Polyclonal Antibodies in Renal Transplantation—A Relook

Polyclonal Antibodies in Renal Transplantation—A Relook M.S. Sidhu, K.S. Nayak, S.V. Subhramanyam, and A. Sankar ABSTRACT Polyclonal antibodies have been used in renal transplantation for the past four decades. Increasing knowledge regarding their varied mechanisms of action have confirmed their versatility in clinical practice. They can be used for induction, reversing acute rejections (especially those resistant to steroids), and possibly conferring an element of allotolerance, thereby reducing chronic allograft nephropathy. Their recent usage as IV bolus, singledose, preoperative infusion as induction therapy in renal transplantation is an attractive and extremely cost-effective strategy, especially in a developing country such as India. T HE SUCCESS OF solid organ transplantation has been directly related to the development of immunosuppressive drug therapies. Induction therapy in renal transplantation is used to produce an initial alteration in recipient’s immunologic milieu with the goal of increasing long-term graft survival. The aim is to provide efficient immunosuppression with acceptable risks of infection, minimize early graft dysfunction, and avoid or delay the occurrence of acute rejection (AR). It is well known that delayed graft function and AR adversely influence graft survival. In addition improved short-term graft survival is a prerequisite for improved long-term graft survival.1 From an immunologic point of view, polyclonal antibodies, which react with many epitopes, seem to offer a good strategy for induction therapy. Polyclonal antibodies have the longest history of any immunosuppressive agent in transplantation.2 Interest in antilymphocyte sera (ALS) began when Metchnikoff and others2 described their anti-inflammatory properties.3 Their immunosuppressive activity was brought to light around half a century later by Woodruff and Forman.4 Medawar expressed a keen interest in the behaviour of skin homografts and how they were rejected.5,6 Monaco in his experimental studies in dogs showed ALS could prolong allograft survival.7 Starzl et al8 began to use these immunosuppressive agents in human transplantation in 1967. Since then, several single-center studies and meta-analyses have shown that induction with polyclonal antibodies or monoclonal antibodies (MAbs) is useful to reduce the incidence of rejection compared to immunosuppressive therapy that does not use induction even in low-risk, white, human leukocyte antigen (HLA)-matched, low panel reactive antibody (PRA) adults.9 These agents have also been used for prevention (induction therapy) in patients with 0041-1345/07/$–see front matter doi:10.1016/j.transproceed.2007.01.072 766 high PRAs,10 African Americans11 and repeat transplant recipients.12 Pediatric patients have been shown to derive immunologic benefit as well, showing decreased incidence of allograft thrombosis when polyclonal agents are used.13 In addition to their role as induction agents, polyclonal antibodies are used in many centers in order to delay administration of nephrotoxic calcineurin inhibitor agents such as cyclosporine (CsA) or tacrolimus until allograft function is established14 and in treatment of AR of organ allografts, including steroid-resistant acute rejection (SRAR),15,16 treatment of graft-versus-host disease after bone marrow transplantation,17 therapy of aplastic anemia,18 and conditioning of recipients of bone marrow from unrelated HLA-matched19 or haploidentical related donors.20 Polyclonal antibodies are raised by the immunization of heterologous species. Horse and rabbits are the species used currently to produce these antibodies. The antigens used initially for ALS production were total leukocyte preparations. They were soon replaced by pure lymphocytes, predominantly T-cell lymphocytes.21 The new preparations were called polyclonal antithymocyte globulin (ATG) or antilymphocyte globulin (ALG), depending on the source of the antigen, whether human thymocytes or cultured human lymphocytes. Human thymocytes and the cultured Jurkat cell line are proven to be very efficacious immunogens.22,23 After an appropriate period of immunization, the serum is harvested from the animals, and the From the Global Hospital, Hyderabad, India. Address reprint requests to Dr K.S. Nayak, Chief Nephrologist and, Head, Department of Nephrology, Global Hospital, LakdiKa-Pul, Hyderabad-500004, India 0091-98480-14555. E-mail: drksnayak@gmail.com © 2007 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 39, 766 –772 (2007) POLYCLONAL ANTIBODIES 767 Table 1. Benefits of Bolus ATG Induction Therapy Author/Year 58 Comparison Group Dose Kaden et al /1992 1) Nonsensitized vs control 2) Sensitized vs control 1) 9 mg/kg single bolus 2) Low-dose, 8-day prophylaxis 3) No prophylaxis Zietse et al59/1993 1) IV bolus ATG, 6 hours after kidney tx 2) IV CsA 1) ATG bolus 2) TDT 1) 8 mg/kg 1) Bolus ATG-F before revascularization. 