New Breakthrough in Biomedical Research Could Revolutionize Immunotherapy and Disease Modeling

A breakthrough in biomedical research has opened doors to greater understanding in immunotherapy and disease modeling. Scientists at The University of Texas Health Science Center at San Antonio have engineered a new type of humanized mouse model that features both a human-like immune system and microbiome. This allows the mice to generate specific and targeted antibody responses.

This long-term research was directed by Dr. Paolo Casali, Ashbel Smith and Distinguished Research Professor at UT's Department of Microbiology, Immunology, and Molecular Genetics in the Joe R. and Teresa Lozano Long School of Medicine. With fifty years of experience, Casali is a distinguished figure in molecular genetics, epigenetics, immunology, and microbiology.

Set to be published in the August 2024 issue of Nature Immunology, the multi-year project sought to overcome the limitations tied to existing in vivo human models. The goal was to develop a humanized mouse endowed with a fully functioning human immune system.

Mice are widely favored in scientific research due to their size, ease of handling, and numerous biological similarities with humans. Additionally, they can be genetically altered for experimental purposes. However, significant genetic differences between human and mouse immune systems have resulted in inconsistent findings, reinforcing the demand for a more human-representative model.

The concept of humanized mice dates back to the 1980s when they were first created to replicate human immune responses during HIV infection. These models, built by introducing human cells into immunocompromised mice, have persisted to this day. However, earlier versions have not displayed fully functional human immune systems, limiting their effectiveness in therapeutic and disease research applications.

In this new approach, Casali's team started by injecting NSG W41 mutant mice (which lack immune defenses) with purified human stem cells from umbilical cord blood. Afterwards, the mice were hormonally treated with 17b-estradiol (E2), the most abundant natural estrogen. Previous findings, including those from Casali’s own research, suggest that estrogen helps boost the survival of human stem cells and enhances the immune system’s production of antibodies.

The resulting humanized mouse model, now named TruHuX (short for “truly human,” or THX), carries a fully developed immune system. Notably, these mice feature human lymph nodes, thymus glands, human-like T and B lymphocytes, and memory cells capable of producing precise antibodies, including autoantibodies.

When exposed to vaccines such as the Pfizer COVID-19 mRNA vaccine and Salmonella flagellin, THX mice developed neutralizing antibody responses robust enough to mimic human reactions to both SARS-CoV-2 and Salmonella Typhimurium. In addition, they exhibited susceptibility to systemic lupus after being injected with a substance known to trigger inflammation.

According to Dr. Casali, the THX model opens new avenues for human-based experimentation, particularly in immunotherapy, vaccine production, and disease modeling. With possibilities spanning cancer treatment and future vaccines for bacterial and viral diseases, the hope is that the THX model may help reduce reliance on non-human primates in biomedical research.

While the relationship between estrogen and immune response is not extensively studied, Dr. Casali is optimistic that this work will spur more investigation into this promising connection.

“Harnessing the power of estrogen to enhance human stem cell survival, immune cell differentiation, and antibody formation, the THX mouse offers an innovative platform for studying human immune responses and developing novel immunotherapies and vaccines,” Casali explained.

With the THX model in place, Dr. Casali and his team are now exploring human immune responses to COVID-19 at systemic and localized levels. Other ongoing research focuses include how nuclear receptor RORα impacts memory B cell generation and the epigenetic mechanisms that drive antibody-producing cells to fight infection, cancer, and other threats.

A humanized mouse model that produces highly specific neutralizing antibodies

Authors: Daniel P. Chupp, Carlos E. Rivera, Yulai Zhou, Yijiang Xu, Patrick S. Ramsey, Zhenming Xu, Hong Zan, and Paolo Casali

Original Release Date: June 25, 2024 | Published in Volume 25, Issue 8 of Nature Immunology (August 2024)

DOI: 10.1038/s41590-024-01880-3

Journal

Nature Immunology

DOI

10.1038/s41590-024-01880-3

Method of Research

Experimental Study

Area of Research

Animal Models

Article Title

A humanized mouse that mounts mature class-switched, hypermutated and neutralizing antibody responses

Publication Date

June 25, 2024

Competing Interests

The authors have disclosed no competing financial interests.