G. Soci, Hmatologie / Greffe Hpital St Louis GvHD Immunobiology of - - PowerPoint PPT Presentation

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G. Soci, Hmatologie / Greffe Hpital St Louis GvHD Immunobiology of HSCT : a & c Past , present & future GvL ID A P P E L B A U M F R . N E N G L J M E D 2 0 0 7 ; 3 5 7 : 1 4 7 2 - 1 4 7 5 . Ann N Y Acad Sci.

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Immunobiology of HSCT: Past , present & future

G. Socié,

Hématologie / Greffe Hôpital St Louis

GvHD a & c GvL ID …

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A P P E L B A U M F R . N E N G L J M E D 2 0 0 7 ; 3 5 7 : 1 4 7 2 - 1 4 7 5 .

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GS / SFGM-TC 2018

Ann N Y Acad Sci.1995;770:34-41. World J Surg. 2000;24:834-43. Br J Haematol.1999;105:330-39. D van Bekkum G Matthé D Thomas Billingham; Nature 1966 & 1968 R Billingham

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SCIENCE, 213, 1981

J Dausset J van Rood

HLA + NIMA /NIPA Minor H-ag

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Nature Reviews Cancer 2010

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F E R R A R A J L , D E E G H J . N E N G L J M E D 1 9 9 1 ; 3 2 4 : 6 6 7 - 6 7 4 .

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GS / SFGM-TC 2018

ZEISER R, BLAZAR BR. N ENGL J MED 2017;377:2167-2179.

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GS / SFGM-TC 2018 N Engl J Med 2017;377:2167-79.

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Chronic GvHD

Blood 2017; 129: 22-29 Blood 2014; 124: 374-84

J Ritz

S Sarantopoulos

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T B TfH

Thymus

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GVHD: balance between alloreactivity/ tissue sensitivity with immune/ tissue tolerance

Il-22

Immunity 2012: 37; 339–350

R-Spondin

J Exp Med 2017: 208; 285-294

Pavan REDDY 2017

NRI 2011

Polly Matzinger

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GVHD lymphoid organs GVHD target organs donor syngeneic allogeneic-target organs allogeneic- lymphoid organs bridging modules

Ronjon Chakraverty

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Tissue compartmentalization in acute GVHD

GvL low PD-1 PD-L1 PD-L2

Lymph node

Low cytotoxic activity Tissue environment Donor CTL

Michonneau D, … Bousso P; Immunity, 2016

Liver

PD-1 High cytotoxic activity Donor CTL GVL efficacious Tissue damages (GVHD)

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GS / SFGM-TC 2018 GVHD’s paradigm :

miHA and HLA

are ubiquitously express

Acute GVHD

mainly affects skin GI & liver

Preferential T-cell migration in damaged tissues Intrinsic tissue sensitivity to allogeneic T-cells Second signal by activated tissue resident APCS

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Blood 2011;118:2951-2959 C Perreault

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Bottom-up
Dynamic
Multi-scalar
Modular
Interactive
Comprehensible
P. Reddy

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Chronic GVHD pathophysiology From Human to mice

Why ?

Acute GVHD pathophysiology From mice to Human

Not inbred Not germ free With Chemo/TBI Age Donor

GvHD prophylaxis

… Pathology; single time point; double vs. multicolor; Treatment ? +++ Cytokines / Chemokines; plasma ELISA vs. Q-PCR tissue +++ Flow cytometry; Cell numbers +++; PB vs. tissue Proteomics; urine vs. tissue Genomics; SNPs, Expression array…; Cell numbers +++ ; Population homogeneity

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Br J Haematol 2001, 115: 630-641 Haematologica 2015; 100(1): 114-23 Blood 2005;105: 2608-2613 Blood 2002;99:1458-1464 TREC

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2007; 4: 69-83

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GVL

S Riddell A Velardi

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Sci. Transl. Med. 10, 19 September 2018

EBMT CI of relapse

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2017;42:-332-40. 2016;374:2209-2221. 2018;2:3070-3080 2018;131(10):1073-1080 Tt for relapse

Drawbacks

Tt after clonal Evolution Too late! Disease kinetics Unnecessary Tt Tt for MRD Tt in CR

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LSA; Leukemia specific antigens; ?? Even for bcr-abl LAA; Leukemia associated antigens; PR1 (CML), WT1 miHA; minor Histocompatibility Ags; HY, HA1-8, HB1 …

Cancer Cell 34, August, 2018

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HLA & Non-HLA immunogenetics

Immunogenetics in 10/10 Allele matched UD Lessons from Genome wide associations

PJ. Martin et al. Blood 2017;129:791-798

W Wang et al. Blood Advances 2018;19:2419-2429

Non permissive DP > HY > miHA

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GS / SFGM-TC 2018 Patient HLA Germline Variation

The susceptibility variants are linked

n patient haplotypes that span . 500,000 base pairs and

involve genes responsible for antigen & processing (HLA-DOA) & presentation HLA DRB-1 E Pettersdorf

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Genes Dev. 2016;30:1589-1597 J Clin Invest. 2017;127(7):2441–2451 Seminal; J. Exp. Med. 2012: 209; 903-911

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Nat Med. 2017: 23; 1080-1085

Median 2.9 x 107 reads per sample

GI- GVHD

In a time dependent Cox model Picobirnaviruses were predictive

f enteric GvHD stage ≥2 HR = 2.66 [1.46;4.86]
f any type of GvHD

HR = 1.75 [1.07;2.865]

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2016; 17(5) AA pathway

P REDDY

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Stern, Front Immunol, 2018 Samusik N et al. Nature Methods 13, 493–496 (2016)

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T Naives T effector memory T central memor y

CD4

T EMRA T Naives T central memor y T EM Tc17

CD8

GvHD Y/N

Descriptive model (FDR<1%) Predictive model spectral flow cytometry

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M Davis

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2017; 547:

36-38
89-93
94-98

2018; 172: 549-63

Predicted Ag-specific binding

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GS / SFGM-TC 2018 The Human Functional Genomics Project: Understanding Generation of Diversity

2016; 167:

1099-110
1111-24
1125-36

2018; 19: 776-86

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published online 18 June 2018; doi:10.1038/nbt.4152

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2018; 173: 1562-65

A Classical statistical association

Associate molecular variants with disease Heterogeneity mask all but strongest effects

B Modern machine learning

Accurate predictions given many samples Black box, high complexity, low sample size

C Experimental Cell Biology

Rapid mapping of biological mechanisms Disconnected from patient data

D Biomedical text mining

Assimilation of data & mechanisms from literature Most answers not in literature

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