Cytomegalovirus-based immunogenic preparations
A technology of cytomegalovirus and human cytomegalovirus, applied in the direction of antiviral agents, viruses, viruses/phages, etc., can solve the problems of restricting the use of CMV tumor vaccines and becoming immunodeficiency
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Embodiment 1
[0195] Example 1: Antitumor efficacy of CMV-loaded antigen-primed CTLs
[0196] A major challenge in developing effective anti-tumor vaccines is overcoming the inability of the immune system to distinguish tumors from self-proteins. More recently, attempts to develop a heritable immuno-sterility control for wild mice have shown that normal self-proteins expressed in recombinant CMV vectors have the potential to become antigenic (Lloyd et al., Biol. Reprod. 68:2024-2032, 2003 and Redwood et al., J. Virol. 79:2998-3008, 2005). In this study, the native sequence of murine zona pellucida 3 (ZP3), a normal mouse protein, was introduced into MCMV behind the immediate early 2 (IE2) promoter. Strikingly, a single inoculation of the virus rendered female mice completely sterile for the length of time as observed (>230 days).
[0197]This example demonstrates that tumor-expressed self-antigens also become immunogenic when expressed in the context of CMV. The therapeutic capacity of t...
Embodiment 2
[0206] Example 2: Infection with replication-deficient ΔgL MCMV elicits durable immunogenic priming and expansion of T cell memory
[0207] On average, humans contribute their memory CD8 to CMV + 10% of the T cell compartment. Research in recent years has revealed that this extraordinary immune response to CMV infection involves several stages. In initial CD8 + Following the T cell response, the T cell response to MCMV begins to decline to the characteristic "memory" level (Munks et al., J. Immunol. 176:3760-3766, 2006). However, it then begins a remarkable process called "memory expansion" (Karrer et al., J. Immunol. 170:2022-2029, 2003 and Munks et al., J. Immunol. 177:450-458, 2006). For a period of several months, CD8 T cell responses to specific epitopes increased in number, eventually plateauing at higher levels such that the total CMV-specific response contained between 10% and 30% CD8 + T cells.
[0208] This example demonstrates that replication-defective MCMVs i...
Embodiment 3
[0221] Example 3: Lack of expansion of T cell memory in response to subcutaneous ΔgL MCMV infection
[0222] As shown in Example 2, CD8 + T cell memory expansion is driven by intraperitoneal infection of mice with wild-type and ΔgLMCMV. It is believed that the ability of ΔgL MCMV to elicit long-lasting self-excited T cell memory is a consequence of establishing CMV latency in HSCs. Thus, any administration of CMV that exposes the virus to HSCs (eg, intravenous administration) will similarly trigger the characteristic expansion of T cell memory. This example shows that subcutaneous administration of replication deficient MCMV failed to detect expansion of T cell memory.
[0223] method
[0224] Mice were infected as in Example 1 and Example 2. However, in this example, mice were anesthetized with isoflurane and infected with either wild-type or ΔgL MCMV by a single injection into the left hind footpad. T cell responses to wild-type and ΔgL MCMV in peripheral blood were det...
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