Treatment with EBV specific cytotoxic T-lymphocytes of paediatric liver transplant recipients affected by EBV-related Post-Transplantation Lymphoproliferative Disorder in early phase
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1
Fondazione Rimed, Italy
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2
ISMETT, Italy
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3
Ospedali Riuniti, Italy
The Epstein-Barr virus (EBV) associated post-transplantation lymphoproliferative disorder (PTLD) is a severe complication of transplantation due to immunosuppressive regimen. The disease results in immortalization and transformation of infected B-cells and it is highly frequent in pediatric transplanted patients since it is related to the virus primary infection in EBV-seronegative recipients.
Aim of our study is to control disease progression by infusion of autologous EBV-specific T lymphocytes (CTL), expanded and activated in vitro, in order to provide persistent cytotoxic activity against infected B-cells in vivo.
Methods: seven liver transplanted children, with a diagnosis of polyclonal EBV-related PTLD (3 polymorphic, 5 “early lesions”, median age at diagnosis 5 years and 6 months), have been enrolled in our Institution. At diagnosis they were symptomatic (nasal obstruction due to adenotonsillar hypertrophy) the IFN- secreting EBV specific lymphocytes measurement at ELISPOT assay resulted low (median value: 0,14±0.96 lymphocytes/l of blood). They were previously treated with change of immunosuppression from Tacrolimus to Rapamycin.
EBV-CTLs were generated from peripheral–blood mononuclear cells (PBMC). For CTLs, PBMC were stimulated with autologous irradiated lymphoblastoid cell line (LCL) and expanded by rounds of restimulation with IL-2. EBV-CTLs, before infusion, are examined for sterility, immunophenotype, potency and EBV specificity. Treatment protocol consisted in 2 blocks of 3 monthly infusions (average dose 1.5x106CTL/Kg) followed by complete histological reassessment.
Results: infusions have been well tolerated and no adverse reactions have been recorded. A check of aminotranspherases activity, performed one week after each dose of CTL, showed no abnormalities. Results of histological assessment in involved tissues (tonsils\adenoids, ileum, colon, stomach and duodenum) after 3 or 6 infusions have documented downgrading of polymorphic PTLD to “Early Lesions” in two patient and complete regression in 5 patients. An overall decrease in EBV–encoded small RNA evaluation (EBER) positive lymphocytes has been found in histological sections.
Conclusions: These preliminary results are encouraging and confirm that CTLs, generated in our facility, are a reliable and a safe tool for cell therapy in liver transplanted children and able to mediate regression of polyclonal EBV related B-cell PTLD.
Keywords:
Epstein-Barr viruses,
post-transplant lymphoproliferative disease,
adoptive cellular therapy,
cytotoxic T lymphocytes,
Liver Transplantation
Conference:
15th International Congress of Immunology (ICI), Milan, Italy, 22 Aug - 27 Aug, 2013.
Presentation Type:
Abstract
Topic:
Translational immunology and immune intervention
Citation:
Miele
M,
Sciveres
M,
Di Bella
M,
Riva
S,
Amico
G,
Liotta
R,
Sonzogni
A,
Grossi
P and
Conaldi
P
(2013). Treatment with EBV specific cytotoxic T-lymphocytes of paediatric liver transplant recipients affected by EBV-related Post-Transplantation Lymphoproliferative Disorder in early phase.
Front. Immunol.
Conference Abstract:
15th International Congress of Immunology (ICI).
doi: 10.3389/conf.fimmu.2013.02.00962
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Received:
25 Jun 2013;
Published Online:
22 Aug 2013.
*
Correspondence:
Dr. Monica Miele, Fondazione Rimed, palermo, Italy, mmiele@ismett.edu