2) No ATG bolus (control). 1) Bolus ATG before revascularization 2) No ATG bolus 1) ATG bolus 2) Basiliximab/daclizumab 1) 9 mg/kg Kaden et al1/1997 Samsel et al60/1999 Yassim et al61/2000 Martins et al62/2000 1) 9 mg/kg 2) No ATG 1) 9 mg/kg 1) 9 mg/kg 2) Two doses of 20 mg each/5 doses of 1 mg/kg on alternate days Nampoory et al63/2002 1) ATG bolus 2) Conventional ATG 3) IL-2 RA 1) 9 mg/kg 2) 3–5 mg/kg for 7–14 days 3) Daclizumab 1 mg/kg (max 100 mg/dose) subsequent dose at 2, 4, 6, and 8 weeks after Tx. Kumar et al64/2002 1) Single dose rabbit ATG induction 2) No ATG induction 1) 3.5–5 mg/kg Tullius et al65/2003 1) ATG bolus 2) Basiliximab 1) 9 mg/kg perioperatively 2) 20 mg perioperatively and on day 4. Maroun et al66/2003 1) ATG-F bolus intraoperatively 2) Extended ATG-F dose 1) a—9 mg/kg b— 6 mg/kg 2) Additional extended dose over 4 days at daily dose of 3 mg/ kg Maroun et al67/2003 1) ATG-F bolus intraoperatively 2) IL-2RA (daclizumab) 1) a—9 mg/kg b— 6 mg/kg 2) a—1 dose b—2 doses (1 mg/ kg) Conclusion In nonsensitized patients, the high-dose single ATG bolus prophylaxis induced T-cell lymphocytopenia lasting 4 –5 days and, in comparison with corresponding controls, resulted in a shortened hospital stay (31.2 vs 36.7 days) reduced rejection episodes, and improved 1 year graft and patient survivals. Single-shot rATG is an attractive, easy, and cost-effective induction scheme with low incidence of DGF and AR episodes. Pretransplant (or intraoperative) high-dose ATG bolus therapy plays an important role. This variant of induction therapy is very efficient; not only as rejection prophylaxis, but also in improvement graft survival time. Preliminary results promising; rejection rates in bolus group significantly lower. Single bolus high dose—ATG protocol is efficient and safe in prophylaxis of renal allograft. Confirmed the safety and the efficacy profiles of these two antibodies (basiliximab/daclizumab). There was a trend to lower rejection rate in the IL-2R group. Induction therapy with bolus ATG effectively prevents AR and prolongs graft life. Its results are comparable to those of conventional ATG or anti–IL-2RA Ab induction treatment. Infection rate was significantly lower when ATG bolus was used. Single-shot low-dose ATG induction therapy reduces the rejection episodes (P ⫽ .05), but it has not shown any improvement in graft survival at 2.5 years. It is associated with higher urinary infection rates. However, long-term follow-up is needed to see any benefit of more than less rejection on long-term graft survival Patients receiving ATG induction therapy demonstrated improved patient and graft survival at 1 year; biopsy-proven episodes were comparable, but vascular rejections were mainly fond in the Simulect group. ATG-F bolus therapy is an effective and safe induction treatment in kidney transplantation that allows for superior immunosuppressants, especially CNIs and corticosteroids. Excellent choice for induction as it matches better graft survival, with lower incidence of graft rejection and infection. Daclizumab vs ATG resulted in lower incidence of infections, shorter hospital stay, and better graft function during first 3 months post transplant. 768 SIDHU, NAYAK, SUBHRAMANYAM ET AL Table 1. (continued) Author/Year 68 Comparison Group Dose Conclusion ATG-F as a bolus therapy is an effective and safe induction treatment in KT. It is associated with a low acute rejection rate, especially among high-risk KT recipients, and with a shortened initial hospitalization. However, the high rate of CMV disease may be related to the donor and recipient CMV status as well as ATG-F use. Moreover, ATG-F–related side effects were mainly hematologic. The reduced intraoperative bolus dose of 6 mg/kg was better tolerated than 9 mg/kg. Both daclizumab and ATG-F were effective and safe as induction therapy in KT. However, daclizumab was superior to ATG-F