Throughout our evolutionary journey, we've developed intricate social structures and ecological niches, bringing along the threats of infectious diseases and environmental toxins. Naturally, our immune systems have evolved alongside us, equipping us with the resilience vital for our species' survival.
Compared to mice, for instance, which have been utilised as experimental models in scientific research for centuries, our immune systems are much more complex.
“The human immune system is highly species specific,” explained Qingfeng Chen, a Senior Principal Investigator at A*STAR’s Institute of Molecular and Cell Biology (IMCB). “The mechanisms of immune ageing, which lead to diseases such as autoimmunity, cancer and Parkinson’s disease, are unique to humans.”
Chen and a team of collaborators, including scientists from A*STAR’s Singapore Immunology Network (SIgN), hypothesised that the weakening of the immune response with age might influence cancer development and the effectiveness of cancer treatments in older individuals.
They were particularly intrigued by how T cell dynamics change within the context of immune ageing, as these cells play a crucial role in cancer defence. To test their theory, they developed a genetically engineered mouse model lacking its own immune system but capable of hosting human immune cells.
“NOD-scid IL2rγ−/− (NIKO) mice lack a functional mouse immune system,” stated Chen. “When human hematopoietic stem cells (HSC) are injected into these mice, they can differentiate into various immune cell types, effectively creating a humanised immune system within the mouse.”
As the mice matured, the researchers noted a decline in the population of naïve T cells—those yet to encounter a pathogen—while the numbers of memory and senescent-like T cells, exhibiting signs of ageing, surged. Furthermore, aged mice demonstrated accelerated liver tumour growth relative to their younger counterparts, suggesting reduced effectiveness of ageing immune systems against cancer.
Chen explained that RNA-sequencing revealed downregulated genes linked to immune responses to cancer cells, supporting the idea that ageing T cells produce fewer cancer-killing cytokines.
The use of humanised mouse models holds promise for yielding more accurate predictions on how elderly populations might react to cancer therapies. This approach also promises to enhance the development and evaluation of new drugs, potentially leading to more effective anti-cancer treatments for older adults.
For Chen's team, their inquiry persists in the quest to advance sophisticated humanised mouse models. "We will delve into more detailed head-to-head data analyses comparing the immune systems of humanised mice and humans to identify potential targets for studying how the immune system ages," concluded Chen.
The A*STAR-affiliated researchers contributing to this research are from the Institute of Molecular and Cell Biology (IMCB) and Singapore Immunology Network (SIgN).
