Anti-thymoglobulin (ATG) treatment does not reverse type 1 diabetes in the acute virally induced rat insulin promoter-lymphocytic choriomeningitis virus (RIP-LCMV) model

Immune modulators such as anti-thymoglobulin (ATG) are under clinical evaluation for the treatment of type 1 diabetes (T1D). Although such agents have cured T1D in the non-obese diabetic (NOD) model, their clinical efficacy has been much lower. In order to improve the odds of successful translation...

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Vydané v:	Clinical and experimental immunology Ročník 163; číslo 3; s. 375 - 380
Hlavní autori:	Bresson, D, von Herrath, M.G
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	Oxford, UK Blackwell Publishing Ltd 01.03.2011 Blackwell Oxford University Press Blackwell Science Inc
Predmet:	Analytical, structural and metabolic biochemistry Animal Models Animals Antibodies Antilymphocyte Serum - administration & dosage Antilymphocyte Serum - therapeutic use anti‐thymoglobulin autoimmunity Biological and medical sciences Blood Glucose - metabolism CD25 antigen CD4 antigen CD4-CD8 Ratio CD4-Positive T-Lymphocytes - immunology CD4-Positive T-Lymphocytes - pathology CD8 antigen CD8-Positive T-Lymphocytes - immunology CD8-Positive T-Lymphocytes - pathology Clinical trials Data processing Diabetes Diabetes mellitus Diabetes Mellitus, Type 1 - blood Diabetes Mellitus, Type 1 - etiology Diabetes Mellitus, Type 1 - immunology Diabetes Mellitus, Type 1 - therapy Diabetes. Impaired glucose tolerance Disease Models, Animal Endocrine pancreas. Apud cells (diseases) Endocrinopathies Etiopathogenesis. Screening. Investigations. Target tissue resistance Fundamental and applied biological sciences. Psychology Immunomodulation Immunoregulation Infection Insulin Insulin - genetics Interleukin-2 Receptor alpha Subunit - metabolism Kinetics Lymphocyte Count Lymphocyte Depletion Lymphocytes T Lymphocytic choriomeningitis virus - genetics Lymphocytic choriomeningitis virus - isolation & purification Medical research Medical sciences Mice Mice, Inbred C57BL Mice, Transgenic Promoter Regions, Genetic - genetics Rats regulatory T cells RIP‐LCMV mice T-Lymphocyte Subsets - immunology T-Lymphocyte Subsets - metabolism T-Lymphocyte Subsets - pathology T-Lymphocytes, Regulatory - immunology T-Lymphocytes, Regulatory - metabolism T-Lymphocytes, Regulatory - pathology Translation Treatment Outcome type 1 diabetes Viral Load - immunology Endocrinopathy Autoimmunity Pancreatic hormone Rat Autoimmune disease Biochemistry Promoter T-Lymphocyte anti-thymoglobulin Antithymocyte globulin Regulatory cell RIP-LCMV mice Immunopathology Acute Rodentia Insulin Arenavirus Virus regulatory T cells Vertebrata Mammalia Treatment Lymphocytic choriomeningitis virus Mouse Type 1 diabetes Animal Reversibility Models Arenaviridae
ISSN:	0009-9104, 1365-2249, 1365-2249
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Shrnutí:	Immune modulators such as anti-thymoglobulin (ATG) are under clinical evaluation for the treatment of type 1 diabetes (T1D). Although such agents have cured T1D in the non-obese diabetic (NOD) model, their clinical efficacy has been much lower. In order to improve the odds of successful translation from bench to bedside, we propose to evaluate this agent under more stringent conditions. Here, we evaluated the capacity of ATG to reverse T1D in the acute rat insulin promoter-lymphocytic choriomeningitis virus (RIP-LCMV) model. RIP-LCMV-glycoprotein (GP) mice were treated after new-onset T1D with murine ATG antibodies. Although ATG treatment did not impair viral clearance it failed to reverse new-onset T1D in this model. The CD4 : CD8 ratio was reduced drastically upon LCMV infection due to an expansion of CD8 effectors but ameliorated in ATG-treated mice. Although the percentage of CD4⁺CD25⁺ regulatory T cells (Tregs) within the CD4⁺ population was increased significantly after ATG therapy, their frequency in the periphery was reduced dramatically and never returned to normal baseline. The inability of ATG treatment to cure T1D in a stringent viral model (RIP-LCMV mice) is due at least partially to the inability to maintain or increase a sufficient CD4⁺CD25⁺ Tregs frequency, in striking contrast with what was reported in the NOD model. Our data would argue for the use of multiple animal models to assess efficacy of promising immune-based interventions and select the most potent therapies for future clinical trials.
Bibliografia:	http://dx.doi.org/10.1111/j.1365-2249.2010.04304.x ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 ObjectType-Article-2 ObjectType-Feature-1
ISSN:	0009-9104 1365-2249 1365-2249
DOI:	10.1111/j.1365-2249.2010.04304.x