with regard to a lower incidence of infections, which are related to the potent and nonselective mmunosuppressive nature of ATG-F. Graft function appeared to be better in the daclizumab group during the first 6 months, which may be related to the use of ATG-F in patients suffering from DGF after transplantation. In addition, Daclizumab treatment reduced both the hospital stay as well as the incidence of side effect, in particular thrombocytopenia. The immunosuppressive protocol of Rapa, CsA, MMF, and prednisone with singlebolus induction ATG achieves excellent immunosuppression and graft survival with no apparent risks in the short and intermediate term. The data clearly establish that a low incidence of AR can be achieved with PRD-, MMF-, and TAC-based immunosuppression with single-shot ATG induction either with ATG-F or thymoglobulin. ATG and PRD should be administered prior to reperfusion. Not only a low total number of AR, even a low incidence of steroid-resistant AR can be noted. Abou-Jaoude et al /2003 A single bolus injection of ATG-F 1) Normal-risk patients either at 9 mg/kg or 6 mg/kg 2) A second ATG-F dose of 9 mg/kg or 6 mg/kg was administered to high-risk patients Abou-Jaoude et al69/2003 1) A single ATG-F bolus injection 2) Daclizumab either 1 or 2 doses 1) 9 mg/kg or 6 mg/kg of ATG-F 2) Either 1 or 2 doses of 1 mg/kg Khauli et al70/2005 1) ATG bolus 2) ATG single or extended course 1) 4 – 6 mg/kg 2) a— 45 4 to 6-mg/kg bolus b— extended course 3–5 days Schulz et al.71/2005 SPK transplant 1) ATG-f 2) Thymoglobulin 1) 4 – 6 mg/kg 2) 1.5–2.5 mg/kg Ab, antibodies; AR, acute rejection; ATG, antithymocyte globulin; CMV, cytomegalovirus; CNI, calcineurin inhibitor; CsA, cyclosporine; DGF, delayed graft function; IL, interleukin; KT, kidney transplantation; MMF, mycophenolate mofetil; PRD, prednisone; Rapa, rapamune; SPK, simultaneous kidney-pancreas transplantation; TDT,. immunoglobulin (Ig) G fraction of the whole serum pool is isolated and subjected to a number of purification processes. The concentrations and specificities of the individual antibodies are variable in the different ATG preparations. The mechanism of action of polyclonal preparations for many years was assumed to primarily involve depletion or sequestration of immunocompetent T cells.24 Within 24 hours of polyclonal antibody administration, peripheral blood lymphocyte counts drop below 100 to 200/mm3. Of the two ATG preparations, rabbit ATG suppressed CD3⫹ T cells to a greater extent than equine ATG. Absolute lymphopenia developed rapidly upon administration of polyclonal antibodies and persisted for almost a full year among patients treated with rabbit ATG but resolved by 14 days in patients receiving equine ATG.25 Lymphocyte depletion may result from complement-dependent opsonization and lysis, even at low concentrations, ATG induces Fas (CD95) and Fas ligand expression, resulting in Fas/Fas-L– mediated apoptosis of activated T cells.26 Long-term specific depletion of the CD4⫹ lymphocyte subset and the preferential generation of a CD8⫹, CD57⫹ immunomodulatory subset of cells have also been postulated to explain the long-term success of polyclonal immunosuppression. It has also been suggested by Merion et al27 that ATG POLYCLONAL ANTIBODIES treatment could lead to T-cell anergy and to the downmodulation of T-cell functional molecules. Modulation by polyclonal ATGs applies to molecules that control T-cell activation (T-cell receptors CD2, CD3, CD4, CD5, CD6, and CD8) and also to molecules involved in leukocyte endothelium interaction such as the ␤2 integrins, especially LFA1 (CD11a). Even low concentrations of ATGs induce a nearly complete disappearance of LFA1 on monocytes, granulocytes and lymphocytes.28 Important lymphocyte activation molecules such as ␤1 and ␤2 integrins and even endothelial inflammatory and adhesion molecules such as ICAM1 are efficiently blocked by ATGs.29 This property may reduce one of the most important features of ischemia– reperfusion injury (IRI), reducing the deleterious effects of the reperfusion in the microvasculature of tissues and solid organs. Chemokines are important for leukocyte– endothelium interactions and leukocyte tracking. Michallet et al30 demonstrated that ATG have functional activity against CXCR4 and CCR7 on lymphocytes and CXCR4 and CCR5 on monocytes, and downmodulate cell surface expression of CCR7. Further more, ATG decreased monocyte chemotactic