year graft survival rates in excess of 80%. Immunosuppressive regimens include calcineurin inhibitors, anti-metabolites, mTOR inhibitors, steroids and antibody-based therapies. These agents target different sites in the T cell activation cascade, usually by inhibiting T cell activation or via T cell depletion. They are used as induction therapy in the immediate peri- and post-operative period, as long-term maintenance medications to preserve graft function and as salvage therapy for acute rejection in liver transplant recipients. This review will focus on existing immunosuppressive agents for liver transplantation and consider newer medications on the horizon.
- Citation: Pillai AA, Levitsky J. Overview of immunosuppression in liver transplantation. World J Gastroenterol 2009; 15(34): 4225-4233
- URL: https://www.wjgnet.com/1007-9327/full/v15/i34/4225.htm
- DOI: https://dx.doi.org/10.3748/wjg.15.4225
Due to advances in immunosuppression and improvements in surgical techniques, liver transplantation has become an extremely successful treatment option for patients with end-stage liver disease, with one-year graft survival rates exceeding 80%[1]. Currently, there are eight patients worldwide who have survived more than three decades after liver transplantation[2].
Organ transplantation initially came to light with the first successful kidney transplantation in 1954 on monozygotic twins; however, immunosuppression was limited to total body irradiation which was largely fatal[3,4]. With the invention of 6-mercaptopurine (6-MP) and azathioprine (AZA) in the 1950s along with the introduction of corticosteroids as combination therapy by Starzl in the 1960s, there was noticeable improvement in kidney allograft survival, although one-year survival still did not exceed 50%[4]. Multiple interventions including splenectomy, thymectomy and thoracic duct drainage were employed with minimal success.
The first successful human liver transplant was performed by Thomas Starzl in Denver in 1967 on an 18-month-old child with unresectable hepatoblastoma[2]. The immunosuppressive regimen included anti-lymphocyte globulin (ALG), AZA and prednisolone and the child survived for more than a year.
However, the next significant breakthrough in immunosuppression did not occur until the discovery of cyclosporine (CYA) in 1972 from the soil fungus Tolypocladium inflatum. Borel et al[5] first described its remarkable immunosuppressive properties in 1976 and by the 1980s there was international affirmation of its effectiveness. CYA quickly became the standard of care for maintenance immunosuppression in solid organ transplant recipients. This paved the way for the current era of liver transplantation, which has since continued to evolve with the discovery of multiple novel immunosuppressive agents.
Effective immunosuppression in transplantation relies on preventing the immune system from rejecting the allograft while preserving immunologic control of infection and neoplasia. Although the mechanism is not completely understood, transplanted livers rarely reject compared to other organs, do not require an HLA-matched donor, and may offer a protective effect for other simultaneously transplanted organs[6,7]. Both micro- and macrochimerism models have been used to explain this phenomenon, as well as that of hepatic dissolution of donor specific antibodies. Ideally, the long-term objective is to achieve immune tolerance or the ability to alter the recipient’s immune system in order to promote long-term graft function without immunosuppressive therapy, while maintaining immunity to infectious agents[8]. Unfortunately, except for a small minority of patients (approximately 20%) who have been successfully weaned off immunosuppressive medications, most experience immunologic rejection with the discontinuation of these drugs and have to be maintained on at least low doses of these medications[9-13].
Immunosuppressive regimens include calcineurin inhibitors, anti-metabolites, mTOR inhibitors, steroids and antibody-based therapies. These agents target different sites in the T cell activation cascade, usually by inhibiting T cell activation or proliferation or via T cell depletion. The selection of agents is based on an individual’s medical history as well as on institution experience and preference. Most immunosuppressive regimens combine drugs with different sites of action of T cell response, allowing for dosage adjustments to minimize side effects and toxicities. Currently, the mainstay of maintenance immunosuppressive regimens are calcineurin inhibitors (CNIs), used in greater than 95% of transplant centers upon discharge, although there is a known increased risk of renal impairment[14,15], metabolic derangements, neurotoxicity and de novo malignancies[16] with the long-term use of these medications.
CYA and tacrolimus are the two CNIs approved for use in organ transplantation and are the principal immunosuppressives used for maintenance therapy. The routine use of these medications in liver transplant recipients has dramatically decreased the incidence of rejection and graft loss. The primary mode of action is inhibition of T cell activation. CYA binds to cyclophilin which results in inhibition of the calcium/calmodulin-dependent phosphatase, calcineurin. The binding to cyclophilin interferes with calcineurin’s de-phosphorylation of nuclear factor of activated T cells (NFAT), preventing translocation of NFAT into the nucleus and up-regulation of pro-inflammatory cytokines. The end result is the inhibition of IL-2 gene transcription and T cell activation and proliferation[4,8]. Tacrolimus also inhibits calcineurin but binds specifically to FK506-binding protein (FKBP-12).
The immunosuppressive effects of the CNIs are related to total drug exposure which can be estimated by measuring blood 12-h troughs. The potency of tacrolimus is estimated to be 100 times greater on a molar level[8] when compared to CYA. Although several earlier studies showed tacrolimus to be superior to CYA in the prevention of cellular rejection[17-19], another more recent multi-center trial showed no significant differences between the two medications with regard to acute rejection episodes, death or graft loss[20]. Both CNIs are metabolized principally by the cytochrome P450 system and therefore have significant interactions with multiple medications requiring careful monitoring of drug levels (Table 1).
| Drugs that increase CNI levels |
| Macrolides: clarithromycin, erythromycin, azithromycin |
| Antifungals: fluconazole, itraconazole, ketoconazole, voriconazole, clotrimazole |
| Calcium channel blockers: verapamil, diltiazem, nifedipine |
| Others: cisapride, metaclopramide, amiodarone, cimetidine, protease inhibitors |
| Drugs that decrease CNI and sirolimus levels |
| Antibiotics: rifabutin, rifampin |
| Anticonvulsants: carbamazepine, phenobarbital, phenytoin, fosphenytoin |
| Others: St. John’s Wort |
CNIs have a wide range of toxicities, many of which are dose-dependent (Table 2). Nephrotoxicity is a well-recognized side effect and it has been documented that nearly 20% of liver transplant recipients experience chronic renal failure within 5 years[15]. This can be best managed by either discontinuation or reduction of the medication. Neurotoxicity is another common problem; one which is more predominant with tacrolimus. The clinical presentation varies from headaches and tremors to agitation, confusion, hallucinations or overt psychosis. Hypertension, hyperlipidemia, hyperkalemia, metabolic acidosis and diabetes are also frequent side effects. Diabetes is more common with tacrolimus use, whereas hypertension and hyperlipidemia tend to be more prominent with CYA use. Gingival hyperplasia and hypertrichosis are specific side effects of CYA only.
| Drug | Adverse effects |
| Tacrolimus | Nephrotoxicity, neurotoxicity1, diabetes1, hyperkalemia, metabolic acidosis, hypertension, hyperlipidemia |
| Cyclosporine | Nephrotoxicity, neurotoxicity, diabetes, hyperlipidemia1, hypertension1, hyperkalemia, metabolic acidosis, gingival hyperplasia, hypertrichosis |
| MMF | Myelosuppression, gastrointestinal side effects, viral infections (CMV, HSV), spontaneous abortions in pregnant women |
| Sirolimus | Hyperlipidemia, myelosuppression, proteinuria, poor wound healing, pneumonitis, skin rash |
| Corticosteroids | Diabetes, hypertension, obesity, osteoporosis, avascular necrosis, growth retardation, Cushingoid features, psychosis, poor wound healing, adrenal suppression, cataracts |
Another important feature of CNIs is their interaction with transforming growth factor-β (TGF-β), a cytokine that augments fibrosis development and promotes tumor cell invasiveness[21]. TGF-β transcription is increased with CNI use, which is of concern given the possibility of hepatocellular carcinoma (HCC) recurrence or the emergence of post-transplant lymphoproliferative disorder (PTLD).
