MICA in HSCT. Mannheim,

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1 MICA in HSCT Mannheim, Joannis Mytilineos MD, PhD Department of Transplantation Immunology Institute for Clinical Transfusion Medicine and Immunogenetics German Red Cross Blood Transfusion Service, and Department of Transfusion Medicine - University Clinic Ulm Ulm, Germany

2 Additional Loci in the MHC-Region

3 Polymorphism of the MIC Genes Gene MICA MICB Alleles Proteins Nulls 2 2

4 MICA 129 Polymorphism

5 MICA 129 Polymorphism Is a Single Nucleotide Polymorphism (SNP; rs ; A G) at position 454 of the MICA gene leads to a single amino acid substitution of methionine (Met) by valine (Val) at position 129 of the protein, designated as MICA- 129Met/Val polymorphism, is of particular interest, since the Met variant is a strong and the Val variant a weak binder of NKG2D. The amino acid 129 is located in the β4 strand of the β-pleated sheet in the α2 domain of the MICA protein The side chain of Met 129 is partially buried and forms hydrophobic interactions with glutamine (Glu) 136, alanine (Ala) 139 and Met 140. Therefore, its substitution by Val likely affects NKG2D binding indirectly by a conformational change (Steinle et al., 2001)

6 MICA/B Sequencing

7 MICA-Alloantibodies and Renal Transplantation Zou et al, NEJM 2007;357: 357;13

8 MICA in HSCT A higher rate of grade II-IV agvhd was seen in MICA-mismatched patients (80% vs 40%, P =.003) irrespective of degree of HLA matching (HLA 10/10 match: 75% vs 39%, P =.02) and HLA any mismatch (83% vs 46%, P =.003). The rate of grade II-IV gastrointestinal agvhd was also higher in MICAmismatched patients (35% vs 17%, P =.05). We conclude that MICA may represent novel a transplantation antigen recognized by human allogeneic T cells. Blood Oct 1;114(14):2884-7

9 MICA genotype, smica and MIC Abs in HSCT

10 MICA genotype, smica and MIC Abs in HSCT MICA-129 val/val genotype and elevated smica serum levels after HSCT are independently associated with the incidence of cgvhd (P =.002 and.001) regardless of history of acute GVHD The presence of MICA Abs before transplantation confers protection against cgvhd (P =.04). There is an inverse relationship between MICA Abs and smica, suggesting an antibody-based neutralization of deleterious effects of smica. Similarly, these genetic and phenotype characteristics of MICA influence the incidence of relapse. Altogether, MICA genotype and phenotype specificities could be used as relevant biomarkers for cgvhd monitoring.

11 Allogeneic Stem Cell Transplantations in Germany

12 Unrelated Donor Searches in Ulm

13 HLA-Compatibility - Searches in Ulm

14 Ulm MICA Study Patients Stored genetic Material from Donors and Recipients Age: 18 Jahre Diagnosis: ALL, AML, AL, MDS, NHL 24 cooperating Transplant Centers Sufficient and plausible clinical data collected within the DRST, verified and completed by the transplant centers transplants

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16 ULM MICA Study Methods We analyzed the effect of MICA-Allele and MICA-129 matching on the outcome of uhsct. We typed 3262 patients and their respective donors by Sanger Sequencing All patients and donors were high-resolution HLA-typed and matched for HLA-alleles as follows: 10/10 (n=2107), 9/10 (n=946) 8/10 (n=209) Within each HLA match group, cases matched and mismatched for MICA-Alleles/MICA-129 were analyzed for the endpoints overall survival (OS), disease free survival (DFS), non-relapse mortality (NRM), relapse-incidence (RI) GvHD.

17 ULM-Study Results 1) Mismatches at the MICA locus as well as MICA-129 increased with the number of HLA mismatches MICA mismatched: 10/10: 7.8%, n=164; 9/10: 23.2%, n=219; 8/10: 39.2%, n=82; MICA-129 mismatched: 10/10 3.3%, n=69; 9/10: 11.5%, n=109; 8/10: 16.3%, n=34 2) Lower survival rates were seen for MICA and MICA-129 mismatched cases in all HLA-match groups.

18 MICA Matching Ulm Study (p<0,002, Overall Survival) Fürst et al, Blood 2016;128(26):

19 MICA/MICA-129 Matching Ulm Study 10/10 HLA-Matches Fürst et al, Blood 2016;128(26): updated cohort

20 MICA/MICA-129 Matching Ulm Study 9/10 HLA-Matches Fürst et al, Blood 2016;128(26): updated cohort

21 MICA/MICA-129 Matching Ulm Study 8/10 HLA-Matches Fürst et al, Blood 2016;128(26): updated cohort

22 MICA/MICA-129 Matching Ulm Study Combined HLA-MICA-129 Match Fürst et al, Blood 2016;128(26):

23 ULM-Study Results 3) In multivariate Analysis, adverse OS was observed in the 10/10 and 8/10 match group if MICA-129 was mismatched 10/10: HR 1.64, CI , p= /10: HR 1.72, CI , p= ) MICA-129 mismatches correlated with a significantly worse outcome for DFS in the 10/10 and 8/10 HLA match group 10/10 HR: 1.46, CI , p=0.016, 8/10: HR 1.76, CI , p= ) Higher rates of agvhd were seen in MICA-129 mismatched cases

24 ULM-Study Conclusions Our results in this extended cohort indicate that MICA- 129 matching is relevant in uhsct. Prospective typing of patients and donors in unrelated donor search may identify mismatches for MICA-129 and compatible donor selection may improve outcome for this small but high-risk subgroup.

25 Many thanks to Dietger Niederwieser (Leipzig) Donald Bunjes (Ulm) Eva Wagner (Mainz) Martin Gramatzki (Kiel) Gerald Wulf (Göttingen) Renate Arnold (Berlin) Hermann Einsele (Würzburg) Bertram Glass (Hamburg) Michael Pfreundschuh (Homburg) und all other cooperating Transplant Teams

26 Many thanks to: Staff in Ulm Daniel Fürst Chysanthi Tsamadou Christine Neuchel Daphne Mytilineos Hubert Schrezenmeier Search Unit Ulm Marlene Fischer Sabine Simon Renate Hanold Martina Baumann DRST Registry Colleagues Carlheinz Müller Helga Neidlinger Franziska Hanke

27 2017 EFI/DGI Meeting Teaching Session I Mannheim, Wednesday, :30 12:00 Role of non-classical HLA in Stem Cell Transplantation Please don t forget to complete the evaluation questionaire (Survey) in your App after the session has been completed!

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