Immunology of aging and immunotherapy of aging-associated diseases

National Institute On Aging

Investigators

Linked publications & trials

Abstract

Previously I reported discovery of novel, aging-associated B1 B cells, termed 4BL cells, which accumulate in elderly humans, primates, and mice Lee-Chang et al., Blood, 2014; Lee-Chang et al., J. Immunol., 2016). Mechanistically, we linked their induction in aged hosts to dysbiosis of microbiota. We showed that the loss of beneficial commensals, such as Akkermansia muciniphila (Akk, which protects epithelial integrity of the gut and supports growth of other beneficial, short-chain fatty acid (SCFA)-producing bacteria) in aged hosts reduces SCFA bacteria and SCFAs such as butyrate, and increases gut leakiness and a chain of inflammatory events. Because butyrate is a potent inhibitor of TLR signaling, its decrease enables endotoxin to induce TLR4 signaling, activate CCR2+ monocytes (MO) to convert B1a B cells into 4BL cells in the omentum. Then, 4BL cells induce insulin resistance. We also demonstrated that this pathway is reversible. For example, a short-term supplementation with Akk blocks MO activation, accumulation of 4BL cells, and increase of insulin resistance in aging (Bodogai et al., Science Transl. Med., 2018). 1. The role of dysregulation of immune cells in cancer outcome in aging remains poorly understood. Our experimentations with aged mice with orthotropic cancers indicate that cancer outcome in aging differs from that of in young hosts and appears to depend on a cancer type and immune cells involved. In aged mice, progression of some tumors decreases while others increases. By performing an extensive profiling of immune cells of these mice we found that B cells deregulated in aging affect cancer fate utilizing different pathways. Interestingly, the same type of B cells appear to either promote or retard tumor growth depending on their crosstalk with cancer cells. As such, depletion of B cells with antibody can either exacerbate or inhibit tumor growth in aged mice. Importantly, we only observe these effects in old, but not young, mice. At present, we are elucidating the mechanism(-s) of these interesting results. 2. Akk is being widely proposed for therapy of metabolic syndromes and inflammatory pathologies of the elderly. However, safety and clinical consequence of its long-term use remain unknown. Although we reported that a brief supplementation with Akk is indeed beneficial, as it reverses inflammation and insulin resistance in aged mice, here we hypothesize that Akk long-term use may not be beneficial or be even harmful in aged hosts. To test this idea and to elucidate safety and consequence of a long-term supplementation with Akk, we initiated a longitudinal study in mice in 2019/2020. We gavaged middle-aged female and male mice with Akk for more than one year. The experimental part of the study is completed, and we are now finishing analyses of results, including immune profiling, metabolic measurement and gut microbiota sequencing data. Overall, despite significant interruption and loss of time and resources due to COVID-19 pandemic, we were able to achieve our goals. We plan to submit results of the study for publication in middle of 2022. 3. Aging is significant risk factor for dementia. Aiming to reverse age-associated dementia, we performed a collaborative study with professor Okun (Bar-Ilan University, Israel) exploring possibilities to induce antibody to neurotoxic antigens expressed in the brains of aged WT and transgenic mice. We found that aged C57BL/6 and 5xFAD mice exhibit a dramatic reduction in antibody production to neurotoxic Amyloid-b (Ab). Because vaccine response in aged hosts is usually impaired, here we devised a novel strategy for inducing amyloid beta (Ab)-specific antibody responses in aged mice that model Alzheimers disease (AD) by first priming with a vaccine carrier when the mice were young. We hypothesized that priming would establish a memory response that could be boosted at older, immunosenescent age. We demonstrate that the deficit in the induction of humoral responses in 18 m-old WT C57BL/6J and 12 m-old 5xFAD mice, an early-onset AD (EOAD) model, was indeed reversed if the mice were primed with HBsAg alone and then boost-immunized at an older age with AbCoreS. Compared with unprimed AD mice, the prime in young and boost in old strategy resulted in more efficient control of AD-related neuropathology. The results of this study we recently published (Illouz et al., Vaccine, 2021) Despite COVID-19 pandemic, which caused marked loss of opportunities, time and resources, we generated novel data with significant scientific and clinical relevance.