responses to CCL5 (RANTES) and the lymphocyte chemotactic response to CCL19 (MIP-3␤). These findings suggest additional mechanisms for prevention of AR and IRI.31 These unique properties of ATG, not achieved by other immunosuppressive agents, make them an interesting subject of study as leukocyte antigens and adhesion molecules play a crucial role in IRI, delayed organ failure, and chronic rejection. However, clinically, the main documented effect of ATG is a massive T-cell depletion in the blood. ATG may be regarded as a mixture of monoclonal antibodies with polyspecific antigen targets producing functional activity that is more efficient than that of monospecific monoclonal antibodies. Polyclonal antibodies can eliminate preactivated, noncycling memory lymphocytes, which may be critical for prophylactic treatment in presensitized recipients and for treatment of SRAR. AR is a redundant, polymolecular response with many costimulatory molecules, adhesion molecules, or cytokines substituting in part for one another. Polyclonal antibodies are particularly suited to modify the transplant immune response with its polyspecific and polycellular actions compared to the monospecific therapy provided by MAb therapy. As early as 1980, ATG was shown to decrease both the incidence and severity of AR episodes as well as the mean daily steroid dose during the first 3 months after kidney transplantation compared to immunosuppression with steroids and azathioprine.32 The use of ATG was later extended to recipients who were sensitized or displayed delayed graft function (DGF) and to treat SRAR.33–36 The incidence of SRAR was decreased to 23% with the introduction of ATG induction therapy.37 However, owing to their nonselective nature, the use of these antibodies can result in a state of generalized immunosuppression, which may enhance incidence of opportunistic infections and lymphoproliferative disorders. To optimize the immuno- 769 suppressive regime in renal transplantation and to decrease the associated complications, Kaden38 introduced the strategy of bolus ATG induction in 1990 with the aim to avoid overimmunosuppression while providing maximal immunosuppression at the time of reperfusion of the graft. The authors observed better posttransplant graft function, reduced rejection frequency, delayed onset of rejection, fewer SRAR, and prolonged graft and patient survival. From an immunologic point of view, prevention of AR is better and easier than reversing the immune response. At least three arguments favor the use of induction therapy in the pretransplant rather than the posttransplant period.1 Recipient sensitization begins with opening of the anastomosis (removing the clamps), and basic immunosuppressive drugs cannot achieve effective blood levels during this crucial period. The possibility of an immunosuppressive pretreatment in cases of cadaveric organ transplantation with respect to the time available is very limited. One possibility to overcome this drawback is the application of ATG in a dosage that guarantees a strong and immediate effect on the recipient’s immune system before it recognizes the foreign antigens. Strong data supporting this concept came from basic immunologic research. In the late 1960s and early 1970s, some investigators reported on efficient suppression of humoral and cellular immune response when ALS was administered shortly before the animals were exposed to the antigens.39 – 44 Hence, the rationale of shifting of ATG application from the posttransplant to the pretransplant period in human organ transplantation. Pretransplant ATG bolus caused the T-cell count to drastically reduce at the time of completion of anastomoses.45 From an immunologic point of view, strong T-cell depletion before completion of anastomoses indicates maximal immunosuppression when the recipient is most likely to respond to the new organ. Besides the T lymphopenia, the counteracting of antibodies with endothelial adhesion molecules as well as the production of interleukin-10 as “natural” immunosuppressor” establishes a mileu that could favor the development of tolerance.46 In the ensemble of all these factors, the pretransplant (or intraoperative) ATG bolus as induction therapy is likely to be efficient, not only as rejection prophylaxis but also in improvement of longterm graft survival. It has also been shown that renal transplant patients who received ATG induction therapy are significantly