Clinical Utility - DORAK · HLA Matching & Transplantation Success Together with ABO, CMV...
Transcript of Clinical Utility - DORAK · HLA Matching & Transplantation Success Together with ABO, CMV...
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HLA Complex Clinical Utility
Mount Sinai Medical Center Department of Pathology
February 23, 2012
M. Tevfik DORAK
Environmental & Occupational Health College of Public Health
Florida International University Miami, USA
http://www.dorak.info
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Part I Genetics & Biology
Part II Clinical utility of HLA typing FDA-approved uses of HLA typing HLA matching for transplantation HLA antibodies and transplantation
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(www)
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Different levels of resolution:
HLA-B44 (serologic specificity / broad specificity)
HLA-B*44 > HLA-B*44:02 > HLA-B*44:02:04
two-digit four digits highest resolution
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DRB1*04
DRB1*07
DRB1*09
DRB1*03
DRB1*11
DRB1*12
DRB1*13
DRB1*14
DRB1*15
DRB1*16
DRB1*10
DRB1*01
DRB4
DRB4
DRB4
DRB3
DRB3
DRB3
DRB3
DRB3
DRB5
DRB5
01/10
01/10
4+ digit alleles
forming
supertypes
Specificities
(2 digit)
Phylogenetic groups
DRB1*08 DRB3 (08)
Functional multi-allelic HLA polymorphisms
SNPs
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HLA-
DRB3/4/5
HLA-
DRB1 HLA-A HLA-B
HLA-C
HLA-
DQB1
Class III
region
C1/C2
epitopes
Bw4/Bw6
epitopes
Codon 114
Codon 116
Cross-reactive groups (CREGs)
Functional supertypes
Functional
supertypes
Codon 86 Codon 57
Phylogenetic
lineages
Codon 114
Codon 116
Functional multi-allelic HLA polymorphisms
Multiple SNPs
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Part I Genetics & Biology
Part II Clinical utility of HLA typing FDA-approved uses of HLA typing HLA matching for transplantation HLA antibodies and transplantation
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Part I Genetics & Biology
Part II Clinical utility of HLA typing FDA-approved uses of HLA typing HLA matching for transplantation HLA antibodies and transplantation
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What Goes on in an HLA Laboratory
HLA typing
Detection of HLA antibodies
for transplantation
for blood transfusion
Disease association studies and other research
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(www)
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A New Era of Immunosuppression
Full HLA matching is no longer required
Emphasis is on matching recipient
antibodies against donor HLA antigens
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(www)
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HLA Typing
Serological Typing
Using antiserum / monoclonal antibodies
DNA-based HLA typing
Conventional PCR methods: SSP, SSOP
Real-time PCR methods: TaqMan, SYBR Green
Sequence-based typing (SBT)
Next-generation sequencing
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HLA Typing: SSP
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HLA Typing: SSP by TaqMan
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HLA Typing: SSP by HRM
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HLA Typing: NGS
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HLA Matching & Transplantation Success
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HLA Matching & Transplantation Success
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HLA Matching & Transplantation Success
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HLA Matching & Transplantation Success
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HLA Matching & Transplantation Success
Together with ABO, CMV compatibility and negative xM:
Absolute requirement in HSCT engraftment (but GvL?)
Other considerations: donor age and gender, KIR matching
Required for increased success of kidney Tx
Useful but not required for heart & lung, pancreas Tx
Other considerations are dominant (cold ischemia time, age- and size-matching)
Not required for corneal transplantation success (except avoidance of first donor’s HLA types in regrafting after rejection)
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HvG versus GvH
HvG score: graft rejection
GvH score: graft-versus-host reaction
A1, A2 B7, B7 DR1 DR4
A1, A2 B7, B8 DR1 DR4
A2, A11 B7, B44 DR1 DR15
A2, A11 B7, B7 DR1 DR15
X X
HvG GvH
H
G
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Sources of Anti-HLA Antibodies
Multiparous women
Multiple blood transfusions
Previous rejection of HLA-mismatched
transplant
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Anti-HLA Antibodies in Transplantation
Hyperacute rejection (<48h)
preformed high-titer IgG complement-fixing Ab
Acute rejection (days-weeks after engraftment)
CD4-mediated (lymphocyte infiltration) or
Ab-mediated (C4d deposition)
Chronic rejection (months-years)
Multifactorial
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Anti-HLA Antibodies in Transfusion
Hemolytic transfusion reactions
Platelet refractoriness
Non-hemolytic febrile reactions
Non-cardiogenic pulmonary edema
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Anti-HLA Antibody Screening
Panel-reactive Antibody Screening
Complement-dependent cytotoxicity
(CDC) Assay
using T-cells (class I) and B-cells (class II)
Flow cytometry-based assays for non-complement-fixing antibodies
ELISA assays
for class I/II and for complement-fixing or nonfixing antibodies
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Anti-HLA Antibody Screening
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Anti-HLA Antibody Screening
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Anti-HLA Antibody Screening
Donor x Recipient Crossmatch to detect preformed anti-HLA antibodies against
a specific donor to avoid hyperacute rejection
1) CDC assay with (IgM) or without DTT (visual xMatch)
2) Flow cytometry: more sensitive; more effective against
IgG antibodies
3) Solid phase methods: Donor cell HLA capture beads
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Anti-HLA Antibody Screening
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Anti-HLA Antibody Screening
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A New Era of Immunosuppression
Full HLA matching is no longer required
Emphasis is on matching recipient
antibodies against donor HLA antigens
Even antibody-positive recipients can be
now be transplanted
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ACKNOWLEDGEMENTS
My current team:
Meredith Peyser
Amy, Sandeep & Karina
Allen, Tiana, Daniel, Karina
Florida International University
RSCPHSW
EOH
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Mehmet Tevfik DORAK
Environmental & Occupational Health College of Public Health
Florida International University Miami, USA
http://www.dorak.info