Role of regulatory T cells for the treatment of type 1 diabetes mellitus.
Beta-cell specific autoreactive T cells can be found in patients with type I diabetes (T1D) and in healthy controls. They are usually controlled by a network of regulatory mechanisms including CD4+CD25+Foxp3+ regulatory T cells (Tregs). It was suspected that defects in Treg number and activity are causally related to the development of T1D. Although there are hints that this concept might be true, it is neither proven in animal models nor in patients with T1D. However, increasing the number of Tregs by adoptive transfer can be used to prevent and treat even established T1D. It was demonstrated that Tregs recognizing beta-cell antigens are far more efficient in treating the disease than polyspecific Tregs. The use of beta-cell specific Tregs is also leading to a tissue specific immunotolerance without perturbing the general immunocompetence. Two sources for beta-cell specific Tregs are currently employed: First natural Tregs specific for beta-cells are expanded IN VITRO and reinfused into diabetic animals. Second naïve or activated T cells specific for beta-cell antigens are IN VITRO converted to Tregs by genetic manipulation or by specific cytokine combinations. Both approaches were successful in treating even established diabetes in animal models. Before such therapies can be used in patients safety measures regarding the fate and the effects of the transferred Tregs have to be studied. Besides this ethical considerations are important in regard to what risks we should take to treat a disease in young patients which can otherwise be treated medically. In the meantime the concept of Tregs for therapy of T1D is supported by successful clinical attempts to induce these cells IN VIVO by administration of monoclonal antibodies against CD3. If subsequent studies show that Tregs represent a safe and efficient source for therapy, they could become an important weapon in the fight against immune mediated pathology.
Jaeckel
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Department of Gastroenterology, Hepatology & Endocrinology, Hannover Medical School, Hannover, Germany. Jaeckel_elmar@yahoo.com
Mpofu
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Saal
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Manns
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D019264:Adoptive Transfer; D000818:Animals; D015704:CD4 Antigens / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000503:physiopathology / Q000628:therapy*; D051858:Forkhead Transcription Factors / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance; D017493:Leukocyte Common Antigens / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000637:transplantation
D015704:CD4 Antigens; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D017493:Leukocyte Common Antigens