| Abstract|| |
Induction therapy has been utilized since the late 70s to reorient the immune system at the time of antigen presentation, decrease acute rejection and improve long-term graft survival. Currently, over 70% of patients undergoing kidney transplantation receive induction therapy. The current agents include OKT3, polyclonal antilymphocyte agents (Thymoglobulin being most frequently used), the anti-interleukin-2 receptor monoclonal antibodies daclizumab and basiliximab and Campath 1H. The current biologic agents are used for short-term therapy although their biologic effects may be prolonged. The next generation of induction agents is being developed for chronic use in calcineurin inhibitorfree and/or steroid-free regimens. These new biologic agents will be developed to simplify immunosuppression regimens, improve compliance and minimize long term toxicities.
|How to cite this article:|
Vincenti F. Current Use and Future Trends in Induction Therapy. Saudi J Kidney Dis Transpl 2005;16:506-13
| Introduction|| |
Induction therapy was introduced in the late 70s to reorient the immune system at the time of transplantation and antigen presentation, and thus was conceived as short term therapy. , The introduction of the biologic agents over the next 25 years adhered to this concept. The polyclonal agents are administered for 5-14 days, OKT3 for 7-10 days, the antiinterleukin-2 (anti-IL2) mAbs in either 2 doses (basiliximab) or 5 doses (daclizumab) and alemtuzumab (Campath 1H) in 1 or 2 doses. However, the future trend in biologic induction will focus on chronic, and possibly indefinite, use.
There are several reasons for this approach. The first is that the mechanism of action of the new agents renders them effective and safe for prolonged therapy. In addition these novel biologic agents are being utilized in immunosuppression regimens that eliminate calcineurin inhibitors (CNIs) and/or corticosteroids thus necessitating an extended period of therapy. Another important reason for this approach is economic. The cost of clinical development of a new biologic for transplantation can be justified only if it is designed for chronic and prolonged (possibly indefinite) use.
| Current Induction Agents|| |
Polyclonal Antilymphocyte Agents
Polyclonal antilymphocyte agents are produced by immunizing animals with human lymphoid cells. , The most frequent immunogen is a thymocyte. The sera from immunized animals are harvested and processed to obtain purified globulin. The final product however contains many antibodies that react against a variety of other targets including red cells, neutrophils and platelets. Within hours of administration polyclonal agents result in lymphocyte depletion secondary to a number of mechanisms including complement dependent and Fc-dependent opsonization and lysis. The polyclonal agents also contain antibodies to a wide variety of cell surface antigens including the components of the IL-2 receptor adhesion molecules and costimulatory molecules. The role of these targets in the overall effectiveness of the polyclonal agents is supported by the findings of a recent study showing that administration of Thymoglobulin intraoperatively as opposed to postoperatively resulted in a decrease of delayed graft function presumably by preventing ischemia reperfusion injury. 
Polyclonal agents are xenogeneic proteins and therefore elicit a number of side effects including fever, chills and gastrointestinal distress. Less commonly they can also induce a serum sickness-like syndrome and rarely ARDS. Anaphylaxis is extremely rare even upon re-exposure.
OKT3 was approved in 1986 for the treatment of acute rejections.  OKT3 is a murine IgG2 monoclonal antibody (mAb) targeting the chain of CD3, a trimeric molecule adjacent to the T-cell receptor. Soon after the injection of OKT3, T-cells disappear from circulation as a result of opsonization and their removal from circulation by mononuclear cells in the liver and spleen. In addition, initially OKT3 can activate T-cells and result in release of several cytokines including IL-2, interferon γ , IL-6, and TNF. These cytokines cause a syndrome that has been referred to as the cytokine release syndrome and consists of fever, chills, headache, gastrointestinal complaints and less commonly ARDS, aseptic meningitis, and encephalopathy. The availability of other induction agents and the severity of the side effects associated with the cytokine release syndrome have resulted in a marked reduction in the use of OKT3 in the past several years. Furthermore, OKT3 is immunogenic in humans and approximately 50% of patients will make antibodies to it following a course of treatment. Many of these patients will develop high titer anti-mouse antibodies that preclude pretreatment with OKT3.
There are several humanized non-activating anti-CD3 mAbs that offer clear-cut advantages over the murine OKT3 but have yet to be developed for use in renal transplantation.
