Induction of T1 (cytotoxic lymphocyte) and/or T2 (antibody) responses to a mucin-1 tumour antigen.
Effective vaccination-based control of intracellular pathogens or parasites and various tumours is dependent upon induction of cytotoxic lymphocytes and other mechanisms of cellular immunity. Such responses are usually described as being antagonistic to an antibody-based immune response. This paper elaborates on previous studies that have demonstrated that conjugation of a fusion protein (FP, incorporating copies of the variable number of tandem repeat sequence of human mucin-1 (MUC1)) to oxidized mannan results in a significant shift from a type-2 response towards a type-1 response. This response induces complete protection upon challenge of immunized mice with MUC1 expressing tumour cells. This report details experiments in which the balance between type-1 and type-2 anti-MUC1 responses is manipulated by altering the dose of mannan-FP (M-FP) delivered. It is also shown that type-1 and type-2 responses may be induced simultaneously by administration of both forms of the antigen (FP/M-FP). Further, when a type-2 response is induced after FP immunization, a type-1 response can also be established by subsequent immunization with M-FP without adversely affecting the initial response. The converse also applies when M-FP is used for the initial immunizations, followed by FP administration. Delivery of interleukin-1 beta as a cytokine adjuvant with M-FP immunizations also enhanced antibody responses to levels fourfold that induced by M-FP alone without adversely affecting the cytotoxic activity induced by M-FP immunization. Contrary to the type-1/type-2 paradigm, cellular and antibody responses to MUC1 were not antagonistic. These results have important implications for the development of vaccination strategies against pathogens for which both the cellular and humoral compartments of the immune response contribute to protection.
Lofthouse
S A
SA
Austin Research Institute, Heidelberg, Vic., Australia.
Apostolopoulos
V
V
Pietersz
G A
GA
Li
W
W
McKenzie
I F
IF
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000595:Amino Acid Sequence; D000818:Animals; D000917:Antibody Formation; D002460:Cell Line; D004306:Dose-Response Relationship, Immunologic; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D008351:Mannans / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D018396:Mucin-1 / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D018074:Vaccines, Conjugate / Q000276:immunology
D000276:Adjuvants, Immunologic; D007375:Interleukin-1; D008351:Mannans; D018396:Mucin-1; D018074:Vaccines, Conjugate