Transcript HLAMATCHMAKER: A MOLECULARLY BASED DONOR …

EFI Satellite Session, Wednesday April 2, 2008
Structurally Based HLA Matching:
Are We Ready for Its Application
in the Clinical Setting?
Matching: The Traditional Way
• Count the number of A, B, DR antigen mismatches
– Why do so many zero-antigen mismatches fail?
– Why are many mismatches successful?
• Determine unacceptable mismatches for highly
sensitized patients
– Why do see so many graft failures?
– Why are many patients never transplanted?
• Crossreactive antigen matching for platelet transfusions
of refractory thrombocytopenic patients
– Why are so many such transfusions unsuccessful?
– Why do some non-crossreactive mismatches work so well?
New Developments in HLA
• Complete typing for all HLA loci
• Better methods for HLA antibody
identification
• HLA structure and polymorphisms
• HLA and transplant immunity
HLA Effect on Transplantation
•
Humoral Immunity
– Complement-dependent antibodies
– Complement-independent antibodies
•
Cellular Immunity
– Direct Allorecognition
• Cytotoxic CD8 T-cells
• Effector CD4 T-cells
• Regulatory T-cells
– Indirect Allorecognition
• Effector CD4 T-cells
– NK cells (KIR)
•
HLA-restricted Immune Responses
– Anti-viral immunity
• Cytotoxic CD8 T-cells
– Recurrent autoimmune disease
• Effector CD4 T-cells
•
Graft-versus-Host Reactivity
– Mediated by donor T-cells
– Transfusion associated lung injury (TRALI)
Antibody Responses to HLA
• Class I HLA antigens
– HLA-A and HLA-B
– HLA-C
– MICA
• Class II HLA antigens
–
–
–
–
DRB1
DRB3, 4, 5
DQB and DQA
DPB and DPA
HLA Antibodies React With Epitopes
Which Can Now Be Defined Structurally
Amino Acid Polymorphisms On
The Molecular Surface Are
Responsible for Epitopes That
Induce Specific Alloantibodies
How can we visualize the polymorphic residues?
Polymorphic Residues on Class I Antigens
HLA-A2
HLA-B27
HLA-Cw3
Topography of Polymorphic Residues on
HLA-DR and HLA-DQ Molecules
HLA-DQ
HLA-DR
1
1
1
1
2
2
2
2
Structural Matching Concept
The HLA type of the antibody producer
determines what structural components of an
immunizing HLA antigen can be “seen” as non-self
Structural Basis of a HLA-B51 Mismatch
Polymorphic
Residues on B51
Structural Basis of a HLA-B51 Mismatch
Polymorphic
Residues on B51
“Seen” by
A2,A68;
B27,B44
Structural Basis of a HLA-B51 Mismatch
Polymorphic
Residues on B51
“Seen” by
A2,A68;
B27,B44
“Seen” by
A2,A68;
B35,B44
Structural Basis of a HLA-B51 Mismatch
Polymorphic
Residues on B51
“Seen” by
A2,A68;
B27,B44
“Seen” by
A2,A68;
B35,B44
“Seen” by
A2,A24;
B7,B8
Important Consideration
Differentiate between
Antigenicity of epitopes
(reactivity with antibodies)
and
Immunogenicity of epitopes
(induction of specific antibodies)
EFI Satellite Session Program
• Rene Duquesnoy (Pittsburgh, Pennsylvania) “Introduction” (5 min)
• Frans Claas (Leiden, The Netherlands) "Structural epitopes and
acceptable mismatching for highly sensitized patients" (25 min)
• Ivan Balasz (Stamford, Connecticut) "Epitope specificities of antibodies
reactive with single HLA alleles in Luminex assays" (15 min)
• Reyna Goodman (Cambridge, United Kingdom) "Predicting the
immunogenicity of HLA class I alloantigens using structural epitope
analysis determined by HLAMatchmaker” (15 min)
• Rene Duquesnoy (Pittsburgh, Pennsylvania) "Clinical relevance of HLA
epitope immunogenicity and antigenicity" (25 min)
• Case presentations and discussion (35 min)