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

G. Socié, Hématologie / Greffe Hôpital 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. 1995;770:34-41. Billingham; Nature 1966 & 1968 Br J Haematol. 1999;105:330-39. R Billingham World J Surg. 2000;24:834-43. D van Bekkum G Matthé D Thomas GS / SFGM-TC 2018

HLA + NIMA /NIPA Minor H-ag J van Rood J Dausset SCIENCE , 213, 1981 GS / SFGM-TC 2018

Nature Reviews Cancer 2010 GS / SFGM-TC 2018

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 .

GS / SFGM-TC 2018 ZEISER R, BLAZAR BR. N ENGL J MED 2017;377:2167-2179.

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

Chronic GvHD J Ritz S Sarantopoulos Blood 2014; 124: 374-84 Blood 2017; 129: 22-29 GS / SFGM-TC 2018

B TfH T Thymus GS / SFGM-TC 2018

GVHD: balance between alloreactivity/ tissue sensitivity with immune/ tissue tolerance Il-22 Polly Matzinger Immunity 2012 : 37; 339 – 350 R-Spondin J Exp Med 2017 : 208; 285-294 NRI 2011 Pavan REDDY 2017 GS / SFGM-TC 2018

donor allogeneic- GVHD GVHD lymphoid organs target organs lymphoid organs syngeneic bridging modules allogeneic-target organs Ronjon Chakraverty GS / SFGM-TC 2018

Tissue compartmentalization in acute GVHD Michonneau D, … Bousso P; Immunity, 2016 Lymph node Donor CTL Liver Donor CTL Tissue PD-1 environment PD-1 PD-L1 High cytotoxic activity PD-L2 Low cytotoxic activity GvL low Tissue damages (GVHD) GVL efficacious 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 Second signal by activated tissue resident APCS Intrinsic tissue sensitivity to allogeneic T-cells GS / SFGM-TC 2018

C Perreault Blood 2011;118:2951-2959 GS / SFGM-TC 2018

Bottom-up • Dynamic • Multi-scalar • Modular • Interactive • Comprehensible • P. Reddy GS / SFGM-TC 2018

Acute GVHD pathophysiology From mice to Human Chronic GVHD pathophysiology From Human to mice Not inbred Not germ free With Chemo/TBI Age Why ? 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 GS / SFGM-TC 2018

Br J Haematol 2001, 115: 630-641 Haematologica 2015; 100(1): 114-23 Blood 2005;105: 2608-2613 TREC Blood 2002;99:1458-1464 GS / SFGM-TC 2018

2007; 4: 69-83 GS / SFGM-TC 2018

GVL A Velardi S Riddell GS / SFGM-TC 2018

EBMT CI of relapse Sci. Transl. Med. 10 , 19 September 2018 GS / SFGM-TC 2018

2016 ;374:2209-2221. 2018 ;2:3070-3080 Drawbacks Tt for relapse Tt after clonal Evolution Tt for MRD Too late! Disease kinetics 2017 ;42:-332-40. Tt in CR Unnecessary Tt 2018 ;131(10):1073-1080 GS / SFGM-TC 2018

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 GS / SFGM-TC 2018

HLA & Non-HLA immunogenetics Immunogenetics in 10/10 Allele matched UD Lessons from Genome wide associations Non permissive DP > HY > miHA PJ. Martin et al. Blood 2017;129:791-798 W Wang et al. Blood Advances 2018;19:2419-2429 GS / SFGM-TC 2018

Patient HLA Germline Variation The susceptibility variants are linked on patient haplotypes that span . 500,000 base pairs and involve genes responsible for antigen & processing ( HLA-DOA ) & presentation HLA DRB-1 E Pettersdorf GS / SFGM-TC 2018

Seminal; J. Exp. Med. 2012 : 209; 903-911 Genes Dev. 2016 ;30:1589-1597 J Clin Invest. 2017 ;127(7):2441 – 2451 GS / SFGM-TC 2018

In a time dependent Cox model Picobirnaviruses were predictive of enteric GvHD stage ≥2 HR = 2.66 [1.46;4.86] of any type of GvHD HR = 1.75 [1.07;2.865] GI- GVHD Median 2.9 x 10 7 reads per sample Nat Med. 2017 : 23; 1080-1085 GS / SFGM-TC 2018

2016; 17(5) P REDDY AA pathway GS / SFGM-TC 2018

Stern, Front Immunol, 2018 Samusik N et al. Nature Methods 13, 493 – 496 (2016) GS / SFGM-TC 2018

GvHD Y/N Predictive model CD4 T central memor y spectral flow cytometry T Naives T effector memory Descriptive model ( FDR<1% ) T EM T EMRA T Tc17 Naives T central memor y CD8 GS / SFGM-TC 2018

M Davis GS / SFGM-TC 2018

Predicted Ag-specific 2017 ; 547: binding - 36-38 - 89-93 - 94-98 2018 ; 172: 549-63 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 GS / SFGM-TC 2018

published online 18 June 2018 ; doi:10.1038/nbt.4152 GS / SFGM-TC 2018

A Classical statistical association Associate molecular variants with disease Heterogeneity mask all but strongest effects Visible B Modern machine learning Intelligence Accurate predictions given many samples Black box, high complexity, low sample size Infrastructure 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 2018 ; 173: 1562-65 GS / SFGM-TC 2018