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Print/PDF Molecular Classification of Inflammation and Uses for Personalized Therapy
Our work is focused on decoupling between four inflammatory molecular states:
i. Disease tolerance activity. Maintenance of health in the presence of stress, injury, infection. Healing through tissue repair and renewal mechanisms.
ii. Antimicrobial activity. Detects, neutralizes, and eliminates the invading pathogen (“resistance”).
iii. Metabolic status. Reflects the abnormal cardiometabolic status related to hypertension, diabetes and atherosclerosis (“metabolic syndrome”, MetS)
iv. Systemic inflammation. The systemic inflammatory reaction due to infection, injury, autoimmunity, an irritant or an unknown cause.
Insights/abilities we already have:
• We defined a quantitative readout as indication for each of these states (both in vivo & in vitro).
• Each readout captures one global aspect of the inflammatory status.
What makes these 4D inflammatory-states different?
1) The four inflammatory states may co-exist in the same cells (all innate/adaptive immune cell types)
2) Together, the four inflammatory states explain most of the transcriptional changes, including changes between individuals and changes between health and disease.
3) Each of the four states explains inter-individual variation in many different tissues
4) The 4D state provides successful diagnostic/prognostics in various immune-related diseases
APPLICATIONS
1) Consider the inflammatory state in precision medicine AI: predictors, disease subtypes, selection of individuals to clinical trials.
2) Ex vivo drug response profiling for response and outcome prediction: Test drugs in vitro at the preclinical stage instead of in vivo models.
EXAMPLE – SEPSIS
• Only two inflammatory states – resistance and systemic inflammation – are sufficient to explain the difference between health and sepsis, and the inter-individual variation within sepsis.
• Sepsis is marked by low resistance relative to the systemic inflammation state
• Prognosis using the resistance and systemic inflammation states outperforms existing classifications
• Guidelines to personalized immunotherapy in sepsis based on the 2D inflammatory state: Blocking inflammation (e.g. anti-cytokine antibodies) or amplifying resistance (e.g., rIFNg, rIL-7), depending on the source of dysfunction in a particular patient.
