Targeted antigen delivery to antigen-presenting cells including dendritic cells by engineered Fas-mediated apoptosis.
Immunity to tumors as well as to viral and bacterial pathogens is often mediated by cytotoxic T lymphocytes (CTLs). Thus, the ability to induce a strong cell-mediated immune response is an important requirement of novel immunotherapies. Antigen-presenting cells (APCs), including dendritic cells (DCs), are specialized in initiating T-cell immunity. Harnessing this innate ability of these cells to acquire and present antigens, we sought to improve antigen presentation by targeting antigens directly to DCs in vivo through apoptosis. We engineered Fas-mediated apoptotic death of antigen-bearing cells in vivo by co-expressing the immunogen and Fas in the same cell. We then observed that the death of antigen-bearing cells results in increased antigen acquisition by APCs including DCs. This in vivo strategy led to enhanced antigen-specific CTLs, and the elaboration of T helper-1 (Th1) type cytokines and chemokines. This adjuvant approach has important implications for viral and nonviral delivery strategies for vaccines or gene therapies.
Chattergoon
M A
MA
Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia 19104, USA.
Kim
J J
JJ
Yang
J S
JS
Robinson
T M
TM
Lee
D J
DJ
Dentchev
T
T
Wilson
D M
DM
Ayyavoo
V
V
Weiner
D B
DB
D000818:Animals; D017304:Annexin A5 / Q000378:metabolism; D000938:Antigen-Presenting Cells / Q000276:immunology* / Q000378:metabolism*; D000941:Antigens / Q000378:metabolism*; D017209:Apoptosis; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002469:Cell Separation; D018076:DNA, Complementary / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors; D007150:Immunohistochemistry; D007167:Immunotherapy / Q000379:methods; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism; D008198:Lymph Nodes / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009132:Muscles / Q000378:metabolism; D010957:Plasmids / Q000378:metabolism; D013154:Spleen / Q000166:cytology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000473:pathology; D018417:Th1 Cells / Q000276:immunology / Q000473:pathology; D013997:Time Factors; D014162:Transfection; D019014:fas Receptor / Q000378:metabolism*
D017304:Annexin A5; D000941:Antigens; D018076:DNA, Complementary; D019014:fas Receptor; D018664:Interleukin-12; D007371:Interferon-gamma