more sensitive to CsA in the posttransplant period as compared to the pretransplant values, possibly through their ability to deplete activated T cells.47 The benefit of prophylactic ATG induction therapy was shown in several large studies of cadaveric renal transplant patients for reducing nephrotoxicity of CsA in the immediate posttransplant period and preventing AR in sensitised patients.48 Kaden et al,38,49 observed better posttransplant graft function, reduced AR, delayed onset of AR, fewer SRAR, and prolonged graft and patient survival. Although these authors recommended bolus dose of 9 mg/kg body weight (BW) of ATG (rabbit), Van Woellwarth et al50 reported 770 good results with a 5 mg/kg bolus used in conjunction with cyclosporine, steroids, and mycophenolate mofetil. Since then, several authors have observed beneficial effects of bolus ATG induction therapy in terms of decreased incidence of AR, lesser infectious episodes, shorter hospital stay and better graft and patient survival (Table 1). The economics of induction therapies is a well-researched topic.51–55 However, single-dose IV bolus pretransplant ATG has not been evaluated in this aspect. This assumes greater significance in a developing economy such as India, where affordability is of crucial importance in the choice of the induction regimen in renal transplantation. Good data are scarce from the Indian population in the absence of a transplant registry. Data available from an observational, noninterventional study from the industry (Multinational Observational Study in Transplantation [MOST], Novartis, Basel, Switzerland) in an Indian renal transplant population with 964 subjects followed up for 5 years showed the lowest incidence of AR in those receiving ATG compared to all other immunosuppressive protocols.56 Our own experience with preoperative IV bolus ATG has been limited but encouraging.57 Thirteen adult recipients (five cadaveric and eight living donors) received 25 mg/kg BW of equine ATG (Thymogam, Bharat Serums and Vaccines, Ltd, Mumbai, India), as a preoperative single bolus infusion (5 mg/kg BW of equine ATG being equivalent to 1 mg/kg BW of rabbit ATG). We encountered no serious adverse effects and the CD3 counts started falling in the 48-hour posttransplant assay, remaining so for a week, before rising to pretreatment values. This was ideal in the clinical setting; therapeutic levels of maintenance immunosuppressives were achieved by this time. We encountered no episodes of AR in this small patient group. The notable feature was that the cost of this induction regimen was equivalent to US$ 750, which was approximately one fifth the cost of monoclonal therapy and less than half the cost of rabbit ATG used similarly. A surge in recent years in the knowledge of the complex mechanisms of actions of polyclonal antibodies in renal transplantation, their more efficient and cost-effective use strategies have ensured a prominent place for them in present day clinical practice. REFERENCES 1. Kaden J, May G, Strobelt V, et al: Intraoperative T-cell depletion prior to completion of anastomoses by high-dose single ATG bolus as a new approach to improve long-term results after kidney transplantation. Transplant Proc 29:344, 1997 2. Brent L: In: A history of transplantation immunology. New York: Academic Press; 1997 3. 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Schroeder TJ, First MR, Mansour ME, et al: Prophylactic use of OKT3 in immunologic high-risk cadaver renal transplant recipients. Am J Kidney Dis 14(5 suppl 2):14, 1989 34. Pomer S, Waldherr R, Mohring K, et al: Prospective trial of OKT3 for early prophylaxis of rejection in immunologic ‘high risk’ renal transplant recipients: Long-term results Transplant Proc 24:1732, 1992 35. Abramowicz D, Goldman M, De Pauwl L, et al: The long-term effects of prophylactic OKT3 monoclonal antibody in cadaver kidney transplantation—a single-center, prospective, randomized study. Transplantation 54:433, 1992 36. Lange H, Muller TF, Ebel H, et al: Immediate and long-term results of ATG induction therapy for delayed graft function compared to conventional therapy for immediate graft function. Transpl Int 12:2, 1999 37. Cockfield SM, Preiksaitis JK, Jewel LD, et al: Posttransplant lymphoproliferative disorder in renal allograft recipients. Clinical experience and risk factor analysis in a single center. 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