Targeting NK Cells With Tofacitinib: A Novel Treatment for ALS
Abstract
Though the cause or causes of amyotrophic lateral sclerosis (ALS) are currently unknown, an increasing body of work suggests that the immune system plays a key role in disease progression. Previous studies in mouse models of ALS, as well as our own preliminary data, demonstrate that altering levels of specific immune populations can affect the disease course. Thus, modulating specific immune cell populations may be a viable therapeutic strategy, but care must be taken to preserve the function of protective immune populations. Natural killer (NK) cells are immune cells that play a key role in combating cancer and infection, but are also responsible for eliminating damaged or dying cells. NK cells are more activated in the blood of ALS subjects, accumulate in the spinal cord of ALS mice, and ALS motor neurons are more vulnerable to NK cell-mediated damage. Our preliminary data suggest that depletion of NK cells from the periphery reduces neuroinflammation and extends survival in mouse models. Tofacitinib is an immune-modulating drug that is commercially available for use in rheumatoid arthritis. Not only does it alter immune polarization toward a less destructive immune phenotype, it has been shown to reduce NK cell levels in human subjects in a dose-dependent manner. In addition, it preserves the levels of protective immune cells, such as CD4 T cells. Our preliminary data show that tofacitinib suppresses NK cell activity in vitro and reduces peripheral NK cell levels in mice. The objective of this proposal is therefore to use tofacitinib to delay disease progression in a preclinical mouse model of ALS using both prevention and intervention drug regimens. In parallel, we will determine if tofacitinib blocks activity in NK cells taken from the blood of ALS subjects, determine the mechanism by which NK cells damage neurons, and determine whether tofacitinib can block this pathway. Overall, successful completion of the proposed studies will offer incredible insight into the potential efficacy of tofacitinib for ALS, and, at the same time, provide important knowledge regarding the contribution and mechanisms of NK cell cytotoxicity in ALS that will facilitate therapeutic and biomarker discovery. These outcomes will thus have a highly significant impact on treatment options for subjects with ALS.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110293
Entities
People
- Benjamin J Murdock
Organizations
- United States Army
- University of Michigan