Both mycophenolate mofetil (MMF) and mycophenolate sodium (MPS) undergo immediate first-pass metabolism in the liver into the active compound mycophenolic acid (MPA), which was first discovered in 1893[22]. However, the immunosuppressive properties of MPA were not recognized until the 1990s. MPA inhibits inosine-5’-monophosphate dehydrogenase (IMPDH)[23], the rate-limiting enzyme in the de novo synthesis of guanosine nucleotides. Inhibition of the IMPDH pathway results in selective blockade of lymphocyte proliferation[24].
The major advantage in using the MPAs is their lack of renal toxicity. In patients with pre-existing renal disease, they have been used in conjunction with low-dose CNIs as part of a renal-sparing protocol with promising results[25,26]. Ideally, these medications should be initiated when renal dysfunction is first noted, although emerging data suggests the benefits of MPAs in reversing long-standing renal disease due to its association with decreased TGF-β levels[27-29]. MPAs are rarely used as monotherapy in transplant recipients given their higher rates of rejection compared to the CNIs[30,31], although more recent data demonstrate the safety of this approach when carried out carefully[32,33]. However, in patients previously on CNIs or mTOR inhibitors with evidence of acute rejection, MPAs are often added as supplemental immunosuppressive therapy.
The predominant side effects of MPAs are related to gastrointestinal disorders and bone marrow suppression (Table 2). Diarrhea is the most common dose-limiting adverse effect, although abdominal pain, nausea and vomiting can frequently occur[34]. Studies have also shown increased incidences of cytomegalovirus (CMV)[35-37], herpes simplex virus (HSV)[38,39], Candida infections, and, rarely, progressive multifocal leukoencephalopathy (PML)[40] with the use of MPAs. In pregnant patients, increased risks of spontaneous abortions during the first trimester and serious congenital malformations have also been reported (http://www.fda.gov). Routine monitoring of MPA levels is not generally employed in clinical practice.
Azathioprine is another antimetabolite which was predominantly used for the prevention of rejection in the 1960s but has since been largely replaced by the MPAs. It is selectively used in a few centers in combination with other immunosuppressive medications, primarily CNIs and steroids.
The two mTOR inhibitors approved for organ transplantation are sirolimus (SRL) and everolimus (EVL), although neither has been approved for use in liver transplantation to date. They bind intracellularly to FK506 binding protein (FKBP12) but unlike tacrolimus, they do not inhibit calcineurin activity. Rather, the complex is a highly specific inhibitor of mammalian target of rapamycin complex 1 (mTORC1)[41] which has a direct effect on the cell signaling pathway required for cell cycle progression. This subsequently inhibits IL-2 signaling to T cells, thus preventing T cell proliferation. Similar to the CNIs, sirolimus is metabolized by the cytochrome P450 system and requires therapeutic drug monitoring (Table 1).
The first reported study illustrating the effectiveness of sirolimus monotherapy for maintenance of immunosuppression in liver transplantation was in 1999 by Watson et al[42]. However, two subsequent large studies examining sirolimus de novo therapy with tacrolimus and corticosteroids were terminated early due to excess hepatic artery thrombosis (HAT). As a result, sirolimus carries a black box label warning which cautions against the possible development of early post-transplant HAT. Subsequent studies have since disputed this finding[43-45]; however, mTOR inhibitors are rarely used as de novo therapy.
Importantly, in patients with CNI-induced nephrotoxicity, conversion to sirolimus therapy has proved to be effective with ensuing improvements in renal function[46-48]. Again, sirolimus conversion should be initiated early since late conversion rarely improves chronic renal dysfunction[49]. In fact, several studies have shown that in patients with pre-existing renal disease, sirolimus can worsen nephrotoxicity and promote proteinuria[50-52].
Recent studies have also shown potential anti-tumor properties of sirolimus[53-56] which might be of importance in patients undergoing liver transplantation for HCC. Zimmerman et al[57] examined the role of sirolimus-based maintenance therapy in post-transplant recipients with a history of HCC and found that overall survival was increased in the sirolimus arm compared to the CNI arm. Clinical trials examining the anti-cancer effects of mTOR inhibitors in liver transplant recipients with HCC have been encouraging[44,58] and new trials are ongoing.
Metabolic side effects of mTOR inhibitors include proteinuria and increases in serum cholesterol and triglycerides (Table 2). Bone marrow suppression, interstitial pneumonitis, peripheral edema, dermatological effects (acne, mouth ulcers) and delayed wound healing are all well-documented. Inhibition of fibroblast growth factor by sirolimus impairs tissue repair and plays a role in delayed wound healing[59]. Interstitial pneumonitis is rarely life-threatening, is dose-dependent and resolves on withdrawal of the drug[60].
Corticosteroids are well-known for their anti-inflammatory properties such as suppression of prostaglandin synthesis, stabilization of lysosomal membranes and reduction of histamine and bradykinin release[30,31]. They also exhibit various immunomodulatory effects including effects on antigen presentation by dendritic cells and induction of a decrease in the number of circulating CD4+ T cells, IL-1 transcription and IL-1-dependent lymphocyte activation[4,8].
High-dose corticosteroids were used judiciously in the 1960s in post-transplant recipients, with resulting increased morbidity due to their well-known deleterious side effects. This led to several studies in the 1980s on renal transplant recipients which confirmed that graft and patient survivals, as well as rejection episodes, were similar in the high- and low-dose steroid groups as long as AZA was also used[61-63]. Currently, intravenous corticosteroids are predominantly used as first-line therapy for the treatment of acute cellular rejection. Regarding maintenance therapy, they are often successfully withdrawn within 3-6 mo post-transplantation in patients without evidence of rejection or liver disease attributed to autoimmune disorders[64]. The primary concern with corticosteroid use is exacerbation of hepatitis C virus (HCV) recurrence and liver fibrosis with high-dose pulsed therapy[65]; however, this has not been evident with low, gradually tapered doses[66,67].
