Antibody treatment partially shields older mice from infections

An antibody treatment given to older mice before pathogen exposure improved immune cell function and increased survival. The antibody, developed against a protein called programmed cell death 1 (PD1), boosts the immune systems of older mice, safeguarding them from microbes that would normally be lethal. Researchers also found the protection resulting from anti-PD1 treatment was dependent on CD8+ T cells, immune cells that target virus- or bacteria-infected cells or cancer cells. Findings from the NIA-funded study, published in Nature Aging, suggest anti-PD1 immunotherapy could reduce the risk of death from infections in older mice. The research could potentially lead to human therapies that enhance immune function in older adults.

As mice get older, their immune systems become weaker and less efficient at removing damaged and dying cells. As a result, these aged cells build up in the body and cause inflammation. When viruses and bacteria infect older mice, the microbes add to an already elevated state of inflammation by inducing the body to release a large number of inflammatory proteins simultaneously. This release is called a cytokine storm and can be life-threatening. The rodent immune system aims to kill the microorganisms and remove infected cells before reaching this dangerous point.

PD1, which appears on the surface of CD8+ T cells and other immune cells, is involved in one of the signaling pathways that leads to cell death. The presence of pathogens in a mouse causes PD1 to initiate a molecular cascade that prevents CD8+ T cells from doing their job of killing infected cells and secreting molecules that suppress inflammation. In this study, a research team led by scientists at the University of Minnesota wanted to know how microbial infections affected mouse CD8+ T cells and whether blocking PD1 with anti-PD1 treatment would reduce the risk of dying from infection in older mice.

Team members used specific pathogen-free mice, which have been tested and determined to be free of a list of disease-causing microorganisms. They subjected the mice to a method in which pathogen-free mice are exposed to microbes commonly found in pet store mice, called dirty mice. Mice that were young (3-6 months) or older (18-24 months) were cohoused with dirty mice for one, three, seven, or nine days. Control mice were housed separately from dirty mice, leaving them unexposed.

The scientists examined tissues from young and older exposed mice at the various timepoints by using several laboratory techniques, such as RT-PCR and RNA sequencing. They found CD8+ T cells from young, exposed mice did not undergo a decline in function, called exhaustion. The authors added the exposure helped young mice develop a mature and more robust immune system in the days and weeks after contact with dirty mice. In contrast, CD8+ T cells from older, exposed mice displayed exhaustion, and the mice experienced acute inflammation as early as day three of exposure. These older mice also had a higher risk of dying.

To find out whether anti-PD1 treatments could improve survival, the researchers gave older female mice anti-PD1 before exposing them to dirty mice. In addition to living longer than nontreated older female mice, they did not generate high levels of inflammatory proteins. The results suggest blocking PD1 increases survival in older female mice by improving the function of the CD8+ T cells and without generating a heightened inflammatory response.

In humans, anti-PD1 is known as pembrolizumab (Keytruda), an FDA-approved medication commonly used for cancer treatment. While more clinical pembrolizumab studies must be conducted to establish whether it improves the immune response in people, this research offers an intriguing strategy that could potentially benefit older adults.

This research was supported in part by NIA grants R00AG058800, R21AG078638, R01AG079913, and T32AG029796.

Reference: Dahlquist KJV, et al. PD1 blockade improves survival and CD8+ cytotoxic capacity, without increasing inflammation, during normal microbial experience in old mice. Nature Aging. 2024;4(7):915-925. doi: 10.1038/s43587-024-00620-4.