Work Package 8: Experimental medicine theme 2: Innate and adaptive immunity. B. Paul Morgan

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2 Work Package 8: Experimental medicine theme 2: Innate and adaptive immunity. B. Paul Morgan

3 Innate and adaptive immunity. Aims and structures: This WP will develop innate and adaptive immunity as a second theme for experimental studies. Preliminary scoping has identified an existing expert community that can be accessed. This expert community has formed around a Wellcome Strategic Award, started 1 st January 2015 Wellcome Consortium for Neuroimmunology of Mood Disorders and Alzheimer s Disease. The WP will develop links with this evolving research programme and develop further sources of funding.

4 Innate and adaptive immunity. Expert Network: Comprises leaders in neuroinflammation, inflammation and immunity: Paul Morgan (Cardiff); Simon Lovestone (Oxford); Jean Manson (Edinburgh); Siddharthan Chandran (Edinburgh); John Iredale (Edinburgh); Tracy Hussell (Manchester); Janet Lord (Birmingham); Paul Wren (GSK).

5 Innate and adaptive immunity. Expert Network- Roles: To support the fifth strategic DP UK objective of developing an experimental programme focussing on the early detection of decline and treatment of dementia; To identify preferred hypotheses and develop and submit proposals to the platform; To review immunology/inflammation related EOIs submitted to calls for EM project proposals.

6 Innate and adaptive immunity. Underpinning assumptions: Inflammation is an early event in the genesis of dementias; Systemic inflammation is a trigger to central damage; Inflammation and Immune biomarkers may predict disease. Obvious overlap with Wellcome Strategic Award

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8 AD WP3: Hypothesis-driven immune system biomarkers. Reproducible peripheral signature in AD that includes immune and inflammatory markers; Confirm and refine this signature in AD, including in AD associated with rare mutations in such markers; Fluid-phase and cellular markers may be included; Large, existing disease cohorts (MCI, AD), developing cohorts and rare mutation (eg. TREM2, CSF1) cohorts; Case-control approaches, correlation with imaging and CSF measures; Multivariate methods to arrive at highly predictive algorithm(s) for early diagnosis, stratification, prediction of progression, response to therapy.

9 Markers in biological fluids Plasma, serum, CSF, urine; Measurement of complement proteins, activation products and key polymorphisms; Pro- (and anti-?) inflammatory cytokines; Cross talk between complement and cytokines other DAMPS, PAMPS etc.; Other biomarkers of disease amyloidspecific, neuron-specific etc.

10 Complement as a target Multi-source evidence of role in AD; Some individual complement markers suggested to be useful; Biomarker discovery, eg. using SOMAscan, identifies complement (and other) candidates; Complement links to other inflammatory systems, coagulation, phagocytosis etc.

11 Complement as a target Eleven analytes measured (C1s, Clu, FI, TCC, C4d, ic3b, Bb, C9, total FH (andy402 and H402 variants); Age, gender and ApoE status as co-variables; Compare AD versus controls (all patients), total 777 (411 AD, 366 controls), dataset of 545 (288 AD, 257 controls) to generate the model, 232 (123 AD, 109 controls) to test the model; Compare AD versus controls (first visit only), total 292 (106 AD, 186 controls), dataset of 206 (75 AD, 131 controls) to generate the model, 86 (31 AD, 55 controls) to test the model; Compare MCI converting to AD versus not converting, total 189 (140 not converted, 49 converted), dataset of 133 (98 not converted, 35 converted) to generate the model, dataset of 56 (42 not converted, 14 converted) to test the model.

12 Innate and adaptive immunity. Expert Network way forward: Identify and build synergy with other parts of the Platform. Decide priorities biomarkers, imaging, trials etc. Generate calls in priority areas. Build network across the UK through communication and meetings. Host a meeting on immunity/ inflammation in dementia?

13 Experimental Medicine Challenge Grants; discovery science in humans MRC seeks, through investment in experimental medicine challenge grants supporting experimentation in humans, to generate new and deeper understanding of human disease mechanisms and identification of potential new therapeutic targets, so accelerating translation of basic science to impact on patient health. Ambitious, innovative, challenge-led programmes of research into disease pathophysiology, conducted in humans, with primary aim of informing a deeper understanding of human disease mechanisms Must be experiment-driven; Proposals which are predominantly descriptive are unlikely to be shortlisted Outputs should lead to better therapeutic target or biomarker ID/validation, and reverse translation to better basic models Range of award sizes from < 1m Pathfinder projects to large programmes Applicants webinar 8th May. Regulatory/ethics workshops 5th and 6th May Outline Deadline 25th June Excellent fit for bid in this area perhaps with imaging?