Well-documented side effects of corticosteroids include diabetes, hypertension, central obesity, Cushingoid features, osteoporosis, avascular necrosis, psychosis, poor wound healing, adrenal suppression and cataracts (Table 2).
Polyclonal antibodies, including anti-thymocyte (ATG) and anti-lymphocyte globulins (ALG), have been used since the early days of liver transplantation and are prepared by inoculating rabbits or horses with human lymphocytes or thymocytes[4]. Their mechanism of action is rapid lymphocyte depletion due to complement-mediated cell lysis and uptake by the reticulo-endothelial system (RES) of opsonized T cells[68]. In addition, they may also cause partial T cell activation and blockade of T cell proliferation[69]. Polyclonal antibodies were routinely used as induction therapy in liver transplantation along with corticosteroids and AZA before the discovery of CYA.
Lymphocyte depletion is believed to play a role in preparing the recipient’s immune system to adapt and recognize the transplanted organ as self and prevent destruction of the allograft. Accordingly, studies have shown that ATG administration results in regulatory T cell (Treg) expansion in vitro and in vivo[70-72]. Tregs or suppressor T cells are responsible for preventing activation of the immune system and maintaining tolerance to self-antigens.
Currently, approximately 20% of transplant centers use these agents for induction purposes[73] and recent data support the administration of thymoglobulin induction to delay CNI use and avoid renal toxicity without increasing the risk of rejection or HCV recurrence[74-76]. A few studies have also successfully shown the benefit of using these medications as induction therapy to avoid post-transplant corticosteroid use[77,78] without an increased incidence of acute rejection. This is especially important in HCV recipients where high-dose pulsed corticosteroid therapy can significantly accelerate liver fibrosis. At present, anti-lymphocyte antibodies are used extensively to treat steroid-resistant acute rejection and are successful in 70%-96% of patients[79-81].
The main side effect of these medications, affecting 80% of patients, is a “first-dose reaction” and febrile episode which can often be ameliorated by pre-medication with antipyretics, antihistamines and intravenous steroids. This effect is likely due to pyrogen release from the massive destruction of lymphocytes[69,82]. Other adverse effects include thrombocytopenia, anemia, CMV infection, PTLD, pruritic skin rashes, serum sickness and anaphylaxis[83-85].
Monoclonal antibodies include the anti-IL-2 receptor (CD25) antibodies, anti-CD52 antibody and muromonab-CD3 (OKT3). The two anti-IL-2 receptor antibodies approved for clinical use are basiliximab (Simulect), a chimeric protein, and daclizumab (Zenapax), a humanized protein. Both antibodies are specific for the α chain of the IL-2 receptor, CD25, which is only expressed on activated T cells[8]. These antibodies remain in the circulatory system for weeks after initiation of therapy and have been used successfully with low-dose CNIs in preventing acute rejection in the early post-transplant period[86-88]. They also have fewer side effects compared to the anti-lymphocyte globulins, rarely cause the typical first-dose infusion reactions and are associated with less risk of opportunistic infections and PTLD.
Muromonab-CD3 (OKT3) targets the CD3 molecule on T cells and causes depletion of lymphocytes by massive T cell lysis[89] and cytokine release[90]. This profound cytokine release can lead to pulmonary edema and acute respiratory distress and rarely, intra-graft thrombosis and aseptic meningitis[91,92]. As a result, antihistamines and intravenous steroids are routinely used as pre-medication to reduce this “cytokine release syndrome”. Several days after OKT3 administration, T lymphocytes no longer express CD3 and are considered to be immunologically incompetent[93]. OKT3 is primarily used in liver transplantation for steroid-resistant acute rejection[94,95] and has a success rate of complete recovery in 50% of patients. OKT3 use should be limited in the HCV population as several studies have confirmed exacerbation of disease recurrence with this agent[96,97].
The humanized anti-CD52 antibody, alemtuzumab (Campath-1) targets lymphocytes, monocytes, macrophages, natural killer cells and thymocytes but spares plasma cells and memory lymphocytes[8,98]. It is unique in that it depletes lymphocytes from the circulation as well as peripheral lymph nodes. Several studies in renal transplant patients have shown its efficacy in preventing rejection when used in combination with low-dose CNIs or sirolimus[99-101]. Tzakis et al[102] compared the use of alemtuzumab induction therapy combined with low-dose tacrolimus in liver transplant recipients receiving standard doses of tacrolimus and corticosteroids. Although patients who received alemtuzumab had less renal dysfunction and acute rejection in the first two months post-transplant, the overall incidence of rejection was not significantly different between the two groups. Similarly, Marcos et al[103] proposed that alemtuzumab, in conjunction with minimal CNI use, is a successful treatment strategy in liver transplant recipients, improving overall graft and patient survival, especially in HCV-infected subjects.
Belatacept is a soluble cytotoxic T-lymphocyte antigen-4 (CTLA-4) agent which binds CD80 and CD86 and inhibits T cell activation[4,8]. Belatacept competes with the CD28 receptor on T cells which normally binds CD80 and CD86 on the antigen presenting cell (APC) as a co-stimulatory signal required for T cell activation. Belatacept is administered intravenously once a month and does not carry the renal toxicity of CNIs. Clinical trials in liver transplant patients are currently ongoing with this agent.
Efalizumab is a humanized leukocyte function-associated antigen-1 (LFA-1; CD11a) specific monoclonal antibody that inhibits T cell-APC stabilization and blocks lymphocyte adhesion to endothelial cells[104,105]. This agent was approved for the treatment of psoriasis in 2003 and has not yet been used in liver transplantation, although a few clinical trials have been carried out in renal transplant patients with mixed results[106]. Although the results regarding immunosuppression were promising, an increased risk for PTLD was shown when efalizumab was used in combination with high-dose CYA.
Other newer agents on the horizon undergoing phase II/III trials include Janus Kinase (JAK) 3 inhibitors, AEB071 (a protein kinase C (PKC) isoforms inhibitor), and Alefacept (a LFA3-IgG1 fusion receptor protein). JAKs are intermediaries between cytokine receptors and signal transducers and activators of transcription (STATs) which lead to immune cell activation[107,108]. JAK-3, a cytoplasmic tyrosine kinase, is primarily found on hematopoetic cells and its stimulation is specific for the IL-2 family of cytokines which makes it a very attractive target for immunosuppression. Clinical trials are underway in renal transplant patients using these agents. AEB071 (PKC inhibitor) is an oral agent that blocks early T cell activation and IL-2 production[109]. Three phase II renal transplant trials using AEB were started, two of which had to be stopped due to increased episodes of acute rejection; the third trial is ongoing in Europe[110]. Alefacept, a LFA3-IgG1 fusion receptor protein initially approved for the treatment of psoriasis, interferes with T-cell activation and produces a dose-dependent reduction in T-effector memory cells[111]. A multi-center clinical trial in renal transplant recipients is currently underway.
