title: Generation of antigen-specific Foxp3+ regulatory T-cells in vivo following administration of diabetes-reversing tolerogenic microspheres does not require provision of antigen in the formulation.
abstract: We have developed novel antisense oligonucleotide-formulated microspheres that can reverse hyperglycemia in newly-onset diabetic mice. Dendritic cells taking up the microspheres adopt a restrained co-stimulation ability and migrate to the pancreatic lymph nodes when injected into an abdominal region that is drained by those lymph nodes. Furthermore, we demonstrate that the absolute numbers of antigen-specific Foxp3+ T regulatory cells are increased only in the lymph nodes draining the site of administration and that these T-cells proliferate independently of antigen supply in the microspheres. Taken together, our data add to the emerging model where antigen supply may not be a requirement in "vaccines" for autoimmune disease, but the site of administration - subserved by lymph nodes draining the target organ - is in fact critical to foster the generation of antigen-specific regulatory cells. The implications of these observations on "vaccine" design for autoimmunity are discussed and summarized.
authors.affiliation: Institute of Cellular Therapeutics, 11th Floor South Tower, Allegheny Health Network, 320 East North Avenue, Pittsburgh, PA, 15212, USA. Electronic address: CEngman@wpahs.org.
authors.forename: Carl
authors.initials: C
authors.lastname: Engman
authors.affiliation: Division of Pharmaceutical Sciences, Mylan School of Pharmacy, Mellon 413, 600 Forbes Avenue, Pittsburgh, PA 15282, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Wen
authors.affiliation: Division of Pharmaceutical Sciences, Mylan School of Pharmacy, Mellon 413, 600 Forbes Avenue, Pittsburgh, PA 15282, USA. Electronic address: meng@duq.edu.
authors.forename: Wilson S
authors.initials: WS
authors.lastname: Meng
authors.affiliation: Institute of Cellular Therapeutics, 11th Floor South Tower, Allegheny Health Network, 320 East North Avenue, Pittsburgh, PA, 15212, USA. Electronic address: RBottino@wpahs.org.
authors.forename: Rita
authors.initials: R
authors.lastname: Bottino
authors.affiliation: Institute of Cellular Therapeutics, 11th Floor South Tower, Allegheny Health Network, 320 East North Avenue, Pittsburgh, PA, 15212, USA. Electronic address: MTrucco1@wpahs.org.
authors.forename: Massimo
authors.initials: M
authors.lastname: Trucco
authors.affiliation: Institute of Cellular Therapeutics, 11th Floor South Tower, Allegheny Health Network, 320 East North Avenue, Pittsburgh, PA, 15212, USA. Electronic address: NGiannou@wpahs.org.
authors.forename: Nick
authors.initials: N
authors.lastname: Giannoukakis
mesh_terms: D000818:Animals; D018122:B7-1 Antigen / Q000235:genetics; D051940:B7-2 Antigen / Q000235:genetics; D001786:Blood Glucose / Q000187:drug effects; D039521:CD11c Antigen / Q000378:metabolism; D019013:CD40 Antigens / Q000235:genetics; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology; D003921:Diabetes Mellitus, Experimental / Q000628:therapy*; D003922:Diabetes Mellitus, Type 1 / Q000628:therapy*; D005260:Female; D051858:Forkhead Transcription Factors / Q000032:analysis; D055785:Gene Knockdown Techniques; D006943:Hyperglycemia / Q000628:therapy*; D017493:Leukocyte Common Antigens / Q000378:metabolism; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D008863:Microspheres; D016376:Oligonucleotides, Antisense / Q000235:genetics; D010179:Pancreas / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D050378:T-Lymphocytes, Regulatory / Q000166:cytology*; D014612:Vaccines / Q000008:administration & dosage / Q000276:immunology
chemical_list: D018122:B7-1 Antigen; D051940:B7-2 Antigen; D001786:Blood Glucose; D039521:CD11c Antigen; D019013:CD40 Antigens; C497965:Cd86 protein, mouse; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D016376:Oligonucleotides, Antisense; D011948:Receptors, Antigen, T-Cell; D014612:Vaccines; D017493:Leukocyte Common Antigens; C516770:Ptprc protein, mouse
keywords: Antigen; Dendritic; Diabetes; Immunotherapy; Microspheres; Tolerogenic