Achieving Remission in Gulf War Illness: A Simulation-Based Approach to Treatment Design

Abstract

Gulf War Illness (GWI) is a chronic multi-symptom disorder affecting up to one-third of the 700,000 returning veterans of the 1991 Persian Gulf War and for which there is no known cure. GWI symptoms span several of the body’s principal regulatory systems and include debilitating fatigue, severe musculoskeletal pain, cognitive and neurological problems. Using computational models, our group reported previously that GWI might be perpetuated at least in part by natural homeostatic regulation of the neuroendocrine-immune network. In this work, we attempt to harness these regulatory dynamics to identify treatment courses that might produce lasting remission. Towards this we apply a combinatorial optimization scheme to the Monte Carlo simulation of a discrete ternary logic model that represents combined hypothalamic-pituitary-adrenal (HPA), gonadal (HPG), and immune system regulation in males. In this work we found that no single intervention target allowed a robust return to normal homeostatic control. All combined interventions leading to a predicted remission involved an initial inhibition of Th1 inflammatory cytokines (Th1Cyt) followed by a subsequent inhibition of glucocorticoid receptor function (GR). These first two intervention events alone ended in stable and lasting return to the normal regulatory control in 40% of the simulated cases. Applying a second cycle of this combined treatment improved this predicted remission rate to 2 out of 3 simulated subjects (63%). These results suggest that in a complex illness such as GWI, a multi-tiered intervention strategy that formally accounts for regulatory dynamics may be required to reset neuroendocrine-immune homeostasis and support extended remission.

Blood Biomarkers of Chronic Inflammation in Gulf War Illness

“…We found white blood cell counts and blood biomarkers related to inflammation could discriminate groups that did or did not meet the current symptom-based criteria for case definition of GWI. Our observations are consistent with conclusions expressed in recent literature reviews that immune dysregulation/neuroinflammation are components of the pathobiology of GWI [ 28 , 29 ]. Appropriate assays for the presence of chronic inflammation could provide objective evidence that would facilitate the diagnosis of GWI+.…”

Treatment Avenues in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Split-gender Pharmacogenomic Study of Gene-expression Modules

“…While in our previous studies the profile of ME/CFS in women suggested targeting the Th2 immune cytokines followed by inhibition of the glucocorticoid receptor system, 69 this predicted drug course has not yet been optimized. 71…”

A Logic Model of Neuronal-Glial Interaction Suggests Altered Homeostatic Regulation in the Perpetuation of Neuroinflammation

“…A simulation algorithm, as described previously in Craddock et al ( 2015 ), was used to analyze the response of the neuroimmune model to external perturbations. Briefly, from any initial state, allowable state evolutions are determined based on the 3-valued logic described in Equation (2).…”

“…To identify a robust intervention capable of moving the neuroimmune signaling system from an alternate, potentially pathological, mode of regulation to that of typical health, putative treatment strategies were simulated. For each candidate treatment strategy, simulations were conducted to evaluate the likelihood of returning the system from an alternate stable regulatory state, to the stable state of typical health, as described previously in Craddock et al ( 2015 ). Specifically, starting from the alternate regulatory stable state, a variable affected by the putative treatment was shifted according to the treatments mode of action: −1 (suppressing), 0 (untreated), and 1 (elevating).…”

“…Such a model can be used to integrate the regulation of microglia with other immune mechanisms in the brain while also incorporating the complex signaling linking the many cell types involved (Craddock et al, 2014 ; Fritsch et al, 2014 ). Ultimately, knowledge of such homeostatic regulation can be used to identify promising applications of pharmaceutical, hormone and/or immune therapy that exploit the body's natural regulation (Craddock et al, 2015 ) to reinforce treatment effects in illnesses characterized by chronic neuroinflammation, such as Alzheimer's disease, Parkinson's disease, major depression, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Gulf War Illness (GWI).…”