The current era of immunosuppressive therapy continues to evolve with the discovery of novel agents, targeting different sites of the immune cascade. Important objectives when using these medications include decreasing the incidence of renal toxicity from CNIs while preserving graft function as well as optimizing immunosuppression without creating an environment for increased infections, aggressive recurrence of hepatitis C or triggering PTLD and other malignancies.
At our institution, high-dose intravenous corticosteroids are used in the immediate peri- and post-operative period and then tapered accordingly. In patients without renal dysfunction post-transplantation, CNIs are the mainstay of therapy with the long-term goal of low levels of immunosuppression and minimization of medication. In patients with renal insufficiency, we have had success with a combination of low-dose CNI therapy and MPAs or a switch to mTOR inhibitors to preserve graft function and prevent further renal deterioration. We typically avoid the switch to mTOR inhibitors within the first 3-6 mo post-transplantation given the risk of hepatic artery thrombosis, rejection, and wound healing. Patients are weaned off corticosteroids within 6 mo to 1 year, providing they do not have evidence of autoimmune disease or recurrent episodes of rejection.
As evidenced by prior studies, the recommended approach to the patient with HCV infection is gradual, cautious weaning of corticosteroids within the first 3-6 mo while continuing low levels of maintenance immunosuppression, typically with CNIs. While HCV recurrence is universal after liver transplantation, avoiding excessive and erratic changes in the immunosuppressive regimen should prevent clinically aggressive disease.
The ultimate goal remains the ability to induce tolerance in transplant recipients. While this is not a current available practice, data from selected patients demonstrate that it may become a viable option with advances in future research and improved understanding of the genetic make-up and predisposition of this population. Until then, finding the balance between preserving graft function and optimizing immunosuppression while minimizing toxicities remains a challenge.
Peer reviewer: Satoshi Yamagiwa, MD, PhD, Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, 757 Asahimachi-dori, Chuo-ku, Niigata 951-8510, Japan
S- Editor Tian L L- Editor Logan S E- Editor Ma WH
| 1. | Waki K. UNOS Liver Registry: ten year survivals. Clin Transpl. 2006;29-39. [Cited in This Article: ] |
| 2. | Groth CG. Forty years of liver transplantation: personal recollections. Transplant Proc. 2008;40:1127-1129. [Cited in This Article: ] |
| 3. | Murray G, Holden R. Transplantation of kidneys, experimentally and in human cases. Am J Surg. 1954;87:508-515. [Cited in This Article: ] |
| 4. | Taylor AL, Watson CJ, Bradley JA. Immunosuppressive agents in solid organ transplantation: Mechanisms of action and therapeutic efficacy. Crit Rev Oncol Hematol. 2005;56:23-46. [Cited in This Article: ] |
| 5. | Borel JF, Feurer C, Gubler HU, Stahelin H. Biological effects of cyclosporin A: a new antilymphocytic agent. Agents Actions. 1976;6:468-475. [Cited in This Article: ] |
| 6. | Kotru A, Sheperd R, Nadler M, Chapman W, Huddleston C, Lowell J. Combined lung and liver transplantation: the United States experience. Transplantation. 2006;82:144-145; author reply 145. [Cited in This Article: ] |
| 7. | Rasmussen A, Davies HF, Jamieson NV, Evans DB, Calne RY. Combined transplantation of liver and kidney from the same donor protects the kidney from rejection and improves kidney graft survival. Transplantation. 1995;59:919-921. [Cited in This Article: ] |
| 8. | Geissler EK, Schlitt HJ. Immunosuppression for liver transplantation. Gut. 2009;58:452-463. [Cited in This Article: ] |
| 9. | Tisone G, Orlando G, Angelico M. Operational tolerance in clinical liver transplantation: emerging developments. Transpl Immunol. 2007;17:108-113. [Cited in This Article: ] |
| 10. | Mazariegos GV, Reyes J, Marino IR, Demetris AJ, Flynn B, Irish W, McMichael J, Fung JJ, Starzl TE. Weaning of immunosuppression in liver transplant recipients. Transplantation. 1997;63:243-249. [Cited in This Article: ] |
| 11. | Girlanda R, Rela M, Williams R, O’Grady JG, Heaton ND. Long-term outcome of immunosuppression withdrawal after liver transplantation. Transplant Proc. 2005;37:1708-1709. [Cited in This Article: ] |
| 12. | Takatsuki M, Uemoto S, Inomata Y, Egawa H, Kiuchi T, Fujita S, Hayashi M, Kanematsu T, Tanaka K. Weaning of immunosuppression in living donor liver transplant recipients. Transplantation. 2001;72:449-454. [Cited in This Article: ] |
| 13. | Eason JD, Cohen AJ, Nair S, Alcantera T, Loss GE. Tolerance: is it worth the risk? Transplantation. 2005;79:1157-1159. [Cited in This Article: ] |
| 14. | Gonwa TA, Mai ML, Melton LB, Hays SR, Goldstein RM, Levy MF, Klintmalm GB. End-stage renal disease (ESRD) after orthotopic liver transplantation (OLTX) using calcineurin-based immunotherapy: risk of development and treatment. Transplantation. 2001;72:1934-1939. [Cited in This Article: ] |
| 15. | Ojo AO, Held PJ, Port FK, Wolfe RA, Leichtman AB, Young EW, Arndorfer J, Christensen L, Merion RM. Chronic renal failure after transplantation of a nonrenal organ. N Engl J Med. 2003;349:931-940. [Cited in This Article: ] |
| 16. | Jain A, Marcos A, Reyes J, Mazariagos G, Kashyap R, Eghtesad B, Marsh W, Fontas P, De Vera M, Costa G. Tacrolimus for primary liver transplantation: 12 to 15 years actual follow-up with safety profile. Transplant Proc. 2005;37:1207-1210. [Cited in This Article: ] |
| 17. | Pichlmayr R, Winkler M, Neuhaus P, McMaster P, Calne R, Otto G, Williams R, Groth CG, Bismuth H. Three-year follow-up of the European Multicenter Tacrolimus (FK506) Liver Study. Transplant Proc. 1997;29:2499-2502. [Cited in This Article: ] |
