Transgenic mice having a human major histocompatibility complex (MHC) phenotype, experimental uses and applications

Abstract

The present invention-relates to transgenic mice and isolated transgenic mouse cells, the mice and mouse cells comprising a disrupted H2 class I gene, a disrupted H2 class II gene, a functional HLA class I transgene, and a functional HLA class II transgene. In embodiments, the transgenic mouse or mouse cells are deficient for both H2 class I and class II molecules, wherein the transgenic mouse comprises a functional HLA class I transgene and a functional HLA class II transgene. In embodiments, the transgenic mouse or mouse cell has the genotype HLA-A2+HLA-DR1+β2m°IAβ°. The invention also relates to methods of using a transgenic mouse of the invention.

Description

CROSS-REFERENCE TO RELATED APPLICATION[0001]This application is based on and claims the benefit of U.S. Provisional Application No. 60 / 490,945, filed Jul. 30, 2003 (Attorney Docket No. 03495.6093), the entire disclosure of which is relied upon and incorporated by reference herein for all purposes.BACKGROUND OF THE INVENTION[0002]Many vaccines are currently being developed for human cancer immunotherapy and for treatment of infectious diseases, such as malaria, AIDS, hepatitis C virus, and SARS. Given the rapidity with which new emerging pathogens can appear, it is important to improve animal models that could be used to evaluate vaccination strategies and the protective capacity of different epitopes quickly and reliably. Furthermore, in vivo studies are already required to assess crucial variables of vaccine behavior that are not easily evaluated or impossible to measure in vitro, such as vaccine immunogenicity, vaccine formulation, route of administration, tissue distribution, and...

AI Technical Summary

Benefits of technology

[0012]The inventors have met this need and more by providing mice transgenic for both HLA-A2.1 and HLA-DR1 molecules, in a background that is deficient for both H-2 class I and class II molecules. Specifically, the invention provides mice comprising (1) mutated H-2 class I and class II molecules; and (2) expressing HLA class I transgenic molecules, or HLA class II transgenic molecules, or HLA class I transgenic molecules and HLA class II transgenic molecules. These mice provide a model useful in the development and optimization of vaccine constructs with maximum in vivo immunogenicity for human use. Specifically, such mice enable a complete analysis of the three components of the immune adaptive response (antibody, helper and cytolytic) in a single animal, as well as an evaluation of the protection specifically conferred by vaccination against an antigenic challenge.

Problems solved by technology

Furthermore, in vivo studies are already required to assess crucial variables of vaccine behavior that are not easily evaluated or impossible to measure in vitro, such as vaccine immunogenicity, vaccine formulation, route of administration, tissue distribution, and involvement of primary and secondary lymphoid organs.

The use of otherwise immunogenic vaccines consisting of attenuated pathogens in humans is hampered, in several important diseases, by overriding safety concerns.

CTL epitope definition based on the usage of human lymphocytes might be misleading due to environmental and genetic heterogeneity that lead to incomplete results, and due to technical difficulties in isolating CTL clones.

This may be partly explained by the failure of these vaccines to induce sufficiently strong CTL responses.

CTL are critical components of protective immunity against viral infections, but the requirements for in vivo priming of CTL are not completely understood.

However, protective immune responses against pathogens, which often require collaboration between T helper and cytotoxic CD8+ T cells, cannot be studied in the single HLA class I- or HLA class II-transgenic mice, which do not allow the simultaneous assessment of HLA class I and II human responses in the same mouse.

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