Abstract The human leukocyte antigen (HLA) system plays a central role in orchestrating adaptive immune responses. While existing single-allele humanized models have been valuable, there is a growing need for preclinical platforms that more fully recapitulate human HLA class I and II restricted immunity to evaluate complex immunotherapies. To address this, we developed a novel MHC I/II dual-humanized mouse model, the B-HLA-A2.1/HLA-DRB1*1.1 mouse.The B-HLA-A2.1/HLA-DRB1*1.1 model was generated by co-integrating the human HLA-A02:01 and HLA-DRB1*01:01 genes into the C57BL/6 background. Human HLA-A2.1 and HLA-DRB1 protein expression was confirmed by flow cytometry on spleen, peripheral blood, and bone marrow leukocytes. Comprehensive immune cell profiling was performed to characterize T and B cell populations. The model's functionality was validated in a therapeutic tumor vaccination study using a human epitope-targeting vaccine.Flow cytometric analysis confirmed stable and robust cell surface expression of both HLA-A2.1 and HLA-DRB1 proteins in homozygous mice. The frequency of CD8+ T cells in the spleen, blood, and lymph node was significantly decreased, while the frequency of CD4+ T cells was significantly increased, demonstrating that the introduction of HLA-A02:01 and HLA-DRB1*01:01 affected the development of T cells. Additional analyses, including hematology, serum biochemistry, and histopathological examination (H Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4384.
Emerson et al. (Fri,) studied this question.