| 18. | Wiesner RH. A long-term comparison of tacrolimus (FK506) versus cyclosporine in liver transplantation: a report of the United States FK506 Study Group. Transplantation. 1998;66:493-499. [Cited in This Article: ] |
| 19. | O’Grady JG, Burroughs A, Hardy P, Elbourne D, Truesdale A. Tacrolimus versus microemulsified ciclosporin in liver transplantation: the TMC randomised controlled trial. Lancet. 2002;360:1119-1125. [Cited in This Article: ] |
| 20. | Levy G, Villamil F, Samuel D, Sanjuan F, Grazi GL, Wu Y, Marotta P, Boillot O, Muehlbacher F, Klintmalm G. Results of lis2t, a multicenter, randomized study comparing cyclosporine microemulsion with C2 monitoring and tacrolimus with C0 monitoring in de novo liver transplantation. Transplantation. 2004;77:1632-1638. [Cited in This Article: ] |
| 21. | Hojo M, Morimoto T, Maluccio M, Asano T, Morimoto K, Lagman M, Shimbo T, Suthanthiran M. Cyclosporine induces cancer progression by a cell-autonomous mechanism. Nature. 1999;397:530-534. [Cited in This Article: ] |
| 22. | Gosio B. Sperimentate su culture pure di bacilli del carbonchio demonstrarano notevole potere antisettica. C R Acad Med Torino. 1893;61:484. [Cited in This Article: ] |
| 23. | Franklin TJ, Cook JM. The inhibition of nucleic acid synthesis by mycophenolic acid. Biochem J. 1969;113:515-524. [Cited in This Article: ] |
| 24. | Allison AC, Eugui EM. Purine metabolism and immunosuppressive effects of mycophenolate mofetil (MMF). Clin Transplant. 1996;10:77-84. [Cited in This Article: ] |
| 25. | Fisher RA, Ham JM, Marcos A, Shiffman ML, Luketic VA, Kimball PM, Sanyal AJ, Wolfe L, Chodorov A, Posner MP. A prospective randomized trial of mycophenolate mofetil with neoral or tacrolimus after orthotopic liver transplantation. Transplantation. 1998;66:1616-1621. [Cited in This Article: ] |
| 26. | Barkmann A, Nashan B, Schmidt HH, Boker KH, Emmanouilidis N, Rosenau J, Bahr MJ, Hoffmann MW, Manns MP, Klempnauer J. Improvement of acute and chronic renal dysfunction in liver transplant patients after substitution of calcineurin inhibitors by mycophenolate mofetil. Transplantation. 2000;69:1886-1890. [Cited in This Article: ] |
| 27. | Gao R, Lu Y, Xin YP, Zhang XH, Wang J, Li YP. The effects of different immunosuppressants on chronic allograft nephropathy by affecting the transforming growth factor-beta and Smads signal pathways. Transplant Proc. 2006;38:2154-2157. [Cited in This Article: ] |
| 28. | Shihab FS, Bennett WM, Yi H, Choi SO, Andoh TF. Combination therapy with sirolimus and mycophenolate mofetil: effects on the kidney and on transforming growth factor-beta1. Transplantation. 2004;77:683-686. [Cited in This Article: ] |
| 29. | Shihab FS, Bennett WM, Yi H, Choi SO, Andoh TF. Mycophenolate mofetil ameliorates arteriolopathy and decreases transforming growth factor-beta1 in chronic cyclosporine nephrotoxicity. Am J Transplant. 2003;3:1550-1559. [Cited in This Article: ] |
| 30. | Schlitt HJ, Barkmann A, Boker KH, Schmidt HH, Emmanouilidis N, Rosenau J, Bahr MJ, Tusch G, Manns MP, Nashan B. Replacement of calcineurin inhibitors with mycophenolate mofetil in liver-transplant patients with renal dysfunction: a randomised controlled study. Lancet. 2001;357:587-591. [Cited in This Article: ] |
| 31. | Stewart SF, Hudson M, Talbot D, Manas D, Day CP. Mycophenolate mofetil monotherapy in liver transplantation. Lancet. 2001;357:609-610. [Cited in This Article: ] |
| 32. | Dharancy S, Iannelli A, Hulin A, Declerck N, Schneck AS, Mathurin P, Boleslawski E, Gugenheim J, Pruvot FR. Mycophenolate mofetil monotherapy for severe side effects of calcineurin inhibitors following liver transplantation. Am J Transplant. 2009;9:610-613. [Cited in This Article: ] |
| 33. | Barrera Pulido L, Alamo Martinez JM, Pareja Ciuro F, Gomez Bravo MA, Serrano Diez-Canedo J, Bernal Bellido C, Suarez Artacho G, Garcia Gonzalez I, Pascasio Acevedo JM, Bernardos Rodriguez A. Efficacy and safety of mycophenolate mofetil monotherapy in liver transplant patients with renal failure induced by calcineurin inhibitors. Transplant Proc. 2008;40:2985-2987. [Cited in This Article: ] |
| 34. | Sollinger HW. Mycophenolates in transplantation. Clin Transplant. 2004;18:485-492. [Cited in This Article: ] |
| 35. | Boucher A, Lord H, Collette S, Morin M, Dandavino R. Cytomegalovirus infection in kidney transplant recipients: Evolution of approach through three eras. Transplant Proc. 2006;38:3506-3508. [Cited in This Article: ] |
| 36. | Jorge S, Guerra J, Santana A, Mil-Homens C, Prata MM. Mycophenolate mofetil: ten years’ experience of a renal transplant unit. Transplant Proc. 2008;40:700-704. [Cited in This Article: ] |
| 37. | Sarmiento JM, Dockrell DH, Schwab TR, Munn SR, Paya CV. Mycophenolate mofetil increases cytomegalovirus invasive organ disease in renal transplant patients. Clin Transplant. 2000;14:136-138. [Cited in This Article: ] |
| 38. | Smak Gregoor PJ, van Gelder T, van Riemsdijk-van Overbeeke IC, Vossen AC, IJzermans JN, Weimar W. Unusual presentation of herpes virus infections in renal transplant recipients exposed to high mycophenolic acid plasma concentrations. Transpl Infect Dis. 2003;5:79-83. [Cited in This Article: ] |
| 39. | Herrero JI, Quiroga J, Sangro B, Pardo F, Rotellar F, Alvarez-Cienfuegos J, Prieto J. Herpes zoster after liver transplantation: incidence, risk factors, and complications. Liver Transpl. 2004;10:1140-1143. [Cited in This Article: ] |
| 40. | Neff RT, Hurst FP, Falta EM, Bohen EM, Lentine KL, Dharnidharka VR, Agodoa LY, Jindal RM, Yuan CM, Abbott KC. Progressive multifocal leukoencephalopathy and use of mycophenolate mofetil after kidney transplantation. Transplantation. 2008;86:1474-1478. [Cited in This Article: ] |
| 41. | Mita MM, Mita A, Rowinsky EK. The molecular target of rapamycin (mTOR) as a therapeutic target against cancer. Cancer Biol Ther. 2003;2:S169-S177. [Cited in This Article: ] |
