title: Factors affecting long-term efficacy of T regulatory cell-based therapy in type 1 diabetes.
abstract: Recent studies suggest that immunotherapy using T regulatory cells (Tregs) prolongs remission in type 1 diabetes (T1DM). Here, we report factors that possibly affect the efficacy of this treatment.
  
  
  
  The metabolic and immune background of 12 children with recently diagnosed T1DM, as well as that of untreated subjects, during a 2-year follow-up is presented. Patients were treated with up to 30 × 106/kg b.w. of autologous expanded CD3+CD4+CD25highCD127-Tregs.
  
  
  
  The disease progressed and all patients were insulin-dependent 2 years after inclusion. The β-cell function measured by c-peptide levels and the use of insulin were the best preserved in patients treated with two doses of Tregs (3/6 in remission), less so after one dose (1/6 in remission) and the worst in untreated controls (no remissions). Increased levels of Tregs could be seen in peripheral blood after their adoptive transfer together with the shift from naïve CD62L+CD45RA+to memory CD62L+CD45RA-Tregs. Increasing serum levels of proinflammatory cytokines were found: IL6 increased in all subjects, while IL1 and TNFα increased only in untreated group. Therapeutic Tregs were dependent on IL2, and their survival could be improved by other lymphocytes.
  
  
  
  The disease progression was associated with changing proportions of naïve and memory Tregs and slowly increasing proinflammatory activity, which was only partially controlled by the administered Tregs. The therapeutic cells were highly dependent on IL2. We conclude that the therapy should be administered at the earliest to protect the highest possible mass of islets and also to utilize the preserved content of Tregs in the earlier phases of T1DM. Trial registration http://www.controlled-trials.com/ISRCTN06128462 ; registered retrospectively.
authors.affiliation: Laboratory of Immunoregulation and Cellular Therapies, Department of Family Medicine, Medical University of Gdańsk, Debinki 2, 80-210, Gdańsk, Poland.
authors.forename: Natalia
authors.initials: N
authors.lastname: Marek-Trzonkowska
authors.affiliation: Department of Pediatric Diabetology and Endocrinology, Medical University of Gdańsk, Debinki 7, 80-210, Gdańsk, Poland.
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Myśliwiec
authors.affiliation: Department of Clinical Immunology and Transplantology, Medical University of Gdańsk, Debinki 7, 80-210, Gdańsk, Poland.
authors.forename: Dorota
authors.initials: D
authors.lastname: Iwaszkiewicz-Grześ
authors.affiliation: Department of Clinical Immunology and Transplantology, Medical University of Gdańsk, Debinki 7, 80-210, Gdańsk, Poland.
authors.forename: Mateusz
authors.initials: M
authors.lastname: Gliwiński
authors.affiliation: Department of Pediatric Diabetology and Endocrinology, Medical University of Gdańsk, Debinki 7, 80-210, Gdańsk, Poland.
authors.forename: Ilona
authors.initials: I
authors.lastname: Derkowska
authors.affiliation: Department of Pediatric Diabetology and Endocrinology, Medical University of Gdańsk, Debinki 7, 80-210, Gdańsk, Poland.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Żalińska
authors.affiliation: Department of Clinical Immunology and Transplantology, Medical University of Gdańsk, Debinki 7, 80-210, Gdańsk, Poland.
authors.forename: Maciej
authors.initials: M
authors.lastname: Zieliński
authors.affiliation: Department of Clinical Immunology and Transplantology, Medical University of Gdańsk, Debinki 7, 80-210, Gdańsk, Poland.
authors.forename: Marcelina
authors.initials: M
authors.lastname: Grabowska
authors.affiliation: Department of Clinical Immunology and Transplantology, Medical University of Gdańsk, Debinki 7, 80-210, Gdańsk, Poland.
authors.forename: Hanna
authors.initials: H
authors.lastname: Zielińska
authors.affiliation: Laboratory of Immunoregulation and Cellular Therapies, Department of Family Medicine, Medical University of Gdańsk, Debinki 2, 80-210, Gdańsk, Poland.
authors.forename: Karolina
authors.initials: K
authors.lastname: Piekarska
authors.affiliation: Regional Center of Blood Donation and Treatment, Hoene-Wrońskiego 4, 80-210, Gdańsk, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Jaźwińska-Curyłło
authors.affiliation: Department of Anaesthesiology and Critical Care, Medical University of Gdańsk, Debinki 7, 80-210, Gdańsk, Poland.
authors.forename: Radosław
authors.initials: R
authors.lastname: Owczuk
authors.affiliation: Department of Paediatrics, Oncology, Haematology and Diabetology, Medical University of Lodz, Sporna 36/50, 91-738, Lodz, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Szadkowska
authors.affiliation: Department of Paediatrics, Oncology, Haematology and Diabetology, Medical University of Lodz, Sporna 36/50, 91-738, Lodz, Poland.
authors.forename: Krystyna
authors.initials: K
authors.lastname: Wyka
authors.affiliation: Section of Transplantation, Department of Surgery, The University of Chicago, 5841 S. Maryland Ave. MC5027, Chicago, IL, 60637, USA.
authors.forename: Piotr
authors.initials: P
authors.lastname: Witkowski
authors.affiliation: Department of Paediatrics, Oncology, Haematology and Diabetology, Medical University of Lodz, Sporna 36/50, 91-738, Lodz, Poland.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Młynarski
authors.affiliation: Department of Paediatrics, Endocrinology and Diabetes, Medical University of Silesia, Poniatowskiego 15, 40-055, Katowice, Poland.
authors.forename: Przemysława
authors.initials: P
authors.lastname: Jarosz-Chobot
authors.affiliation: Department of Peadiatrics, Endocrinology, Diabetology with Cardiology Division, Medical University of Bialystok, Jana Kilińskiego 1, 15-089, Białystok, Poland.
authors.forename: Artur
authors.initials: A
authors.lastname: Bossowski
authors.affiliation: Laboratory of Immunoregulation and Cellular Therapies, Department of Family Medicine, Medical University of Gdańsk, Debinki 2, 80-210, Gdańsk, Poland.
authors.forename: Janusz
authors.initials: J
authors.lastname: Siebert
authors.affiliation: Department of Clinical Immunology and Transplantology, Medical University of Gdańsk, Debinki 7, 80-210, Gdańsk, Poland. ptrzon@gumed.edu.pl.
authors.forename: Piotr
authors.identifier: 0000-0001-5287-5210
authors.initials: P
authors.lastname: Trzonkowski
mesh_terms: D000293:Adolescent; D001323:Autoantibodies / Q000097:blood; D001402:B-Lymphocytes / Q000276:immunology; D015415:Biomarkers / Q000378:metabolism; D002470:Cell Survival; D002648:Child; D016207:Cytokines / Q000097:blood; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000276:immunology* / Q000628:therapy*; D018450:Disease Progression; D005500:Follow-Up Studies; D006801:Humans; D018836:Inflammation Mediators / Q000097:blood; D016131:Lymphocyte Subsets / Q000276:immunology; D010641:Phenotype; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D001323:Autoantibodies; D015415:Biomarkers; D016207:Cytokines; D018836:Inflammation Mediators
keywords: Children; Diabetes type 1; Immunotherapy; T regulatory cells