J-LEAPS vaccines initiate murine Th1 responses by activating dendritic cells.
The Ligand Epitope Antigen Presentation System (LEAPS) converts a peptide containing a T cell epitope as small as 8 amino acids into an immunogen and directs the nature of the subsequent response. Tandem synthesis of the J peptide (a peptide from the beta-2-microglobulin) with peptides of 15 or 30 amino acids from HSV-1 or HIV made them immunogenic and promoted Th1 immune responses. Immunization of A/J or C57BL/6 mice with J-LEAPS heteroconjugates containing an epitope from the HSV-1 glycoprotein D (JgD) or an epitope from the HIV gag protein (JH) emulsified with Seppic ISA51 induced increased levels of IL-12p70 by day 3 and increased levels of interferon gamma (IFN-gamma) on days 10 and 24. Interestingly, levels of IL-10, TNF-alpha, and IL-6 did not change. Neither the H nor the gD peptides alone elicited responses and only weak responses followed immunization with the J peptide. Bone marrow (BM) cells became CD86 and CD11c positive within 48 h of treatment with JgD or JH. JH or JgD treatment promoted IL-12p70 production and expression of CD8 denoting the maturation and activation of a subclass of myeloid DCs. Pure cultures of immature myeloid DCs also responded to JgD treatment, forming clusters, developing dendrites, and producing IL-12p70 within 24 h. The JH or JgD treated bone marrow cells (JgD-DC) were necessary and sufficient to activate splenic T cells to produce IFN-gamma and the JgD-DC provided an antigen specific booster response to T cells from JgD immunized mice. Adoptive transfer of JgD-DC was also sufficient to initiate protective antigen specific immunity from lethal challenge with HSV-1. The J-LEAPS vaccines appear to act as an adjuvant and immunogen on DC precursors in a unique manner to promote activation and maturation into IL-12p70 producing DCs which then can initiate sufficient Th1 immune responses to elicit protection without production of acute phase cytokines.
Taylor
P R
PR
Northeastern Ohio Universities Colleges of Medicine and Pharmacy, Rootstown, OH 44272, United States.
Koski
G K
GK
Paustian
C C
CC
Bailey
E
E
Cohen
P A
PA
Moore
F B-G
FB
Zimmerman
D H
DH
Rosenthal
K S
KS
D019264:Adoptive Transfer; D000818:Animals; D017951:Antigen Presentation; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D006561:Herpes Simplex / Q000276:immunology / Q000517:prevention & control; D018259:Herpesvirus 1, Human / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology; D018664:Interleukin-12 / Q000276:immunology; D051379:Mice; D008805:Mice, Inbred A; D008810:Mice, Inbred C57BL; D018417:Th1 Cells / Q000276:immunology*; D014759:Viral Envelope Proteins / Q000276:immunology; D014765:Viral Vaccines / Q000276:immunology*; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000276:immunology
D018984:Epitopes, T-Lymphocyte; D014759:Viral Envelope Proteins; D014765:Viral Vaccines; D054301:gag Gene Products, Human Immunodeficiency Virus; C039447:glycoprotein D, Human herpesvirus 1; D018664:Interleukin-12; D007371:Interferon-gamma