Towards epitope matching in kidney allocation

Transcription

1 Sebastiaan Heidt Leiden University Medical Center EFI TEACHING SESSION,

2 HLA matching is still relevant in the presence of efficient immunosuppression HLA matching improves graft survival rate Many transplants are performed with some degree of HLA mismatch Collaborative Transplant Study 2010

3 Chance to find an HLA identical unrelated individual is very low HLA is encoded on several genes: HLA class I: HLA-A, -B and -C HLA class II: HLA-DR, -DQ and -DP HLA is extremely polymorphic: HLA-A HLA-B HLA-C HLA-DR HLA-DQ HLA-DP Not all HLA mismatches lead to antibody formation

4 HLA antigens share antibody epitopes Immunization by pregnancy: antibodies induced by HLA-A2 react also with HLA-B17

5 In the past our interpretation of the humoral immune response to HLA was too simple

6 Structural analysis of HLA molecules enables the prediction of their immunogenicity HLA-A2 HLA-A68 HLA-B27 HLA-B35 HLA-B51 HLA-B44

7 Amino acid residues are building blocks of proteins HLA molecules consist of amino acid residues HLA amino acid sequence can be numbered from beginning to end

8 Polymorphic structures are often shared between different HLA alleles A* KM 62QE 65RNM 66RNH 77ANT 163RG 184P 193PI 248VK A* RM 62GE 65RKV 70KAH 77VDT 163TW 184A 193AV 248VK A* RM 62GE 65RKV 70KAH 77VDT 163TW 184A 193AV 248VK A* RM 62GE 65RKV 70KAH 77VDT 163TW 184A 193AV 248VK A* RM 62GE 65RKV 70KAH 77VDT 163TW 184A 193AV 248VK A* RM 62QE 65RNV 66RNQ 77VDT 163TW 184P 193PI 248VK A* RM 62QE 65RNV 66RNQ 77VDT 163TW 184P 193PI 248VK A* RM 62QE 65RNV 66RNQ 77VDT 163RW 184P 193PI 248VK A* RM 62QE 65RNV 66RNQ 77VDT 163RW 184P 193PI 248VK A* RM 62EE 66GKH 70KAH 77ENI 163TG 184P 193PI 248VK A* RM 62EE 66GKH 70KAH 77ENI 163TG 184P 193PI 248VK A* RM 62EE 66GKH 70KAH 77ENI 163TW 184P 193PI 248VK A* RM 62RN 65RNV 66RNH 77ESI 163RW 184A 193AV 248VK A* RM 62RN 65RNV 66RNH 77ANT 163RW 184A 193AV 248VK A* RM 62LQ 65RNV 66RNQ 77ANT 163TW 184A 193AV 248VK A* RM 62LQ 65RNV 66RNQ 77ANT 163TW 184A 193AV 248VK A* RM 62QE 65RNV 66RNQ 77VDT 163TW 184P 193PI 248VK A* RM 62QE 65RNV 66RNH 77ENT 163TW 184P 193PI 248VK A* RM 62QE 65RNV 66RNH 77VDT 163TW 184P 193AV 248VK Legend: K: Lysine R: Arginine M: Methionine

9 An HLA antigen has a unique epitope set - individual epitopes can also be present on other HLA antigens Tambur & Claas, AJT 2015

10 HLA Matchmaker principle Claas et al., Hum Immunol

11 Immunogenicity of a specific HLA mismatch is different for individual patients Number of foreign "epitopes on the same HLA-B51 mismatch for: Patient A Many Patient B Patient C Quite some Few Patient D Few Patient E None

12 The number of epitope mismatches predicts HLA antibody production after renal allograft rejection Dankers et al., Transplantation 2005

13 HLA Epitope Matching less antibodies and better outcome Wiebe et al., AJT 2013

14 Which HLA mismatches to avoid once HLA antibodies have been formed? Preventing antibody formation The number of epitope mismatches predicts the chance that an HLA mismatch will lead to de novo antibody formation Once a patient is immunized An immunogenic epitope can induce antibody formation in a patient. Additional amino acid differences in the vicinity of the immunogenic epitope determines whether antibody binding will occur Determine acceptable and unacceptable mismatches: virtual crossmatch

15 Antibody structure Variable part: - antigen specificity - binding strength Constant part: - effector function

16 Six contact sites between antibody and antigen CDR3 binds to few amino acids and determines specificity, other CDRs stabilize the binding and determine the binding strength

17 Crucial amino acid configurations determine the reactivity of an HLA antibody Strong binding Weak/no binding No binding No binding

18 Simple antibody reactivity: an antibody induced by 62GE reacts with all 62GE carrying alleles Allele Immunogenic epitope Immunogenic Epitope Antibody Binding C1q fixation Cytotoxicity Sequence positions with residue differences <15Å A*02:01 62GE Yes Yes Yes F S Q M E K V H S H V D V L T A*02:03 62GE Yes Yes Yes F S Q M E K V H S H V D E W T A*02:06 62GE Yes Yes Yes F S Q M E K V H S H V D V L T B*57:01 62GE Yes Yes Yes Y A P M A N M S A Y E N V L L B*57:03 62GE Yes Yes Yes Y A P M A N M S A Y E N V L L B*58:01 62GE Yes Yes Yes Y A P T E N M S A Y E N V L L Others No No No Amino acids in the vicinity of immunizing epitope Crucial position for antibody reactivity: Duquesnoy et al Legend: G: Glycine E: Glutamic Acid

19 Complex reactivity: antibody induced by 144TKR reacts only with some 144TKR carrying alleles Allele Immunogenic epitope Immunogenic Epitope Antibody Binding C1q fixation Sequence positions with residue differences <15Å A*11:01 144TKR Yes Yes V D G T R G D N A H A Q A A*11:02 144TKR Yes Yes V D G T R G D N A H A Q A A*01:01 144TKR Yes Yes A N G T R G D N V H A R V A*03:01 144TKR Yes Yes V D G T R G D N A H E L A A*24:02 144TKR Yes Yes E N R I L R Y K A H V Q A A*24:03 144TKR Yes Yes E N R I L R Y K A H V Q A A*36:01 144TKR Yes Yes A N G T R G D N V H A R V A*80:01 144TKR No No A N G T R G D N A R R L A Others No No Amino acids around immunizing epitope are relevant Crucial positions for antibody reactivity: Duquesnoy, Mulder et al Reactivity is specific for 144TKR+151H Legend: T: Threonine K: Lysine R: Arginine H: Histidine

20 Knowledge on HLA epitopes allows virtual crossmatching

21 Future matching strategies will be based on "epitope matching 1. Less complicated and epitope matching prevents antibody formation More than 10,000 HLA class I alleles Polymorphism can be explained by about crucial epitopes 2. Enables predictionof acceptable mismatches Knowledge of the actual epitopes recognized by existing antibodies enables prediction of a negative crossmatch in immunized patients