At present, animal models used in preclinical research mainly include small animal models with high repeatability and low cost, such as inbred mice. However, many small animal models cannot accurately predict human response due to their different genetic backgrounds and cannot eliminate the influence of species specificity on preclinical research, so many preclinical animal experimental results are very different from the human clinical response.
Some studies have shown that major histocompatibility complex (MHC) plays important roles in biological defense system by expressing a variety of antigen peptides and inducing T cell immune response, and the genetic difference of MHC molecules among species is one of the important factors leading to this difference. Therefore, it can be considered to replace animal MHC molecules with human leukocyte antigen (HLA) molecules in the experimental animals, so as to effectively improve the accuracy of animal models in predicting human immune response. Creative Biolabs makes full use of this difference and cooperates with partners to develop the HLA transgenic mouse model. With the unique SIAT® platform, we can provide a one-stop in vivo immunogenicity analysis service.
Fig.1 Immunogenicity assessment workflow.
T cell receptors (TCRs) are the antigen recognition mechanism on the surface of T lymphocyte. TCR forms homologous interactions with antigens through MHC in mice, human HLA on the surface of somatic cells, and specialized antigen-presenting cells of the innate immune system. TCR recognition activates the downstream immune response, which produces strong adaptive immunity.
The transplantation of HLA into immunocompromised mice is an important new tool for understanding human-specific pathogens and their immune responses. Using the mouse model, we can find the specific haplotype T cell epitope, which provides a powerful evaluation method for immunogenicity analysis.
Fig.2 Genetic humanization of individual targets or of entire portions of the immune system. (Zitvogel, 2016)
Immunologic analysis in HLA transgenic mice as the most important step in the immunogenicity test, a large amount of literature research and information retrieval are needed in the early stage. This model that can replicate human antigen presentation with HLA epitope binding specificity will continue to be used in more and more ways. Traditional vaccine methods, including epitope identification and validation, have been extended to cancer vaccine research. The evaluation of the antitumor activity of the tumor vaccine can be carried out directly in HLA transgenic mice. In T cell immunotherapy, HLA transgenic mice have been used to identify the sequence of high-affinity TCR, so as to develop a new chimeric antigen receptor (CAR) T-cell therapy. With the increase of immunotherapy research, these tools will become more and more important.
In addition, an experiment has been applied to the evaluation of HLA transgenic mice to Graves' disease. Scientists combined the histocompatibility complex binding test with the immune and tolerance induction test of HLA transgenic mice to prepare epitopes (antigen processing independent epitopes) from the thyroid-stimulating hormone receptor (TSHR). When the HLA transgenic mice were injected, the mixture of two immunodominant epitopes was sufficient to inhibit the response of T cells and antibodies to TSHR without damaging the tolerance of the mice.
In terms of immunologic analysis, Creative Biolabs has rich experimental experience and advanced technology. If you have any requirements, please contact us.
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