Wednesday 18 July 2012 Supplement to Transplantation November 27, 2012, Volume 94 Number 10S 247 1113 Rabbit Antithymocyte Globulin Impairs the Capacity for Homeostatic Proliferation of T Cells in Kidney Transplant Patients Bouvy A.P. 1 , Kho M.M.L. 1 , Klepper M. 1 , IJzermans J.N.M. 2 , Weimar W. 1 , Baan C.C. 1 1 Erasmus MC, University Medical Center Rotterdam, Internal Medicine, Transplantation, Rotterdam, Netherlands, 2 Erasmus MC, University Medical Center Rotterdam, Surgery, Rotterdam, Netherlands Introduction: Short term rabbit antithymocyte globulin (rATG) induction therapy leads to long-lasting depletion of T cells. Numbers of T cells return to baseline levels approximately one year after kidney transplantation. The biological mechanism of this phenomenon is not elucidated yet. Here we studied the hypothesis that it could be explained by an effect on the homeostatic proliferation of T cells. Material and methods: The phenotype and homeostatic proliferation capacity of T cells from renal transplant recipients (n=14) treated with rATG induction therapy (3x2mg/kg/day) in combination with tacrolimus, mycophenolate mofetil (MMF) and steroids were investigated in the frst year after transplantation by whole blood phospho-specifc fow cytometry. Patients (n=23) treated with the non-depleting basiliximab induction therapy (day 0; 4; 20 mg) served as a control group. Results: After a signifcant decrease in the absolute number of both CD4 and CD8 T cells one week after rATG therapy (p< 0.0001), T cells begin to repopulate. However, while CD8 T cells reach baseline levels approximately 3 months after induction therapy, CD4 T cells do not reach 40% of their baseline levels 12 months after transplantation. Functional analysis of the repopulated CD4 and CD8 T cells revealed an impaired Interleukin 7 (IL-7) induced Signal Transducer and Activator of Transcription 5 (STAT5) phosphorylation capacity of repopulated T cells. CD4 memory T cells, including central memory (CD45RO+CCR7+) and effector memory (CD45RO+CCR7-) subpopulations, showed a decrease in the proportion of IL-7 induced phosphorylation of STAT5 (p< 0.04 vs pre-transplantation). After rATG induction therapy, also in the CD8 memory T cells an impaired IL-7 induced STAT5 phosphorylation capacity was found that even decreases further during follow-up the frst year after transplantation (p< 0.022 vs pre-transplantation). This decreased STAT5 phosphorylation capacity included the central memory, effector memory and EMRA (CD45RO-CCR7-) subpopulations. CD4 and CD8 T cells of basiliximab treated patients did not show impaired IL-7 induced STAT5 phosphorylation responses. Conclusion: CD4 and CD8 T cells showed a long-lasting impaired IL-7 induced phosphorylation capacity of STAT5 after rATG induction therapy which can explain the absence of full immune reconstitution approximately one year after rATG induction therapy. 1566 Sotrastaurin, a Novel Protein Kinase C- Inhibitor: Evaluation of a CNI-Free Combination with Everolimus in Renal Transplant Recipients Tedesco-Silva H. 1 , Weimar W. 2 , Hartmann A. 3 , Vitko S. 4 , Russ G. 5 , Toselli L. 6 , Colussi G. 7 , Rostaing L. 8 , Krishnan I. 9 , Gopalakrishnan U. 10 , Klupp J. 9 1 Division of Nephrology, Hospital do Rim e Hipertensão - UNIFESP, São Paulo, Brazil, 2 Erasmus University Medical Center Rotterdam, Rotterdam, Netherlands, 3 Oslo Universitetssykehus HF, Rikshospitalet, Oslo, Norway, 4 Institute for Clinical and Experimental Medicine, Praha, Czech Republic, 5 The Queen Elizabeth Hospital, Woodville, Australia, 6 CRAI Norte, San Martin, Buenos Aires, Argentina, 7 Az.Ospedaliera Niguarda Ca’ Granda, Milano, Italy, 8 CHU de Rangueil, Toulouse, France, 9 Novartis Pharma AG, Basel, Switzerland, 10 Novartis Healthcare Pvt. Ltd., Hyderabad, India Introduction: Identifying an ideal combination partner for mTOR inhibitor is still an unmet need. Sotrastaurin (AEB071; STN), a selective protein kinase C inhibitor, inhibits early T-cell activation via a calcineurin- independent pathway. The present regimen-fnding study evaluates the effcacy and safety of STN in combination with everolimus (EVR) in de novo renal transplant recipients. Methods: This 12-month, randomized, multicenter, open-label, study had a sequential design of two stages (Stage 1: evaluation of effcacy and Stage 2: regimen fnding). Stage 1 randomized 131 patients (2:1) to STN 300 mg + EVR (4-8 ng/mL) (STN 300) vs cyclosporine A + EVR (4-8 ng/mL) (CsA). Stage 2 randomized 180 patients (1:1:1) to STN 300 or STN 200 mg + EVR (8-12 ng/mL) (STN 200) or CsA. All patients received basiliximab induction and corticosteroids. The primary endpoint was Kaplan-Meier (KM) estimate of composite effcacy failure rate at Month 12 defned as treated biopsy-proven acute rejection (tBPAR), graft loss, death or lost to follow-up. The main safety objective was estimated glomerular fltration rate (eGFR) evaluated by Modifcation of Diet in Renal Disease (MDRD) formula. Results: At Month12, in Stage 1, composite effcacy failure rate was 16.5% for STN 300 and 10.9% for CsA. In Stage 2, composite effcacy failure rates were 27.2%, 34.5% and 19.4% for STN 200, STN 300 and CsA groups, respectively (Table). Differences in population (more sites, more deceased donors) may have contributed to the higher rate of effcacy failures in Stage 2. tBPAR was more frequent in the STN arms (Table). eGFR (MDRD formula) was signifcantly better in both the STN groups compared to CsA at almost all time points. [Table-Effcacy and safety of STN+EVR at M12]