A vaccine conjugate of 'ISCAR' immunocarrier and peptide epitopes of the E7 cervical cancer-associated protein of human papillomavirus type 16 elicits specific Th1- and Th2-type responses in immunized mice in the absence of oil-based adjuvants.
TraT protein, known as ISCAR (= Immunostimulatory Carrier), is one of a family of integral membrane proteins (Imps) of Escherichia coli representing powerful carrier molecules which when injected into experimental animals generate substantial antibody and T proliferative responses to molecules conjugated to it. We extend these findings to show that ISCAR functions to stimulate Th1- and Th2-type responses, including specific cytotoxic T cells and tumour protection. We report here that by conjugating to ISCAR a 19mer peptide containing linear B epitopes, a T helper (Th) epitope, and a H-2b-restricted T cytotoxic (CTL) epitope of E7 protein of human papillomavirus type 16 (HPV16), and immunizing C57B1/6 (H-2b) mice, we elicited (i) specific IgG2a and IgG1 antibodies; (ii) IL-2 and IL-4 production by specifically recalled lymph node cells in vitro; (iii) cytotoxic T lymphocytes which specifically killed both E7 peptide-pulsed, and whole E7 gene-transfected tumour target cells; and (iv) in vivo protection against an E7 gene-transfected tumour cell inoculum. These findings have implications for the design of vaccines to stimulate immune responses to endogenously processed target antigens (e.g. tumour-associated antigens) without the unwanted side effects of oil-based adjuvants. In addition they support the case for a E7-targeted therapeutic vaccine for HPV-associated human cervical cancer.
Tindle
R W
RW
Department of Medicine, University of Queensland, Princess Alexandra Hospital, Brisbane, Australia.
Croft
S
S
Herd
K
K
Malcolm
K
K
Geczy
A F
AF
Stewart
T
T
Fernando
G J
GJ
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000595:Amino Acid Sequence; D000818:Animals; D000914:Antibodies, Viral / Q000096:biosynthesis / Q000097:blood; D000951:Antigens, Neoplasm / Q000276:immunology; D001425:Bacterial Outer Membrane Proteins / Q000276:immunology*; D000939:Epitopes / Q000276:immunology*; D029968:Escherichia coli Proteins; D005260:Female; D007114:Immunization; D007376:Interleukin-2 / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009374:Neoplasms, Experimental / Q000517:prevention & control; D009856:Oncogene Proteins, Viral / Q000276:immunology*; D027383:Papillomaviridae; D050725:Papillomavirus E7 Proteins; D053918:Papillomavirus Vaccines; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D018074:Vaccines, Conjugate / Q000494:pharmacology; D014765:Viral Vaccines / Q000494:pharmacology*
D000276:Adjuvants, Immunologic; D000914:Antibodies, Viral; D000951:Antigens, Neoplasm; D001425:Bacterial Outer Membrane Proteins; D000939:Epitopes; D029968:Escherichia coli Proteins; D007376:Interleukin-2; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D053918:Papillomavirus Vaccines; C036297:TraT protein, E coli; D018074:Vaccines, Conjugate; D014765:Viral Vaccines; C059731:oncogene protein E7, Human papillomavirus type 16; D015847:Interleukin-4