Targeting the MIF/CD74 Immune Axis to Treat GWI Astrocyte, Neuronal, and Cognitive Dysfunction
Abstract
Gulf War Illness (GWI) is a debilitating illness characterized by diverse symptoms that include widespread pain, cognitive difficulties, fatigue, gastrointestinal problems, respiratory symptoms, chronic headaches, sleep problems, and other abnormalities that are not explained by established medical diagnoses or standard laboratory tests. Approximately 25-32% (or 175,000 to 224,000) of the nearly 700,000 of the Veterans who served in the 1990-1991 Gulf War present one or more of these wide-ranging symptoms that persist for decades, and no treatment options are available. Thus, it is of the utmost importance to identify potential therapeutic targets that can be rapidly translated into clinical treatments for individuals suffering from GWI. There is mounting evidence that chronic inflammation, including neuroinflammation, contributes to the diverse symptoms of GWI, possibly as a result of exposure to specific chemical agents which many of the Gulf War troops encountered. Central to the proposed research, previous clinical and preclinical studies demonstrated strong evidence for an innate immune response in GWI patients and GWI models. This immune response includes both peripheral immune changes and neuroinflammation. Neuroinflammation in GWI includes reactive astrocytes, a key cell type that can help to regulate neurons and cognition. Along with innate immune changes, GWI has also been associated with an adaptive immune response., The adaptive immune response includes changes in T cells, B cells, and NK cells in GWI patients. Importantly, innate and adaptive immune mechanisms may underlie distinct symptom domains. Therefore, selectively targeting both the innate and adaptive immune responses may be needed to confer maximum therapeutic benefit for this complex multi-symptom disorder. Published studies and our previous work have identified distinct potential therapeutic targets that play a role in selectively regulating the innate and adaptive immune responses in GWI. The innate immune target is a pro-inflammatory protein known as macrophage migration inhibitory factor (MIF). MIF has been identified as a potential target in GWI, and we have previously shown that blocking MIF reverses neuroinflammation and astrocyte activation. Thus, we will block MIF in a GWI model and assess its therapeutic potential to improve inflammation. A second therapeutic target, a small protein called CLIP, is involved in the adaptive immune response. We have shown that blocking CLIP reverses the adaptive immune response, is neuroprotective, and improves functional outcomes. Thus, we will reverse chronic adaptive immune activation by blocking CLIP in a GWI model and assess its therapeutic efficacy at treating GWI. Because we believe that the innate immune response and the adaptive immune response underlie distinct symptom pathogenesis in GWI, we propose a combinatorial therapy that will block MIF and CLIP to determine whether this combination therapy will confer maximal therapeutic benefit in the GWI preclinical model. Importantly, both MIF and CLIP are targets in other disorders, and drugs that block these proteins are in various stages of either clinical or preclinical trials. Therefore, should the results from the current study support blocking either the innate, the adaptive, or both the innate and adaptive immune systems as a treatment for GWI, there is an immediate path to translation. This work may lead to therapeutic strategies that can help to treat GWI-related pathology and improve the long-term quality of life for our Gulf War Veterans.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310916
Entities
People
- Lee Shapiro
Organizations
- Texas A&M Health Science Center
- United States Army