Dendritic cell–expanded, islet-specific CD4+ CD25+ CD62L+ regulatory T cells restore normoglycemia in diabetic NOD mice

Abstract

Most treatments that prevent autoimmune diabetes in nonobese diabetic (NOD) mice require intervention at early pathogenic stages, when insulitis is first developing. We tested whether dendritic cell (DC)–expanded, islet antigen–specific CD4+ CD25+ suppressor T cells could treat diabetes at later stages of disease, when most of the insulin-producing islet β cells had been destroyed by infiltrating lymphocytes. CD4+ CD25+ CD62L+ regulatory T cells (T reg cells) from BDC2.5 T cell receptor transgenic mice were expanded with antigen-pulsed DCs and IL-2, and were then injected into NOD mice. A single dose of as few as 5 × 104 of these islet-specific T reg cells blocked diabetes development in prediabetic 13-wk-old NOD mice. The T reg cells also induced long-lasting reversal of hyperglycemia in 50% of mice in which overt diabetes had developed. Successfully treated diabetic mice had similar responses to glucose challenge compared with nondiabetic NOD mice. The successfully treated mice retained diabetogenic T cells, but also had substantially increased Foxp3+ cells in draining pancreatic lymph nodes. However, these Foxp3+ cells were derived from the recipient mice and not the injected T reg cells, suggesting a role for endogenous T reg cells in maintaining tolerance after treatment. Therefore, inoculation of DC-expanded, antigen-specific suppressor T cells has considerable efficacy in ameliorating ongoing diabetes in NOD mice.

Inhibition of type 1 diabetes in filaria‐infected non‐obese diabetic mice is associated with a T helper type 2 shift and induction of FoxP3+ regulatory T cells

“…The suppressive capability of natural regulatory T cells of NOD mice decreases with age 32 and T-regulatory cells expanded from 4-week-old NOD mice are more protective against diabetes than those expanded from older NOD mice. 33 Since a single administration of islet-specific regulatory T cells can block diabetes development in 13-week-old prediabetic NOD mice, 34 we hypothesize that the increase in CD4 + CD25 + FoxP3 + regulatory T cells observed in L. sigmodontis-infected NOD mice may be a mechanism by which helminths protect against autoimmune disease. Determining whether this hypothesis is correct, and assessing whether helminth infection affects regulatory T-cell functionality, will be the focus of future studies.…”

Dendritic cells: Understanding immunogenicity

“…DC can differentiate T regs in the thymus [78] and in the periphery [79], and expand them once the T regs have formed [80][81][82]. Antigen-specific T regs are much more effective than polyclonal populations in suppressing immunity in vivo [79,[81][82][83]. For many years, the major approach to the induction of peripheral tolerance has been to inject very large doses of antigen.…”

Treatment of autoimmune diabetes in NOD mice by Toll-like receptor 2 tolerance in conjunction with dipeptidyl peptidase 4 inhibition

“…Both goals are not easy to achieve using the techniques currently available for patients. Numerous immunological methods have been employed to inhibit autoimmune responses to beta cells in human or animal models of type 1 diabetes [17][18][19][20][21][22][23][24][25][26][27]. However, immunological methods alone were largely unsuccessful in the treatment of clinically overt type 1 diabetes, probably because of the already significantly compromised beta cell mass.…”