Anti IL-2R Monoclonal Antibodies
The successful introduction of two mAbs, daclizumab (Zenapax®, Roche Laboratories), and basiliximab (Simulect®, Novartis Pharmaceuticals Inc.), targeting the α chain of the IL-2R, can be attributed to the extensive investigative efforts performed on the IL-2R in the early 1980s. ,,, The α chain was the first of the three IL-2R subchains to be fully characterized, and was initially identified as Tac (for T-cell activation) protein. The IL-2R γand β chains are required to transduce the IL-2 signal inside the cell, while the addition of the α chain leads to the expression of the high-affinity IL-2R. An mAb with the ability to block the interaction between IL-2 and the α chain has the potential to block the amplification of the immune response and the prevention of rejection. The chimerization and humanization of rodent antibodies resulted in more humanized constructs that had prolonged half-life and lacked immunogenecity. The phase 3 trials with daclizumab and basiliximab provided convincing and conclusive proof that blockade of the IL-2 pathway can result in significant reduction in acute rejection. ,,,
Induction: Depleting Antibodies Versus Anti-IL-2R mAbs
Several studies have compared the effectiveness and safety of Thymoglobulin to the anti IL-2R mAbs antibodies. , The first study is an open label randomized multicenter French trial comparing the efficacy and tolerability of Thymoglobulin versus basiliximab.  The protocol compared basiliximab plus immediate (within the first 24-hours post transplantation) cyclosporine therapy versus Thymoglobulin plus delayed (initiated when the serum creatinine is less than 250 µg/L) cyclosporine therapy. All patients also received corticosteroids and MMF at standard doses beginning on the day of transplantation. Fifty predominantly low to moderate immunologic risk patients were randomized to each treatment group. The incidence of acute rejection and overall outcome was similar between the two treatment groups but patients in the Thymoglobulin arm had a higher incidence of side effects [Table - 1]. In contrast Brennan et al performed a prospective, randomized, multicenter study of Thymoglobulin compared with basiliximab for induction immunosuppression in high immunologic risk patients.  High immunologic risk patients were defined as recipients of kidneys likely to have delayed graft function, retransplants, patients with panel reactive antibodies (PRA level greater than 20%), 6 antigen mismatch and patients of African decent. Maintenance immunosuppression consisted of cyclosporine, mycophenolate mofetil (MMF) and prednisone. [Table - 2] shows that patients treated with Thymoglobulin as compared with basiliximab had significantly lower composite endpoints as well as biopsy proven rejection. Taken together these two studies suggest that for lower immunologic risk patients the antiIL2 mAbs may be the safer choice while for the higher immunologic risk patients, the depleting antibodies such as Thymoglobulin are likely to be the more effective therapy.
Alemtuzumab (Campath 1H)
The CD52 is the most prevalent surface antigen on the lymphocytes and is also present on some monocytes and NK cells. Campath 1H is a humanized anti-CD52 mAb. Administration of Campath 1H to humans results in profound depletion of peripheral lymphocytes, monocytes and NK cells. Full repopulation may not occur for over 1 year, although partial recovery is observed within two months. ,
Campath 1H has been approved for use in chronic lymphocytic leukemia although there are several reports of its use in transplantation and autoimmune disease. Calne et al reported the first use of Campath 1H with low-dose cyclosporine in the prophylaxis of rejection in renal transplantation in a Lancet article in 1989.  More recently Campath 1H was utilized in renal transplantation to eliminate steroids and/or calcineurin inhibitors. Kirk et al attempted treatment of 7 renal transplant recipients with Campath 1H monotherapy.  All the patients had acute rejection episodes. Knechtle et al induced 29 patients with Campath 1H and maintained them on sirolimus.  12/29 had rejection episodes; several of the rejections were antibody-mediated or were associated with vasculitis. A recent modification of this approach is to use tacrolimus for several months and then attempt its withdrawal. Determination of the efficacy and safety of Campath 1H will require randomized multicenter studies. Currently all studies with Campath 1H are limited to single center investigator-initiated trials.
| Novel Agents for Chronic Induction|| |
The new biologic agents, whether chimeric, humanized monoclonal antibodies or fusion receptor proteins, have long half-life and prolonged biologic effects.  They lack immunogenecity and can be reused chronically. Their administration is not associated with acute toxicities or cytokine release. The mechanism of action of these novel agents as well as their use in pro-tolerogenic regimens can lead to better long-term graft acceptance and possibly tolerance. [Table - 3] lists the current biologic agents and their status in clinical development. Anti-CD40 and anti-IL15 are still in preclinical development.