| 42. | Watson CJ, Friend PJ, Jamieson NV, Frick TW, Alexander G, Gimson AE, Calne R. Sirolimus: a potent new immunosuppressant for liver transplantation. Transplantation. 1999;67:505-509. [Cited in This Article: ] |
| 43. | Dunkelberg JC, Trotter JF, Wachs M, Bak T, Kugelmas M, Steinberg T, Everson GT, Kam I. Sirolimus as primary immunosuppression in liver transplantation is not associated with hepatic artery or wound complications. Liver Transpl. 2003;9:463-468. [Cited in This Article: ] |
| 44. | Kneteman NM, Oberholzer J, Al Saghier M, Meeberg GA, Blitz M, Ma MM, Wong WW, Gutfreund K, Mason AL, Jewell LD. Sirolimus-based immunosuppression for liver transplantation in the presence of extended criteria for hepatocellular carcinoma. Liver Transpl. 2004;10:1301-1311. [Cited in This Article: ] |
| 45. | McAlister VC, Peltekian KM, Malatjalian DA, Colohan S, MacDonald S, Bitter-Suermann H, MacDonald AS. Orthotopic liver transplantation using low-dose tacrolimus and sirolimus. Liver Transpl. 2001;7:701-708. [Cited in This Article: ] |
| 46. | Kniepeiss D, Iberer F, Grasser B, Schaffellner S, Tscheliessnigg KH. Sirolimus and mycophenolate mofetil after liver transplantation. Transpl Int. 2003;16:504-509. [Cited in This Article: ] |
| 47. | Fairbanks KD, Eustace JA, Fine D, Thuluvath PJ. Renal function improves in liver transplant recipients when switched from a calcineurin inhibitor to sirolimus. Liver Transpl. 2003;9:1079-1085. [Cited in This Article: ] |
| 48. | Nair S, Eason J, Loss G. Sirolimus monotherapy in nephrotoxicity due to calcineurin inhibitors in liver transplant recipients. Liver Transpl. 2003;9:126-129. [Cited in This Article: ] |
| 49. | Lam P, Yoshida A, Brown K, Abouljoud M, Bajjoka I, Dagher F, Moonka DK. The efficacy and limitations of sirolimus conversion in liver transplant patients who develop renal dysfunction on calcineurin inhibitors. Dig Dis Sci. 2004;49:1029-1035. [Cited in This Article: ] |
| 50. | Bumbea V, Kamar N, Ribes D, Esposito L, Modesto A, Guitard J, Nasou G, Durand D, Rostaing L. Long-term results in renal transplant patients with allograft dysfunction after switching from calcineurin inhibitors to sirolimus. Nephrol Dial Transplant. 2005;20:2517-2523. [Cited in This Article: ] |
| 51. | Diekmann F, Gutierrez-Dalmau A, Lopez S, Cofan F, Esforzado N, Ricart MJ, Rossich E, Saval N, Torregrosa JV, Oppenheimer F. Influence of sirolimus on proteinuria in de novo kidney transplantation with expanded criteria donors: comparison of two CNI-free protocols. Nephrol Dial Transplant. 2007;22:2316-2321. [Cited in This Article: ] |
| 52. | Letavernier E, Pe’raldi MN, Pariente A, Morelon E, Legendre C. Proteinuria following a switch from calcineurin inhibitors to sirolimus. Transplantation. 2005;80:1198-1203. [Cited in This Article: ] |
| 53. | Koehl GE, Andrassy J, Guba M, Richter S, Kroemer A, Scherer MN, Steinbauer M, Graeb C, Schlitt HJ, Jauch KW. Rapamycin protects allografts from rejection while simultaneously attacking tumors in immunosuppressed mice. Transplantation. 2004;77:1319-1326. [Cited in This Article: ] |
| 54. | Guba M, von Breitenbuch P, Steinbauer M, Koehl G, Flegel S, Hornung M, Bruns CJ, Zuelke C, Farkas S, Anthuber M. Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor. Nat Med. 2002;8:128-135. [Cited in This Article: ] |
| 55. | Guertin DA, Sabatini DM. Defining the role of mTOR in cancer. Cancer Cell. 2007;12:9-22. [Cited in This Article: ] |
| 56. | Luan FL, Hojo M, Maluccio M, Yamaji K, Suthanthiran M. Rapamycin blocks tumor progression: unlinking immunosuppression from antitumor efficacy. Transplantation. 2002;73:1565-1572. [Cited in This Article: ] |
| 57. | Zimmerman MA, Trotter JF, Wachs M, Bak T, Campsen J, Skibba A, Kam I. Sirolimus-based immunosuppression following liver transplantation for hepatocellular carcinoma. Liver Transpl. 2008;14:633-638. [Cited in This Article: ] |
| 58. | Toso C, Meeberg GA, Bigam DL, Oberholzer J, Shapiro AM, Gutfreund K, Ma MM, Mason AL, Wong WW, Bain VG. De novo sirolimus-based immunosuppression after liver transplantation for hepatocellular carcinoma: long-term outcomes and side effects. Transplantation. 2007;83:1162-1168. [Cited in This Article: ] |
| 59. | Dean PG, Lund WJ, Larson TS, Prieto M, Nyberg SL, Ishitani MB, Kremers WK, Stegall MD. Wound-healing complications after kidney transplantation: a prospective, randomized comparison of sirolimus and tacrolimus. Transplantation. 2004;77:1555-1561. [Cited in This Article: ] |
| 60. | Haydar AA, Denton M, West A, Rees J, Goldsmith DJ. Sirolimus-induced pneumonitis: three cases and a review of the literature. Am J Transplant. 2004;4:137-139. [Cited in This Article: ] |
| 61. | Morris PJ, Chan L, French ME, Ting A. Low dose oral prednisolone in renal transplantation. Lancet. 1982;1:525-527. [Cited in This Article: ] |
| 62. | Papadakis J, Brown CB, Cameron JS, Adu D, Bewick M, Donaghey R, Ogg CS, Rudge C, Williams DG, Taube D. High versus “low” dose corticosteroids in recipients of cadaveric kidneys: prospective controlled trial. Br Med J (Clin Res Ed). 1983;286:1097-1100. [Cited in This Article: ] |
| 63. | d’Apice AJ, Becker GJ, Kincaid-Smith P, Mathew TH, Ng J, Hardie IR, Petrie JJ, Rigby RJ, Dawborn J, Heale WF. A prospective randomized trial of low-dose versus high-dose steroids in cadaveric renal transplantation. Transplantation. 1984;37:373-377. [Cited in This Article: ] |
| 64. | Greig P, Lilly L, Scudamore C, Erb S, Yoshida E, Kneteman N, Bain V, Ghent C, Marotta P, Grant D. Early steroid withdrawal after liver transplantation: the Canadian tacrolimus versus microemulsion cyclosporin A trial: 1-year follow-up. Liver Transpl. 2003;9:587-595. [Cited in This Article: ] |
| 65. | Henry SD, Metselaar HJ, Van Dijck J, Tilanus HW, Van Der Laan LJ. Impact of steroids on hepatitis C virus replication in vivo and in vitro. Ann N Y Acad Sci. 2007;1110:439-447. [Cited in This Article: ] |
