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Immune Signatures for Therapy Stratification in Major Mood Disorders

Periodic Reporting for period 2 - MOODSTRATIFICATION (Immune Signatures for Therapy Stratification in Major Mood Disorders)

Reporting period: 2019-07-01 to 2020-12-31

The hypothesis of our project is that a large proportion of severe mood disorders are the result of deviant immune reactions, caused by (Inborn and acquired) monocyte/macrophage and T cell defects which result in
1. mal development and malfunctioning of the brain, and
2. flares of chronic inflammation, further impacting brain functioning.
We test and refine this novel concept by further exploring the earlier collected large datasets of previous EU funded research MOODINFLAME (2008–2012) and PSYCH-AID (2013-2017).
The aim of MOODSTRATIFICATION is not only to refine the hypotheses above, but also to develop simple blood tests to measure the above mentioned immune defects in clinical practice (WP1).
Another aim is to carry out proof-of-principle clinical studies with T cell enforcing therapies (thymus hormone and low dose IL-2) to correct the defects (WP2), and to develop in later phases of the project – on the basis of the outcomes of our refinement studies (see WP1) new immune correcting therapies in immune-stratified patients using the developed simple blood tests. We have now done so and we perform clinical studies into the effects of endurance physical trainig schemes on depression and immunosenescence, a hallmark of the defective immune system of major depressed patients. Immune stratification is meant to select patients with a high likely hood to react to physical endurance therapy, i.e. those with clear signs of immunosenescence (WP3). In WP4 we estimate the economic costs and benefits of physical endurance therapy, particularly in patients with recurrent and difficult to treat depression.
WP1. Further refinement studies into the immune defects of mood disorder patients
In the coordinator’s opinion break-through progress has been made on the immune pathogenesis of severe mood disorders on the basis of the outcomes of the new assays and by studying the entire cohort of MOODINFLAME and PSYCHAID.
A. In essence most of the found immune aberrancies in monocytes/macrophages, lymphocytes and cytokines/growth factors in mood disorders can be categorized under the concept of Premature Immuno-Senescence (PIS). The found components of PIS are:
1. Enhanced mitochondrial apoptosis of monocytes/macrophages leading to enhanced ROS/TNF production
2. T cell defects leading to higher levels of T memory cells with poorer function, in this abnormality also chronic CMV infection plays a role.
3. Abnormalities in T effector/T regulator ratio’s with poor suppressor function
4. Proneness to inflammation (so-called “inflammaging”): High activities of the “inflammasome” (high CRP, IL-6 and IL-1β)
5. Low levels of IL-7, IL-7 plays a prominent role in immuno-senescence.
In major depressive disorder the monocyte apoptosis and monocyte inflammation were found to be the most outspoken abnormalities within the PIS syndrome. In case of childhood adversity, this strongly enhances the inflammatory state of monocytes/macrophages via reduction of mevalonate kinase. These “high inflammatory” patients are also at higher risk for suicide.
In bipolar disorder T cell defects and abnormalities in the T effector/T regulator ratio are the most outspoken abnormalities within the PIS syndrome.
We have developed gene correlates (TGFBR3, NFATC2, CAMP, MRC1, ABCG1, HMOX-1, FOXP3, TBX21 and ROR-γ) in whole blood for the monocyte inflammatory state and the abnormalities in the T effector/T regulator state. This has enabled us to desing a simple finger prick assay to measure this. We have also developed an ELISA system to measure the most important abnormal serum analytes.

WP2. T cell enforcement studies in mood disorder and immune deficient patients
Partners (EMC, AP-HP, KU-Leuven and OSR) worked hard to prepare all documents for ethical approval for use of thymus hormone and/or low dose L-2 therapy of mood disorder patients. This turned out to be a lengthy procedure. For this reason (and the delays suffered by the COVID-pandemic) we adapted out time schedule and made a 3rd amendment to the GA. The situation in Jan 2021 is as follows:
1. AP-HP and OSR have got approvals for the low dose IL-2 studies. They are halfway for the final recruitment of 54 depressed patients. They foresee to complete the trial before end 2021.
2. EMC will only be allowed (after discussions with their ethical board) to use thymus hormone in CVID patients, if they sufficiently show that the depression in this patients is linked to defects in T cells. EMC has indeed found a significantly higher burden of distress, depression, anxiety and somatization in their CIVD patients than in general population. The partner also collected detailed clinical and immunological information of 40 CVID patients and 26 age/gender matched controls, showing a clear T cell defect in the depressed CIVD patients, i.e. a reduced level of naive CD4+ T cells. EMC continues the experiments and discussion with the ethical board and plans starting the thymus hormone trial mid 2021.
3. KU-Leuven will not use thymus hormone or low-dose IL-2 for treatment of 22Q11DS patients (not ethically allowed in the patients, and too expensive), but will support the trials in WP3, investigating the state of physical fitness on the immune senescent state of 22Q11DS patients.

WP3. Collection of historical controls and planning of further Interventions on the basis of outcomes in WP1.
All centers collect data and blood from mood disorder patients treated as usual. In a series of meetings partnesr discussed outcomes of WP1 and chose for physical endurance training as the intervention in WP3 (effective in mood improvement as well as correcting immunosenescence). WWU, UULM and KU-Leuven have started their trails as described in the clinical study IMMUNOSTRATA in the GA. UMCG will soon follow.

WP4. Estimate the socio-economic benefits from the novel immune diagnostic and immune therapeutic approaches.
AU found that individuals with treatment resistant depression have a rostrum of more severe signs of depression (e.g. suicide) and form socially and economically a higher burde for society (various publications).
The main conclusion we can draw after the 1st 36 months of study in MOODSTRATIFICATION is that we are changing the conventional DSM psychiatric diagnosis “Severe Mood Disorder” (based on meticulous description of subjective symptoms) to a diagnosis of “Premature Immune-Senescence (PIS)” (based on objective immune parameters) and comprising various other somatic conditions (proneness to auto-immunity, infection and vasculopathy). The inflammatory aspects of PIS can be aggravated by (early) life stress, acting via changes in the immune-metabolism (MVK in the cholesterol pathway) and CMV infection. Clinically applicable relatively simple test systems have been developed to diagnose PIS and its inflammatory aspects. Many components of PIS have impact on brain development and function.
The impact of the paradigm shift (psychiatric diagnosis to immune diagnosis) is that we investigate novel treatments targeting PIS (physical endurance training, IL-2, thymus hormone) and the possibilities to predict outcome on the basis of immune signatures.