Efalizumab is a humanized IgG1 monoclonal antibody targeting the CD11 α chain of LFA1.
Efalizumab binds to LFA1 preventing LFA1ICAM interaction.  Anti-CD11α has been shown to block T-cell adhesion, trafficking and activation.  Pre-transplant therapy with anti-CD11 α prolonged survival of murine skin and heart allografts and monkey heart allografts. Efalizumab has been approved for use in patients with psoriasis. In a phase I/II open label, dose ranging, multidose, multicenter trial, efalizumab was administered subcutaneously, weekly for 12 weeks following renal transplantation.  [Table - 4] shows the doses of efalizumab that were used in this study. Efalizumab was used as chronic induction (for 3 months) with a maintenance regimen of full dose or half-dose of cyclosporine. At three months 7.8% of patients had reversible rejection episodes and at six months there was one additional rejection for a cumulative rejection rate of 10.4%. Pharmacokinetic and pharmacodynamic studies showed that the lower doses of efalizumab (0.5 mg/kg) produced saturation and 80% modulation of CD11 α within 24 hours of therapy. In a subset of 10 patients who received the high dose efalizumab (2 mg/kg) with full dose cyclosporine, MMF and steroids, 3 of 10 patients developed post transplant lymphoproliferative diseases. While efalizumab appears to be an effective immunosuppressive agent, it should be used in a lower dose (0.5 mg/kg) and with an immunosuppressive regimen that spares calcineurin inhibitors. A combination of efalizumab and costimulatory blockade is potentially a very interesting therapeutic strategy.
A multicenter study with anti-IL2 mAbs induction and mycophenolate mofetil with steroids (CNIs free) resulted in an incidence of acute rejection of 48% at 6 months.  The rejection was probably mediated by IL15 as both circulating and intragraft lymphocytes had fully saturated IL2 receptor with the antiIL2 mAbs. IL15 has been shown to mediate the escape rejection during therapy with anti IL2 mAbs. , Anti-IL15 mAbs and anti IL15 α receptor mAbs may be developed for chronic induction for use in conjunction with the anti-IL2 mAbs in a CNI free regimen.
The most characterized costimulatory pathway is CD28-CD80/CD86.  T-cell activation requires 2 signals: the first is delivered by allopeptides to the T-cell receptor (defining the specificity of the response) and the second is mediated by CD28 following its ligation by CD80/CD86. Without costimulation, the T-cell does not proliferate, does not produce cytokines, becomes anergic and undergoes apoptosis. Several experimental models have confirmed the potential benefits of costimulation blockade in inducing either tolerance or effective immunosuppression. ,,, Two approaches have been used to block CD28-mediated T-cell activation. The first was to target CD80/CD86 with the humanized monoclonal antibodies h1F1 and h3D1. In vitro h1F1 and h3D1 were shown to block CD28 dependent T-cell proliferation and decrease mixed lymphocyte reactions. The monoclonal antibodies need to be used in tandem since either CD80 or CD86 are sufficient to stimulate T-cells via CD28. Anti CD80 and CD86 mAbs were shown to be effective in renal transplantation in nonhuman primates, in monotherapy or in combination with steroids or cyclosporine.  Their use however did not result in durable tolerance. A phase I study of h1F1 and h3D1 in renal transplant recipients was performed in patients receiving maintenance therapy consisting of cyclosporine, MMF and steroids.  Patients received a single pre-transplant dose ranging from .15 mg/kg to 5 mg/kg of each mAb. The preliminary results of this phase I study in 24 patients showed that h1F1 and h3D1 were safe but additional studies with prolonged therapy are required to determine their efficacy.
The second approach to block the CD28CD80/CD86 pathway is the fusion receptor protein CTLA4Ig (the extracellular portion of CTLA4 fused to the Fc fragment of IgG1).  CTLA4 is homologous to CD28, is up-regulated after T-cell activation and has higher avidity to CD80/CD86 than CD28. However, unlike CD28, CTLA4 transduces negative signals and interrupts T-cell activation. CTLA4 sequesters CD80/CD86 and blocks their binding to CD28. LEA29Y is a second generation CTLA4Ig, which has been re-engineered with 2 point mutations in the CTLA4 binding sites to increase the avidity to CD80 (2-fold) and CD86 (4-fold). 21 LEA29Y is 10-fold more effective than CTLA4Ig in vitro on a per dose basis in inhibiting T-cell effector functions. 