| 66. | Vivarelli M, Burra P, La Barba G, Canova D, Senzolo M, Cucchetti A, D’Errico A, Guido M, Merenda R, Neri D. Influence of steroids on HCV recurrence after liver transplantation: A prospective study. J Hepatol. 2007;47:793-798. [Cited in This Article: ] |
| 67. | Berenguer M, Aguilera V, Prieto M, San Juan F, Rayon JM, Benlloch S, Berenguer J. Significant improvement in the outcome of HCV-infected transplant recipients by avoiding rapid steroid tapering and potent induction immunosuppression. J Hepatol. 2006;44:717-722. [Cited in This Article: ] |
| 68. | Taniguchi Y, Frickhofen N, Raghavachar A, Digel W, Heimpel H. Antilymphocyte immunoglobulins stimulate peripheral blood lymphocytes to proliferate and release lymphokines. Eur J Haematol. 1990;44:244-251. [Cited in This Article: ] |
| 69. | Oettinger CW, D’Souza M, Milton GV. In vitro comparison of cytokine release from antithymocyte serum and OKT3. Inhibition with soluble and microencapsulated neutralizing antibodies. Transplantation. 1996;62:1690-1693. [Cited in This Article: ] |
| 70. | Feng X, Kajigaya S, Solomou EE, Keyvanfar K, Xu X, Raghavachari N, Munson PJ, Herndon TM, Chen J, Young NS. Rabbit ATG but not horse ATG promotes expansion of functional CD4+CD25highFOXP3+ regulatory T cells in vitro. Blood. 2008;111:3675-3683. [Cited in This Article: ] |
| 71. | Lopez M, Clarkson MR, Albin M, Sayegh MH, Najafian N. A novel mechanism of action for anti-thymocyte globulin: induction of CD4+CD25+Foxp3+ regulatory T cells. J Am Soc Nephrol. 2006;17:2844-2853. [Cited in This Article: ] |
| 72. | Lytton SD, Denton CP, Nutzenberger AM. Treatment of autoimmune disease with rabbit anti-T lymphocyte globulin: clinical efficacy and potential mechanisms of action. Ann N Y Acad Sci. 2007;1110:285-296. [Cited in This Article: ] |
| 73. | 2003 Organ Procurement and Transplantation Network/Scientific Registry of Transplant Recipients Annual Report: Transplant Data 1993-2002. US Department of Health and Human Services, Health Resources and Services Administration, Special Programs Bureau, Division of Transplantation; United Network of Organ Sharing; University Renal Research Education Association (Table 9.6). Available from: URL: http://www.ustransplant.org/cgi-bin/ar?p=data_tables_10.htm&y=2003. [Cited in This Article: ] |
| 74. | Soliman T, Hetz H, Burghuber C, Gyori G, Silberhumer G, Steininger R, Muhlbacher F, Berlakovich GA. Short-term induction therapy with anti-thymocyte globulin and delayed use of calcineurin inhibitors in orthotopic liver transplantation. Liver Transpl. 2007;13:1039-1044. [Cited in This Article: ] |
| 75. | Tector AJ, Fridell JA, Mangus RS, Shah A, Milgrom M, Kwo P, Chalasani N, Yoo H, Rouch D, Liangpunsakul S. Promising early results with immunosuppression using rabbit anti-thymocyte globulin and steroids with delayed introduction of tacrolimus in adult liver transplant recipients. Liver Transpl. 2004;10:404-407. [Cited in This Article: ] |
| 76. | De Ruvo N, Cucchetti A, Lauro A, Masetti M, Cautero N, Di Benedetto F, Dazzi A, Del Gaudio M, Ravaioli M, Zanello M. Preliminary results of immunosuppression with thymoglobuline pretreatment and hepatitis C virus recurrence in liver transplantation. Transplant Proc. 2005;37:2607-2608. [Cited in This Article: ] |
| 77. | Eason JD, Loss GE, Blazek J, Nair S, Mason AL. Steroid-free liver transplantation using rabbit antithymocyte globulin induction: results of a prospective randomized trial. Liver Transpl. 2001;7:693-697. [Cited in This Article: ] |
| 78. | Eason JD, Nair S, Cohen AJ, Blazek JL, Loss GE Jr. Steroid-free liver transplantation using rabbit antithymocyte globulin and early tacrolimus monotherapy. Transplantation. 2003;75:1396-1399. [Cited in This Article: ] |
| 79. | Matas AJ, Tellis VA, Quinn T, Glichlick D, Soberman R, Weiss R, Karwa G, Veith FJ. ALG treatment of steroid-resistant rejection in patients receiving cyclosporine. Transplantation. 1986;41:579-583. [Cited in This Article: ] |
| 80. | Midtvedt K, Fauchald P, Lien B, Hartmann A, Albrechtsen D, Bjerkely BL, Leivestad T, Brekke IB. Individualized T cell monitored administration of ATG versus OKT3 in steroid-resistant kidney graft rejection. Clin Transplant. 2003;17:69-74. [Cited in This Article: ] |
| 81. | Richardson AJ, Higgins RM, Liddington M, Murie J, Ting A, Morris PJ. Antithymocyte globulin for steroid resistant rejection in renal transplant recipients immunosuppressed with triple therapy. Transpl Int. 1989;2:27-32. [Cited in This Article: ] |
| 82. | Guttmann RD, Caudrelier P, Alberici G, Touraine JL. Pharmacokinetics, foreign protein immune response, cytokine release, and lymphocyte subsets in patients receiving thymoglobuline and immunosuppression. Transplant Proc. 1997;29:24S-26S. [Cited in This Article: ] |
| 83. | Buchler M, Hurault de Ligny B, Madec C, Lebranchu Y. Induction therapy by anti-thymocyte globulin (rabbit) in renal transplantation: a 1-yr follow-up of safety and efficacy. Clin Transplant. 2003;17:539-545. [Cited in This Article: ] |
| 84. | Ducloux D, Kazory A, Challier B, Coutet J, Bresson-Vautrin C, Motte G, Thalamy B, Rebibou JM, Chalopin JM. Long-term toxicity of antithymocyte globulin induction may vary with choice of agent: a single-center retrospective study. Transplantation. 2004;77:1029-1033. [Cited in This Article: ] |
| 85. | Lundquist AL, Chari RS, Wood JH, Miller GG, Schaefer HM, Raiford DS, Wright KJ, Gorden DL. Serum sickness following rabbit antithymocyte-globulin induction in a liver transplant recipient: case report and literature review. Liver Transpl. 2007;13:647-650. [Cited in This Article: ] |
| 86. | Ramirez CB, Doria C, di Francesco F, Iaria M, Kang Y, Marino IR. Anti-IL2 induction in liver transplantation with 93% rejection-free patient and graft survival at 18 months. J Surg Res. 2007;138:198-204. [Cited in This Article: ] |
