The effect of low and ultra-low dosages Thymoglobulin on peripheral T, B and NK cells in kidney transplant recipients M.M.L. Kho ⁎, A.P. Bouvy, M. Cadogan, R. Kraaijeveld, C.C. Baan, W. Weimar Department of Internal Medicine, Erasmus (University) Medical Centre, PO Box 2040, 3000 CA Rotterdam, The Netherlands abstract article info Article history: Received 23 December 2011 Received in revised form 24 February 2012 Accepted 27 February 2012 Keywords: r-ATG Thymoglobulin Lymphocyte subsets Kidney transplantation Monitoring Introduction: Rabbit Anti-Thymocyte Globulin (r-ATG) is a polyclonal antibody preparation, used to prevent and treat acute rejection episodes after organ transplantation. However, despite more than 40 years of clin- ical use, the optimal dose of r-ATG is still not defined. To find a better balance between efficacy and infectious complications, we embarked on a controlled study and monitored the effect of low and ultra-low dosages Thymoglobulin (Genzyme) on peripheral T, B, and NK cells. Patients and methods: Kidney transplant recipients received either 0.5 mg/kg, 1.0 mg/kg or 2.0 mg/kg on the first 3 consecutive days post-transplantation. Thus, total doses were 1.5 mg/kg, 3.0 mg/kg and 6.0 mg/kg. A total of 40 patients were enrolled, including 11 controls. All patients were treated with Prednisolon, Advagraf (Astellas) and Mycophenolate Mofetil (Roche). T (CD3 +), B (CD19 +) and NK (CD3-CD16 + 56 +) cells were analyzed by flow cytometry. Baseline cell counts were compared to forty age and sex matched healthy per- sons. Post-transplantation cell counts of the 3 Thymoglobulin groups were compared to the 11 control pa- tients, who received no induction therapy. Results: Absolute numbers of T, B, and NK cells were comparable in all patients pre-transplantation, but T and B cells were lower than in healthy persons (p = 0.007 and p = 0.0003, Mann Whitney test). In the first week, T cells and NK cells were significantly lower in all Thymoglobulin groups compared to controls. B cells were not affected. One month after Thymoglobulin NK cells had returned to control numbers in all groups, while T cells had already recovered to control counts in the 1.5 mg/kg group. During follow-up, T cells in the 3.0 mg/ kg group also returned to control values, but at one year the patients in the 6.0 mg/kg group still had signif- icantly lower T cells (p = 0.03). Patient and graft survival, rejection and infection incidence and renal function did not differ between groups. Conclusion: Patients with end stage renal disease have significantly lower peripheral T and B cell counts than healthy persons. (Ultra-) low Thymoglobulin schedules deplete peripheral lymphocytes in a dose dependent way. Knowledge of the duration of this depletion contributes to finding the optimal immunosuppressive strategy for kidney transplant recipients. © 2012 Elsevier B.V. All rights reserved. 1. Introduction Rabbit Anti-Thymocyte Globulin (r-ATG) is a lymphocyte depleting polyclonal antibody preparation, used to treat and to prevent acute re- jection after organ transplantation. However, the optimal dose of r-ATG is still not defined despite the clinical use of anti-lymphocyte agents for more than 40 years. The concept to prepare a serum specifically active against one cell type was developed by Metchnikoff in 1899. After more than 50 years of animal studies, the first use of a rabbit anti-human-lymphocyte globulin to prevent skin alloreactivity was described by Monaco in 1967 [1]. One year later Kashiwagi et al. reported the administration of an anti-lymphocyte globulin in human kidney transplant recipients [2]. In the following decade various rabbit or horse anti-lymphocyte preparations were developed in the USA and Europe. At the moment, the most widely used depleting agent to prevent acute rejection of organ transplants is Thymoglobulin (Genzyme, Cambridge, USA) [3,4]. The main goal of induction therapy is to reduce the risk of acute rejection in the first weeks after organ transplantation. Indeed, induc- tion therapy with Thymoglobulin does result in a lower acute rejec- tion rate, but also in a higher risk of infections and malignancies [5–8]. The most recent meta-analysis of the Cochrane database reported a benefit of ATG therapy over IL-2 receptor antibodies for BPAR at 1 year, but at the cost of a 75% increase in malignancy and a 32% increase in cytomegalo virus disease [9]. These complications re- flect over-immunosuppression and are associated with depletion of peripheral T cells [10] and low pre-transplant thymic function [11]. Transplant Immunology 26 (2012) 186–190 ⁎ Corresponding author. Tel.: + 31 10 7040704; fax: + 31 10 4366372. E-mail addresses: m.kho@erasmusmc.nl (M.M.L. Kho), a.bouvy@erasmusmc.nl (A.P. Bouvy), m.cadogan@erasmusmc.ml (M. Cadogan), r.kraaijeveld@erasmusmc.nl (R. Kraaijeveld), c.c.baan@erasmusmc.nl (C.C. Baan), w.weimar@erasmusmc.nl (W. Weimar). 0966-3274/$ – see front matter © 2012 Elsevier B.V. All rights reserved. doi:10.1016/j.trim.2012.02.003 Contents lists available at SciVerse ScienceDirect Transplant Immunology journal homepage: www.elsevier.com/locate/trim