A phase II trial of chronic LEA29Y (belatacept) therapy with MMF and steroids in a CNI free regimen was recently presented at the 2004 American Transplant Congress.  The immunosuppression protocol and the LEA29Y regimen are shown in [Figure - 1]. Two-hundred and seventeen primary or retransplants were randomized to receive one of two regimens of LEA29Y or a cyclosporine-based immunosuppression therapy [Figure - 1]. At 6 months, acute rejection was similar between the LEA29Y treated patients and the cyclosporine treated patients. Therapy with LEA29Y was associated with better renal function, lower blood pressure levels and lower LDL values when compared to cyclosporine treated patients.  Patients in this trial have been treated with LEA29Y for up to 4 years, demonstrating the feasibility of chronic induction.
Ultimately for chronic induction therapy to be widely accepted it may have to facilitate the elimination of both CNIs and steroids and deliver improved outcome (i.e. less toxicity) with immunosuppression drug simplification.
A prototype of this approach is a primate study reported by Adams et al.  In this trial pancreatectomized non human primates exhibited prolonged allogeneic islet-cells survival with therapy with LEA29Y and sirolimus. Based on this study, we plan to conduct a trial (in collaboration with Dr. Chris Larsen at Emory University) supported by the Immune Tolerance Network in recipients of living donor kidneys using chronic induction with LEA29Y (and a brief anti-IL2 mAb therapy) and sirolimus monotherapy. Patients with no evidence of rejection and a quiescent anti-donor immunologic profile may be withdrawn from sirolimus at one year and LEA29Y at 2 years after transplantation. This immunosuppression regimen allows complete withdrawal in selected patients that exhibit tolerance to the allograft.
Additional targets of costimulation are CD154 and CD40 on the surface of T-cells and antigen presenting cells, respectively but not exclusively. The first clinical trial of anti-CD154 was stopped because of thromboembolic complications.  A safer approach may be to target CD40 with mAbs. These agents are currently in preclinical trials.
In summary, chronic induction therapy offers a wide range of therapeutic opportunities to decrease dependence on toxic drugs, improve outcome, allow drug minimization and simplification and ultimately facilitate induction of tolerance.
| References|| |
|1.||Starzl TE, Marchioro TL, Hutchinson DE, Porter KA, Cerilli GJ, Brettschneider L. The clinical use of antilymphocyte globulin in renal homotransplantation. Transplantation 1967;5:1100-5. |
|2.||Howard RJ, Condie RM, Sutherland DE, Simmons RL, Najarian JS. The use of antilymphoblast globulin in the treatment of renal allograft rejection. Transplant Proc 1981;13:473-4. [PUBMED] |
|3.||Gaber AO, First MR, Tesi RJ, et al. Results of the double-blind, randomized, multicenter, phase III clinical trial of thymoglobulin versus Atgam in the treatment of acute graft rejection episodes after renal transplantation. Transplantation 1998;66:29-37. [PUBMED] [FULLTEXT]|
|4.||Monaco AP. A new look at polyclonal antilymphocyte antibodies in clinical transplantation. Graft 1999; 2:S2-S5. |
|5.||Goggins WC, Pascual MA, Powelson JA, et al. A prospective, randomized clinical trial of intraoperative versus postoperative Thymoglobulin in adult cadaveric renal transplant recipients. Transplantation 2003;76:798-802. [PUBMED] [FULLTEXT]|
|6.||Ortho Multicenter Transplant Study Group. A randomized clinical trial of OKT3® monoclonal antibody for acute rejection of cadaveric renal transplants. N Engl J Med 1985;313:337-42. |
|7.||Vincenti F, Kirkman R, Light S, et al. Interleukin-2-receptor blockade with daclizumab to prevent acute rejection in renal transplantation. N Engl J Med 1998; 338:161-5. [PUBMED] [FULLTEXT]|
