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Critical Reviews™ in Immunology
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Critical Reviews™ in Immunology

DOI: 10.1615/CritRevImmunol.2013006782
pages 415-434

Infectious Tolerance as Candidate Therapy for Type 1 Diabetes: Transfer of Immunoregulatory Properties from Human Regulatory T Cells to Other T Cells and Proinflammatory Dendritic Cells

Fleur S. Kleijwegt
Department of Immunohematology & Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands
Bart O. Roep
Department of Immunohematology & Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands

ABSTRACT

Type 1 diabetes is a T-cell−mediated autoimmune disease in which the insulin-producing cells in the islets of Langerhans are selectively destroyed. Although symptomatic insulin therapy is able to control glucose levels in the blood, many patients do not obtain the desired glycemic control, which increases the risk of diabetic complications. While many immunotherapeutic efforts to intervene in the disease process focus on systemic immune-suppressive therapies, antigen-specific immune modulation represents an attractive alternative. Dendritic cells modulated with 1.25(OH)2 vitamin D3, and dexamethasone (tolerogenic DCs) loaded with islet antigens induce Ag-specific regulatory CD4 T cells (iaTregs), offering a tissue-specific intervention therapy. iaTregs exert their function via linked suppression to diminish effector cells by modulating pro-inflammatory DCs to upregulate inhibitory receptors. In turn, these re-educated mature DCs induce IL-10−producing cells from the naive T-cell pool. Thus, tolerogenic DCs transfer regulatory properties to pro-inflammatory DCs via iaTregs (i.e., infectious tolerance). In this review, we describe the current knowledge regarding regulatory mechanisms of these tolerogenic DCs and the Tregs that they induce, and we propose that cell therapy with human tolerogenic DCs provides new opportunities for immune intervention in patients with autoimmune diseases.


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