The neuroimmune system protects our brain from harmful invaders, but recent research has linked it to Alzheimer’s disease (AD) progression. When this system becomes imbalanced, it can mistakenly attack healthy brain cells, leading to neurodegeneration. Adding to this problem, immune cells from the rest of the body can cross the blood-brain barrier (BBB) and contribute to brain inflammation and damage.
Killer T cells, a type of adaptive immune cell, play a crucial role in this process. Recent work by the Holtzman lab, which earned them the inaugural Jeffrey L. Morby Prize, revealed increased numbers of killer T cells in tau-affected brain areas in both mice and human AD patients. The study also discovered that microglia help killer T cells infiltrate the brain and cause damage in areas affected by tau protein buildup. Killer T cells represent only one type of T cell in the body’s immune system. Different T cell types have distinct, and sometimes opposing, functions. Helper T cells coordinate immune responses by summoning macrophages and killer T cells to sites of infection. In contrast, regulatory T cells (Tregs) act as the immune system’s brakes to stop the immune response once the pathogen is cleared. They also prevent killer T cells from overreacting and attacking nearby healthy cells. Drs. Tessier and Holtzman believe this natural balance offers a potential therapeutic strategy: rather than simply blocking killer T cells in response to AD pathology, they propose boosting the number of T cells that naturally counteract them. They hypothesize that increasing Tregs in the brain will reduce neuroinflammation and related AD pathologies.
Dr. Tessier’s team is focused on IL-2, a signaling molecule that increases the number of Treg cells. However, getting IL-2 into the brain is a challenge because it has a short lifespan and cannot easily cross the BBB. To overcome this, Dr. Tessier developed bAb-IL-2, a bi-specific antibody made from two antibody fragments: one targets a BBB transporter molecule to facilitate brain entry, while the other binds to a brain-specific protein once inside. They hypothesize that this dual-targeting approach will successfully deliver IL-2 into the brain, increasing Treg numbers and preventing tau-mediated neurodegeneration. Given the success of intravenously delivered immunotherapies in clinical trials, bAb-IL-2 has immense translational potential. To test their hypothesis, they are using a tauopathy mouse model with the human APOE4 gene, created in collaboration with Dr. Holtzman and partially funded by CureAlz.
The Tessier and Holtzman labs are evaluating the effectiveness of bAb-IL-2s in treating AD across two aims. In Aim 1, the Tessier team is testing multiple bAb-IL-2 fusion proteins to identify the optimal dose needed to increase Tregs in the brain without expanding the population of Tregs in the periphery (the rest of the body). The team is measuring the absorption, distribution, metabolism, and excretion (pharmacokinetics) of IL-2 in the brain, spleen, and blood. They are using radiotracing, staining, and flow cytometry for these measurements. In Aim 2, the Holtzman lab is testing whether bAb-IL-2 prevents neurodegeneration and cognitive impairments in the tau P301S/APOE4 mouse model by evaluating the ability of IL-2 to reduce T cell infiltration and microglial activation, as well as preserve hippocampal volume using staining and biochemical measurements. Additionally, they are expanding these studies to include behavioral assays to determine if the treatment affects cognitive abilities.
In the first year of funding, the team made significant progress. In Aim 1, they demonstrated in mice that their bi-specific antibody-IL-2 fusion protein successfully crosses the BBB, accumulates in the brain and spinal cord, and selectively expands Tregs without activating effector T cells in the CNS or periphery. This delivery method is both highly specific and sustained and drives Treg expansion without triggering unwanted immune activation. Repeat dosing continues to show robust Treg expansion, with the team carefully monitoring modest effects of anti-drug antibodies. For Aim 2, they launched a pilot study to determine whether the same dosing strategies are effective in tau/APOE4 transgenic mice, a strain known to exhibit age-related increases in neuroinflammation. In the coming year, they will build on these findings to assess whether this approach can reduce neuroinflammation and prevent neurodegeneration in vivo.