|8.||Nashan B, Light S, Hardie IR, Lin A, Johnson JR. Reduction of acute renal allograft rejection by daclizumab. Daclizumab Double Therapy Study Group. Transplantation 1999;67:110-5. |
|9.||Nashan B, Moore R, Amlot P, Schmidt AG, Abeywickrama K, Soulillou JP. Randomized trial of basiliximab versus placebo for control of acute cellular rejection in renal allograft recipients. CHIB 201 International Study Group. Lancet 1997;350:1193-8. |
|10.||Kahan BD, Rajagopalan PR, Hall M. Reduction of the occurrence of acute cellular rejection among renal allograft recipients treated with basiliximab, a chimeric antiinterleukin-2-receptor mono-clonal antibody. United States Simulect Renal Study Group. Transplantation 1999; 67:276-84. |
|11.||Lebranchu Y, Bridoux F, Buchler M, et al. Immunoprophylaxis with basiliximab compared with antithymocyte globulin in renal transplant patients receiving MMFcontaining triple therapy. Am J Transplant 2002;2:48-56. |
|12.||Brennan DC. The Thymoglobulin Induction Study Group. A prospective, randomized, multi-center study of thymoglobulin compared to basiliximab for induction immunosuppression: preliminary results. Am J Transplant [Abstract 398] 2002;2:238. |
|13.||Kirk AD, Hale DA, Mannon RB, et al. Results from a human renal allograft tolerance trial evaluating the humanized CD52-specific monoclonal antibody alemtuzumab (CAMPATH1H). Trans-plantation 2003;76:120-9. |
|14.||Knechtle SJ, Pirsch JD, Fechner HJ Jr, et al. Campath - 1H induction plus rapamycin monotherapy for renal transplantation: results of a pilot study. Am J Transplant 2003;3:722-30. |
|15.||Calne R, Friend P, Moffatt S, et al. Prope tolerance, perioperative Campath 1H, and low-dose cyclosporin monotherapy in renal allograft recipients. Lancet 1998;351:1701-2. [PUBMED] [FULLTEXT]|
|16.||Vincenti F. What's in the pipeline? New immunosuppressive drugs in transplantation. Am J Transplant 2002;2:898-903. |
|17.||Amaout MA. Structure and function of the leukocyte adhesion molecules CD11/CD18. Blood 1990;75:1037-50. |
|18.||Vincenti F, Ramos E, Brattstrom C, et al. Multicenter trial exploring calcineurin inhibitors avoidance in renal transplantation. Transplantation 2001;71:1282-7. [PUBMED] [FULLTEXT]|
|19.||Pavlakis M, Strehlau J, Lipman M, Shapiro M, Maslinski W, Strom TB. Intragraft IL15 transcripts are increased in human renal allograft rejection. Transplantation 1996;62: 543-545. [PUBMED] [FULLTEXT]|
|20.||Baan CC, Knoop CJ, van Gelder T, et al. Anti-CD25 therapy reveals the redundancy of the intragraft cytokine network after clinical heart transplantation. Transplantation 1999;67:870-6. [PUBMED] [FULLTEXT]|
|21.||Sayegh MH, Turka LA. The role of T-cell costimulatory activation pathways in transplant rejection. N Engl J Med 1998;338:1813-21. [PUBMED] [FULLTEXT]|
|22.||Larsen CP, Elwood ET, Alexander DZ, et al. Long-term acceptance of skin and cardiac allografts after blocking CD40 and CD28 pathways. Nature 1996;381:434-8. [PUBMED] [FULLTEXT]|
|23.||Kirk AD, Tadaki DK, Celniker A, et al. Induction therapy with monoclonal antibodies specific for CD80 and CD86 delays the onset of acute renal allograft rejection in non-human primates. Transplantation 2001; 72:377-84. [PUBMED] [FULLTEXT]|
|24.||Larsen CP, Pearson TC, Adams AB, et al. Rational development of LEA29Y (belatacept), a high-affinity variant of CTLA4-Ig with potent immunosuppressive properties. Am J Transplant 2005;5:443-53. [PUBMED] [FULLTEXT]|
|25.||Vincenti F, Muehlbacher F, Nashan B, et al. Co-stimulation blockade with LEA29Y in a calcineurin inhibitor-free maintenance regimen: 6 month efficacy and safety. Am J Transplant 2004 [Abstract 1037]; Supplement 8, 442. |
|26.||Adams AB, Shirasugi N, Durham MM, et al. Calcineurin inhibitor-free CD28 blockadebased protocol protects allogeneic islets in nonhuman primates. Diabetes 2002;51:265-70. [PUBMED] [FULLTEXT]|
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[Figure - 1]
[Table - 1], [Table - 2], [Table - 3], [Table - 4]