Enhancing Adaptive Immunity in THX Mice: Metabolite-Driven Strategies for Improved Antibody Responses

• Grant number: 25/06682-3
• Support Opportunities: Scholarships abroad - Research Internship - Master's degree
• Start date: August 20, 2025
• End date: February 19, 2026
• Field of knowledge: Biological Sciences - Immunology - Applied Immunology
• Principal Investigator: Priscila Pini Zenatti Salles
• Grantee: Maysa de Souza Cavalcante
• Supervisor: Paolo Casali
• Host Institution: Centro Infantil de Investigações Hematológicas Dr Domingos A Boldrini (CIB). Campinas , SP, Brazil
• Institution abroad: University of Texas Health Science Center at San Antonio (UTHSCSA), United States
• Associated to the scholarship: 24/01331-5 - Development of a humanized mice model for the study of humanized anti-IL7R antibodies in the treatment of acute lymphocytic leukemia, BP.MS

Abstract

Humanized mice (HuMice) are murine models in which the immune system is reconstituted with human immune cells. THX (Truly Human Xenograft) mice are humanized models conditioned with the administration of 17-¿-estradiol (E2), developed at the University of Texas Health Science Center under the supervision of PhD. Paolo Casali. THX mice exhibit elevated circulating human immunoglobulins (IgM, IgD, IgG, IgA, IgE), a diverse human leukocyte population in the spleen, and human-like red blood cells and platelets. Their huBCR and huTCR repertoires closely mirror those of humans. Moreover, they can mount both T-dependent and T-independent immune responses, producing high-affinity antibodies (huIgG1, huIgG2, huIgG3, huIgA, huIgE). B cells from THX mice have demonstrated the ability to undergo class switching to IgG, IgA, and IgE, generating plasmablasts and memory B cells in vitro, highlighting their differentiation capacity in vivo. Previous studies have shown that vitamin A and vitamin C metabolites, such as retinoic acid and ascorbate, are promising in enhancing immune development through epigenetic mechanisms mediated by ten-eleven translocation (TET) enzymes and toll-like receptors (TLR). Thus, this project aims to further develop the THX humanized mouse model, while also evaluating the impact of vitamin A and C metabolites on the differentiation of B cells into plasmablasts and memory B cells. Class switch recombination (CSR) and somatic hypermutation (SHM) will be evaluated in THX mice immunized with Escherichia coli lipopolysaccharide (LPS), assessing their ability to generate protective immune responses, including neutralization capacity and resistance to infection.