Scientists at UT Health San Antonio have created mice with fully functioning human immune systems that could revolutionize how researchers study all kinds of things that require an immune response, from cancer medications to organ transplantation.
Paolo Casali, M.D. is a University of Texas Ashbel Smith Professor and Distinguished Research Professor, Department of Microbiology, Immunology and Molecular Genetics in the Joe R. and Teresa Lozano Long School of Medicine. He leads the team that created what they call THX mice and is the lead author of the paper published this summer in nature immunology. The TH stands for Truly Human, and Casali says what’s impressive about them is the power of their immune response. They make all of the well-known immune system warriors, including macrophages, lymphocytes, monocytes, and T cells. Notably, they also make memory B cells, which create antibodies against invaders, and then remember them.
“Without memory B cells, vaccines could not exist,” Casali said. “A vaccine can be a vaccine only because it generates good memory B cells.”
UT Ashbel Smith Professor and Distinguished Research Professor
Department of Microbiology, Immunology & Molecular Genetics
The University of Texas Health Science Center at San Antonio
Casali’s team wanted to know how the THX immune system responded to vaccines, so it tested them using Salmonella Typhimurium. Their immune response was robust. Then, they moved to COVID-19.
“We wanted to see whether we could induce a neutralizing antibody response to SARS-CoV-2 using the Pfizer messenger RNA vaccine with a schedule identical to the one used in humans,” Casali said. “We did.”
This demonstrates the potential usefulness of THX mice in vaccine development, but what makes Casali’s mice different from earlier humanized mice?
Humanized mice are injected with human stem cells not long after they’re born. THX mice are no different. The goal is for those cells to graft, meaning they will replace the mouse’s immune system with a human one.
“We graft those mice by injecting cells in the left ventricle of the heart,” Casali said. “The mice are very small. They have no hair to speak of. So the skin is translucent and the left ventricle beats, and you can see it very easily.”
They inject the cells with a tiny insulin needle, and the process is not that different from the process that creates other humanized mice.
What is different — and what makes THX immune systems so robust — is that when THX mice are a few weeks old, they get a dose of something else. Estrogen. Casali called this the “critical point.”
“Estradiol is the most potent and abundant estrogen, and we put it in their drinking water,” Casali explained. “What we found, is that the graft mice administered estrogen develop a fully functional human immune system.”
Casali said that’s not a surprise, because women typically mount a greater and more effective response to infectious agents than men.
“And when I say greater, I mean three, four, fivefold greater than men,” Casali said. “The big question is why estrogen does all that.”
Casali hopes this inspires researchers to focus on answering that question, which could lead to an improved understanding of the human immune system. It also might help us understand why women are at much greater risk of developing autoimmune diseases like lupus.
Science & Medicine is a collaboration between TPR and The University of Texas Health Science Center at San Antonio that explores how scientific discovery in San Antonio advances the way medicine is practiced everywhere.
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