Disease-modifying capability of murine Flt3-ligand DCs in experimental autoimmune encephalomyelitis.
Dendritic cells (DCs) bridge the innate and adaptive immune response, are uniquely capable of priming naïve T cells, and play a critical role in the initiation and regulation of autoimmune and immune-mediated disease. At present, in vivo expansion of DC populations is accomplished primarily through the administration of the recombinant human growth factor fms-like tyrosine kinase 3 ligand (hFL), and in vitro DCs are generated using cytokine cocktails containing GM-CSF +/- IL-4. Although hFL has traditionally been used in mice, differences in amino acid sequence and biological activity exist between murine FL (mFL) and hFL, and resultant DC populations differ in phenotype and immunoregulatory functional capabilities. This study developed and characterized mFL-generated DCs and determined the therapeutic capability of mFL DCs in the autoimmune disease experimental autoimmune encephalomyelitis (EAE). Our findings demonstrate that mFL and hFL expand splenic DCs equally in vivo but that mFL-expanded, splenic DCs more closely resemble normal, resting, splenic DCs. In addition, a novel method for generating mFL-derived bone marrow-derived DCs (BM-DCs) was developed, and comparison of mFL with hFL BM-DCs found mFL BM-DCs to be less mature (i.e., lower MHC Class II, CD80, and CD86) than hFL BM-DCs. These immature mFL DCs up-regulated costimulatory molecules in response to maturation stimuli LPS and TNF-alpha. Mature mFL BM-DCs were immunogenic and exacerbated the clinical disease course of EAE.
Papenfuss
Tracey L
TL
Departments of Veterinary Biosciences, The Ohio State University, 370 Veterinary Medical Academic Building, 1900 Coffey Road, Columbus, OH 43210, USA. papenfuss.1@osu.edu
Kithcart
Aaron P
AP
Powell
Nicole D
ND
McClain
Melanie A
MA
Gienapp
Ingrid E
IE
Shawler
Todd M
TM
Whitacre
Caroline C
CC
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects; D039521:CD11c Antigen / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology* / Q000473:pathology; D004194:Disease; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000276:immunology*; D005260:Female; D006801:Humans; D007700:Kinetics; D008297:Male; D008565:Membrane Proteins / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010641:Phenotype; D011994:Recombinant Proteins / Q000494:pharmacology; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects
D039521:CD11c Antigen; D008565:Membrane Proteins; D011994:Recombinant Proteins; C084881:flt3 ligand protein