Protection against experimental autoimmune encephalomyelitis generated by a recombinant adenovirus vector expressing the V beta 8.2 TCR is disrupted by coadministration with vectors expressing either IL-4 or -10.
Adenovirus vectors are increasingly being used for genetic vaccination and may prove highly suitable for intervention in different pathological conditions due to their capacity to generate high level, transient gene expression. In this study, we report the use of a recombinant adenovirus vector to induce regulatory responses for the prevention of autoimmune diseases through transient expression of a TCR beta-chain. Immunization of B10.PL mice with a recombinant adenovirus expressing the TCR Vbeta8.2 chain (Ad5E1 mVbeta8.2), resulted in induction of regulatory type 1 CD4 T cells, directed against the framework region 3 determinant within the B5 peptide (aa 76-101) of the Vbeta8.2 chain. This determinant is readily processed and displayed in an I-A(u) context, on ambient APC. Transient genetic delivery of the TCR Vbeta8.2 chain protected mice from Ag-induced experimental autoimmune encephalomyelitis. However, when the Ad5E1 mVbeta8.2 vector was coadministered with either an IL-4- or IL-10-expressing vector, regulation was disrupted and disease was exacerbated. These results highlight the importance of the Th1-like cytokine requirement necessary for the generation and activity of effective regulatory T cells in this model of experimental autoimmune encephalomyelitis.
Braciak
Todd A
TA
Division of Immune Regulation, La Jolla Institute for Allergy and Immunology, San Diego, CA 92121, USA. tbraciak@tpims.org
Pedersen
Brian
B
Chin
Judy
J
Hsiao
Clay
C
Ward
E Sally
ES
Maricic
Igor
I
Jahng
Alex
A
Graham
Frank L
FL
Gauldie
Jack
J
Sercarz
Eli E
EE
Kumar
Vipin
V
D000260:Adenoviruses, Human / Q000235:genetics* / Q000276:immunology*; D000595:Amino Acid Sequence; D000818:Animals; D002455:Cell Division / Q000235:genetics / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D004306:Dose-Response Relationship, Immunologic; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000517:prevention & control*; D005260:Female; D005822:Genetic Vectors / Q000008:administration & dosage / Q000138:chemical synthesis / Q000276:immunology*; D006801:Humans; D007114:Immunization; D016056:Immunodominant Epitopes / Q000633:toxicity; D007135:Immunoglobulin Variable Region / Q000235:genetics / Q000276:immunology; D016130:Immunophenotyping; D007273:Injections, Intramuscular; D007274:Injections, Intraperitoneal; D016753:Interleukin-10 / Q000096:biosynthesis*; D015847:Interleukin-4 / Q000096:biosynthesis*; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D004676:Myelin Basic Protein / Q000633:toxicity; D010446:Peptide Fragments / Q000276:immunology / Q000633:toxicity; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D011995:Recombination, Genetic / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism
D016207:Cytokines; D016056:Immunodominant Epitopes; D007135:Immunoglobulin Variable Region; D004676:Myelin Basic Protein; D010446:Peptide Fragments; D016693:Receptors, Antigen, T-Cell, alpha-beta; C074815:myelin basic protein 1-9; D016753:Interleukin-10; D015847:Interleukin-4