CORDIS

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. Immune stratification is meant to select patients with a high likely hood to react to these novel immune therapies (WP3). In WP4 we estimate the economic costs and benefits of these new interventions.

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 all 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
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.
B. 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.
C. In bipolar disorder (not fully evaluated at present) T cell defects and abnormalities in the T effector/T regulator ratio are the most outspoken abnormalities within the PIS syndrome.
D. 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 enables us to design simpler assays.

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 and administrative approval for use of thymus hormone and/or low dose L-2 therapy of mood disorder patients. This turned out to be a lengthy and cumbersome procedure. For this reason we adapted out time schedule and made an amendment in the original time schedule. The situation in July 2019 is as follows:
1. AP-HP has got approval. The low dose IL-2 clinical study will start in the fall of 2019. AP-HP will use IL-2 from our partner ILTOO.
2. OSR has got approval from their ethical committee, but needs some last approvals from a central drug registration office in Rome (minor questions). They also foresee to start in the fall of 2019. OSR will use IL-2 from Novartis and has bought enough stock to also supply KU-Leuven
3. EMC has delivered the paper work to their ethical committee, after having prepared all documents with a clinical trial office in discussion with the ethical committee. They will be allowed to use thymus hormone initially in a pilot trial of 5 CVID patients. This is also planned for the fall of 2019. Thereafter we will evaluate if it is worth to expand the thymus hormone studies
4. KU-Leuven will not use thymus hormone for treatment of 22Q11DS patients, but will switch to the Novartis low dose IL-2. They have to clear some laboratory issues regarding blood collection and will then deliver to documents to the ethical committee
With regard to the psychological/psychiatric state of Primary Immune deficiency patients EMC found a significantly higher burden of distress, depression, anxiety and somatization in the patient population than in general population controls (a paper is in preparation). The partner has also collected detailed clinical information and frozen leukocytes/serum of 40 well-typed CVID patients and 26 age/gender matched controls. The control series will be expanded to 40 in the coming months and then tests will be carried out and evaluated.

WP3. Collection of historical controls and planning of further Interventions on the basis

The main conclusion we can draw after the 1st 18 months of study in MOODSTRATIFICATION is that we are gradually 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 internal 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). 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 (see Figure)
The impact of the concept change (psychiatric diagnosis to immune diagnosis) is that we will design novel treatments targeting the abnormalities of PIS (IL-2, IL-7 and anti-inflammatory therapy, intensive exercise).