Tissue-targeted therapy of autoimmune diabetes using dendritic cells transduced to express IL-4 in NOD mice

Abstract

A deficit in IL-4 production has been previously reported in both diabetic human patients and nonobese diabetic (NOD) mice. In addition, re-introducing IL-4 into NOD mice systemically, or as a transgene, led to a beneficial outcome in most studies. Here, we show that prediabetic, 12-wk old female NOD mice have a deficit in IL-4 expression in the pancreatic lymph nodes (PLN) compared to age-matched diabetes-resistant NOD.B10 mice. By bioluminescence imaging, we demonstrated that the PLN was preferentially targeted by bone marrow-derived dendritic cells (DCs) following intravenous (IV) administration. Following IV injection of DCs transduced to express IL-4 (DC/ IL-4) into 12-wk old NOD mice, it was possible to significantly delay or prevent the onset of hyperglycemia. We then focused on the PLN to monitor, by microarray analysis, changes in gene expression induced by DC/IL-4 and observed a rapid normalization of the expression of many genes, that were otherwise under-expressed compared to NOD.B10 PLN. The protective effect of DC/IL-4 required both MHC and IL-4 expression by the DCs. Thus, adoptive cellular therapy, using DCs modified to express IL-4, offers an effective, tissue-targeted cellular therapy to prevent diabetes in NOD mice at an advanced stage of pre-diabetes, and may offer a safe approach to consider for treatment of high risk human pre-diabetic patients.

Human mesenchymal stem cells and derived extracellular vesicles induce regulatory dendritic cells in type 1 diabetic patients

“…Indeed, it has been shown that antigenprimed DCs induce better protection in NOD mice and that cognate antigen-MCH class II complexes enhance IL-2 induced Treg proliferation [37][38][39].…”

“…The key therapeutic attribute of both MSCs and DCs is related to their ability to selectively migrate to sites of tissue injury and draining lymph nodes [3,11,39,40]. This may allow further local antigen provision and interaction with activated T cells in situ.…”

Lymphoid tissue–specific homing of bone marrow–derived dendritic cells

“…In contrast to our previously published study, where DCs were transduced by lentivirus to express the Luc gene, 23 we obtained the L2G85 Luc-transgenic mouse on the FVB background, 24 which we backcrossed onto the NOD, NOD.B10, and BALB/c backgrounds. We first performed a kinetic analysis of DC homing in FVB and NOD mice, starting from 1 day after intravenous or intraperitoneal inoculation until the bioluminescent signal became undetectable.…”

“…11,12,[16][17][18][19][20][21][22] Probably due to limited sensitivity, resolution, or time duration of the methods used, these in vivo imaging studies failed to demonstrate lymph node homing, unless ex vivo biodistribution was performed, but this has not been well characterized. 17,18 Prompted by our initial observation that bone marrow-derived DCs (BM-DCs), modified by lentivirus to express the Firefly luciferase (Luc) reporter gene and injected intravenously into nonobese diabetic (NOD) mice, home preferentially to the pancreatic lymph nodes (PLNs), 23 we set out to conduct a more detailed analysis of the biodistribution of BM-DCs from different Luctransgenic mice following intravenous and intraperitoneal injection. In this report, we show that systemic administration of DCs does not result in uniform homing among lymph nodes, a feature that was previously overlooked.…”

Cancer stem cells from human breast tumors are involved in spontaneous metastases in orthotopic mouse models

“…Optical imaging approaches that use multifunctional reporter genes permit thorough analyses of disease models by linking in vivo and ex vivo assays and guiding the experimental design (27)(28)(29)(30)(31)(32). Such reporters include firefly luciferase (Luc) for whole-body tracking of cells via bioluminescence imaging (BLI) (33) and fluorescent proteins that facilitate intravital imaging and ex vivo analyses (e.g., fluorescence microscopy and flow cytometry).…”