| 87. | Neuhaus P, Clavien PA, Kittur D, Salizzoni M, Rimola A, Abeywickrama K, Ortmann E, Chodoff L, Hall M, Korn A. Improved treatment response with basiliximab immunoprophylaxis after liver transplantation: results from a double-blind randomized placebo-controlled trial. Liver Transpl. 2002;8:132-142. [Cited in This Article: ] |
| 88. | Liu CL, Fan ST, Lo CM, Chan SC, Ng IO, Lai CL, Wong J. Interleukin-2 receptor antibody (basiliximab) for immunosuppressive induction therapy after liver transplantation: a protocol with early elimination of steroids and reduction of tacrolimus dosage. Liver Transpl. 2004;10:728-733. [Cited in This Article: ] |
| 89. | Hong JC, Kahan BD. Immunosuppressive agents in organ transplantation: past, present, and future. Semin Nephrol. 2000;20:108-125. [Cited in This Article: ] |
| 90. | Wilde MI, Goa KL. Muromonab CD3: a reappraisal of its pharmacology and use as prophylaxis of solid organ transplant rejection. Drugs. 1996;51:865-894. [Cited in This Article: ] |
| 91. | Vallhonrat H, Williams WW, Cosimi AB, Tolkoff-Rubin N, Ginns LC, Wain JC, Preffer F, Olszak I, Wee S, Delmonico FL. In vivo generation of C4d, Bb, iC3b, and SC5b-9 after OKT3 administration in kidney and lung transplant recipients. Transplantation. 1999;67:253-258. [Cited in This Article: ] |
| 92. | Ferran C, Dy M, Merite S, Sheehan K, Schreiber R, Leboulenger F, Landais P, Bluestone J, Bach JF, Chatenoud L. Reduction of morbidity and cytokine release in anti-CD3 MoAb-treated mice by corticosteroids. Transplantation. 1990;50:642-648. [Cited in This Article: ] |
| 93. | Caillat-Zucman S, Blumenfeld N, Legendre C, Noel LH, Bach JF, Kreis H, Chatenoud L. The OKT3 immunosuppressive effect. In situ antigenic modulation of human graft-infiltrating T cells. Transplantation. 1990;49:156-160. [Cited in This Article: ] |
| 94. | Colonna JO 2nd, Goldstein LI, Brems JJ, Vargas JH, Brill JE, Berquist WJ, Hiatt JR, Busuttil RW. A prospective study on the use of monoclonal anti-T3-cell antibody (OKT3) to treat steroid-resistant liver transplant rejection. Arch Surg. 1987;122:1120-1123. [Cited in This Article: ] |
| 95. | Solomon H, Gonwa TA, Mor E, Holman MJ, Gibbs J, Watemberg I, Netto G, Goldstein RM, Husberg BS, Klintmalm GB. OKT3 rescue for steroid-resistant rejection in adult liver transplantation. Transplantation. 1993;55:87-91. [Cited in This Article: ] |
| 96. | Rosen HR, Shackleton CR, Higa L, Gralnek IM, Farmer DA, McDiarmid SV, Holt C, Lewin KJ, Busuttil RW, Martin P. Use of OKT3 is associated with early and severe recurrence of hepatitis C after liver transplantation. Am J Gastroenterol. 1997;92:1453-1457. [Cited in This Article: ] |
| 97. | Everson GT. Impact of immunosuppressive therapy on recurrence of hepatitis C. Liver Transpl. 2002;8:S19-S27. [Cited in This Article: ] |
| 98. | Magliocca JF, Knechtle SJ. The evolving role of alemtuzumab (Campath-1H) for immunosuppressive therapy in organ transplantation. Transpl Int. 2006;19:705-714. [Cited in This Article: ] |
| 99. | Barth RN, Janus CA, Lillesand CA, Radke NA, Pirsch JD, Becker BN, Fernandez LA, Thomas Chin L, Becker YT, Odorico JS. Outcomes at 3 years of a prospective pilot study of Campath-1H and sirolimus immunosuppression for renal transplantation. Transpl Int. 2006;19:885-892. [Cited in This Article: ] |
| 100. | Bloom DD, Chang Z, Fechner JH, Dar W, Polster SP, Pascual J, Turka LA, Knechtle SJ. CD4+ CD25+ FOXP3+ regulatory T cells increase de novo in kidney transplant patients after immunodepletion with Campath-1H. Am J Transplant. 2008;8:793-802. [Cited in This Article: ] |
| 101. | Pascual J, Bloom D, Torrealba J, Brahmbhatt R, Chang Z, Sollinger HW, Knechtle SJ. Calcineurin inhibitor withdrawal after renal transplantation with alemtuzumab: clinical outcomes and effect on T-regulatory cells. Am J Transplant. 2008;8:1529-1536. [Cited in This Article: ] |
| 102. | Tzakis AG, Tryphonopoulos P, Kato T, Nishida S, Levi DM, Madariaga JR, Gaynor JJ, De Faria W, Regev A, Esquenazi V. Preliminary experience with alemtuzumab (Campath-1H) and low-dose tacrolimus immunosuppression in adult liver transplantation. Transplantation. 2004;77:1209-1214. [Cited in This Article: ] |
| 103. | Marcos A, Eghtesad B, Fung JJ, Fontes P, Patel K, Devera M, Marsh W, Gayowski T, Demetris AJ, Gray EA. Use of alemtuzumab and tacrolimus monotherapy for cadaveric liver transplantation: with particular reference to hepatitis C virus. Transplantation. 2004;78:966-971. [Cited in This Article: ] |
| 104. | Pribila JT, Quale AC, Mueller KL, Shimizu Y. Integrins and T cell-mediated immunity. Annu Rev Immunol. 2004;22:157-180. [Cited in This Article: ] |
| 105. | Dedrick RL, Walicke P, Garovoy M. Anti-adhesion antibodies efalizumab, a humanized anti-CD11a monoclonal antibody. Transpl Immunol. 2002;9:181-186. [Cited in This Article: ] |
| 106. | Vincenti F, Mendez R, Pescovitz M, Rajagopalan PR, Wilkinson AH, Butt K, Laskow D, Slakey DP, Lorber MI, Garg JP. A phase I/II randomized open-label multicenter trial of efalizumab, a humanized anti-CD11a, anti-LFA-1 in renal transplantation. Am J Transplant. 2007;7:1770-1777. [Cited in This Article: ] |
| 107. | O’Shea JJ. Jaks, STATs, cytokine signal transduction, and immunoregulation: are we there yet? Immunity. 1997;7:1-11. [Cited in This Article: ] |
| 108. | Podder H, Kahan BD. Janus kinase 3: a novel target for selective transplant immunosupression. Expert Opin Ther Targets. 2004;8:613-629. [Cited in This Article: ] |
| 109. | Tan SL, Parker PJ. Emerging and diverse roles of protein kinase C in immune cell signalling. Biochem J. 2003;376:545-552. [Cited in This Article: ] |
| 110. | Vincenti F, Kirk AD. What’s next in the pipeline. Am J Transplant. 2008;8:1972-1981. [Cited in This Article: ] |
| 111. | Krueger GG. Clinical response to alefacept: results of a phase 3 study of intravenous administration of alefacept in patients with chronic plaque psoriasis. J Eur Acad Dermatol Venereol. 2003;17 Suppl 2:17-24. [Cited in This Article: ] |