Abstract
We have established an HLA-A2.1 transgenic rabbit /cottontail rabbit papillomavirus (CRPV) infection model. Using this novel transgenic animal model, we reported earlier that a multivalent epitope DNA vaccine (CRPVE1ep1-5) containing five HLA-A2.1 restricted epitopes from CRPVE1 (42-50, 149-157, 161-169, 245-253 and 303-311) was successful in providing strong and specific protective and therapeutic immunity. Among these five epitopes, two (161-169 and 303-311) have been proven to stimulate strong immunity in both HLA-A2.1 transgenic mouse and rabbit models. In the current study, we further identified the remaining three epitopes (CRPVE1/42-50,149-157, 245-253) in both animal models. CRPVE1/149-157 was able to induce specific CTL responses in HLA-A2.1 transgenic mice by DNA immunization but undetectable by peptide immunization. CRPVE1/42-50 and 245-253 failed to respond in HLA-A2.1 transgenic mice either by peptide or DNA immunization. All the three epitopes when administrated as DNA vaccines, however, were able to stimulate strong protective immunity in HLA-A2.1 transgenic rabbits in a dose dependent manner. Among the five epitopes, two (CRPVE1/ 303-311and CRPVE1/149-157) DNA vaccines also showed specific therapeutic effects in CRPV-infected HLA-A2.1 transgenic rabbits. Taken together, the HLA-A2.1 transgenic rabbit model recognized more epitopes than did the HLA-A2.1 transgenic mouse model. Our data demonstrate that the HLA-A2.1 transgenic rabbit model can complement the HLA-A2.1 transgenic mouse model for the development and testing of new HLA-A2.1 restricted prophylactic and therapeutic T cell based DNA vaccines.
Highlights
HLA-A2.1 is a prevalent human MHCI molecule [1,2]
We carried out studies using both HLA-A2.1 transgenic mouse and rabbit models to screen and characterize three remaining HLA-A2.1 restricted epitopes from our previous work(CRPVE1/ 245-253, 42-50 and 149-157) predicted by online MHCI epitope prediction programs for immunogenicity and protective immunity [19]
Our initial hypothesis was that the epitopes would behave consistently between these two transgenic animal models
Summary
Many well characterized HLA-A2.1 restricted epitopes have been tested for their therapeutic effects for viral infection or tumor formation in the HLA-A2.1 transgenic mouse (HHD) model [3,4,5,6]. Show limited susceptibility to certain human pathogens such as ocular HSV-1, HTLV-1, tuberculosis and syphilis for which rabbits are susceptible [7,8,9]. Our recently established HLA-A2.1 transgenic rabbit provides an excellent host to test the immunogenicity of different epitope vaccines from these pathogens to compensate for certain limitations of the HHD mouse model [10, 11]. The viruses show high species specificity and no animal model is available to study HPV infection in vivo [13,14,15]. We and others have used the cottontail rabbit papillomavirus (CRPV) / rabbit model as a surrogate model for high-risk HPV infections in the human population [15,16,17,18]
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