Dendritic cells expressing transgenic galectin-1 delay onset of autoimmune diabetes in mice.
Type 1 diabetes (T1D) is a disease caused by the destruction of the beta cells of the pancreas by activated T cells. Dendritic cells (DC) are the APC that initiate the T cell response that triggers T1D. However, DC also participate in T cell tolerance, and genetic engineering of DC to modulate T cell immunity is an area of active research. Galectin-1 (gal-1) is an endogenous lectin with regulatory effects on activated T cells including induction of apoptosis and down-regulation of the Th1 response, characteristics that make gal-1 an ideal transgene to transduce DC to treat T1D. We engineered bone marrow-derived DC to synthesize transgenic gal-1 (gal-1-DC) and tested their potential to prevent T1D through their regulatory effects on activated T cells. NOD-derived gal-1-DC triggered rapid apoptosis of diabetogenic BDC2.5 TCR-transgenic CD4+ T cells by TCR-dependent and -independent mechanisms. Intravenously administered gal-1-DC trafficked to pancreatic lymph nodes and spleen and delayed onset of diabetes and insulitis in the NODrag1(-/-) lymphocyte adoptive transfer model. The therapeutic effect of gal-1-DC was accompanied by increased percentage of apoptotic T cells and reduced number of IFN-gamma-secreting CD4+ T cells in pancreatic lymph nodes. Treatment with gal-1-DC inhibited proliferation and secretion of IFN-gamma of T cells in response to beta cell Ag. Unlike other DC-based approaches to modulate T cell immunity, the use of the regulatory properties of gal-1-DC on activated T cells might help to delete beta cell-reactive T cells at early stages of the disease when the diabetogenic T cells are already activated.
Perone
Marcelo J
MJ
Thomas E. Starzl Transplantation Institute and Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA 15213-2582, USA.
Bertera
Suzanne
S
Tawadrous
Zakaria S
ZS
Shufesky
William J
WJ
Piganelli
Jon D
JD
Baum
Linda G
LG
Trucco
Massimo
M
Morelli
Adrian E
AE
D019264:Adoptive Transfer / Q000379:methods; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D002450:Cell Communication / Q000276:immunology; D003713:Dendritic Cells / Q000378:metabolism / Q000637:transplantation*; D003921:Diabetes Mellitus, Experimental / Q000517:prevention & control / Q000628:therapy*; D037483:Galectin 1 / Q000008:administration & dosage* / Q000235:genetics / Q000494:pharmacology* / Q000627:therapeutic use; D015316:Genetic Therapy / Q000379:methods; D007371:Interferon-gamma / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D014161:Transduction, Genetic
D037483:Galectin 1; D007371:Interferon-gamma