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First Movement Practicale: Fine-tuning the Instrument of Epitope-Based Histocompatibility. Rene Duquesnoy University of Pittsburgh Medical Center. Lecture Outline. Immunogenicity and antigenicity of epitopes CDRs and antigen-antibody interactions

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first movement practicale fine tuning the instrument of epitope based histocompatibility

First Movement Practicale: Fine-tuning the Instrumentof Epitope-Based Histocompatibility

Rene Duquesnoy

University of Pittsburgh Medical Center

lecture outline
Lecture Outline
  • Immunogenicity and antigenicity of epitopes
  • CDRs and antigen-antibody interactions
  • HLAMatchmaker analysis of antibody reactivity with Luminex single allele panels
  • Commonly recognized class II epitopes
  • Epitope immunogenicity
  • HLAMatchmaker and platelet transfusions
identification of structurally defined hla epitopes
Identification of Structurally Defined HLA Epitopes
  • Empirical approach
    • Look for correlations between antibody reactivity patterns and the presence of distinct polymorphic amino acid residues in different sequence positions on reactive alleles
    • Conduct absorption/elution of sera with selected alleles
  • HLAMatchmaker
    • Epitope structure is based on three-dimensional modeling of different antigen-antibody complexes, molecular contact points between epitope and paratope and the contribution of important residues to epitope functionality
    • Consider the immunogenetic relationship between antibody producer and immunizer: concept of immunogenicity versus antigenicity
    • Determine if the antibody reactivity patterns correspond to HLAMatchmaker-predicted epitope mismatches
slide4

Important Consideration

Differentiate between

Immunogenicity of epitopes (induction of specific antibodies) 

and

Antigenicity of epitopes

(reactivity with antibodies)

hla mismatch immunogenicity
HLA Mismatch Immunogenicity
  • Mismatched HLA antigens have different epitope loads
  • HLA epitopes have different degrees of immunogenicity

A better understanding of HLA immunogenicity will permit a permissible mismatch strategy for non-sensitized transplant patients

antigenicity
Antigenicity
  • Reactivity of epitopes with specific antibodies
  • Serum screening methods
    • Complement-dependent lymphocytotoxicity: CDC, AHG
    • Antigen-binding assays: Elisa, Flow cytometry, Luminex with single antigens
  • Technique-dependent antibody reactivity
six complementarity determining regions of the antibody combining site
Six Complementarity-Determining Regions of the Antibody Combining Site
  • CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3 represent the “binding face” or “paratope” which contacts the structural epitope comprising 15-25 amino acids
slide9

Crystal Structure of HLA-A1-MAGE-A1 Complex with Fab-Hyb3

Hulsmeyer et al. J. Biol. Chem., 2005. 280: 2972-2980, 2005

six complementarity determining regions of the antibody combining site11
Six Complementarity-Determining Regions of the Antibody Combining Site
  • CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3 represent the “binding face” or “paratope” which contacts the structural epitope comprising 15-25 amino acids
  • The antibody specificity is often determined by a centrally located loop (CDR-H3) that binds to the functional epitope a configuration of 3-6 amino acids in the structural epitope
  • Eplets may define these functional epitopes
  • Other CDRs serve as contact sites to stabilize binding to antigen (they play a role in the affinity of antibody)
slide15

Structural Basis of a HLA-B51 Mismatch

“Seen” by

A2,A68;

B27,B44

“Seen” by

A2,A68;

B35,B44

Polymorphic

Residues on B51

slide16

B51 for

A2,A68;

B27,B44

B51 for

A2,A68;

B35,B44

?

?

How do antibodies react with structurally defined epitopes?

slide17

HLAMatchmaker-Based Analysis of Human Monoclonal Antibody Reactivity Demonstrates the Importance of an Additional Contact Site for Specific Recognition of Triplet-Defined Epitopes

Rene J. Duquesnoy, Arend Mulder, Medhat Askar, Marcelo Fernandez-Vina and Frans H.J. Claas

Human Immunology 66: 749-761 2005

two examples of mabs ok2h12 anti 62qe ok4f9 anti 142mi

Antibody Producer : A2,A68; B7,B27; Cw2,Cw7

Immunizer: A3 (pregnancy)

Triplets: 62Qe,142mI,144tKr,151aHe,163dT

Two examples of mAbs:

OK2H12: anti-62Qe

OK4F9: anti-142mI

slide20

56G is the only residue shared between HLA-A3 and 62Qe-carrying alleles that react with OK2H12

slide21

Shared Polymorphic Amino Acids in the 62Qe-Defined Specificity Site

Critical

Second

Contact Site

Antibody Specificity Site

slide22

Shared Polymorphic Amino Acids in the 62Qe-Defined Specificity Site

Critical

Second Contact Site

Antibody Specificity Site

Distance between 56G and 62Q is 11 Angstroms,

sufficient for contact by two different CDRs

slide23

Shared Polymorphic Amino Acids in the 62Qe-Defined Specificity Site

Critical

Second

Contact Site

is a

Self Residue

Antibody Specificity Site

Distance between 56G and 62Q is 11 Angstroms,

sufficient for contact by two different CDRs

immunizing hla a3 triplotype 62qe 142mi 144tkr 151ahe 163dt

Immunizing HLA-A3 Triplotype:62Qe,142mI,144tKr,151aHe,163dT

Two examples of mAbs:

OK2H12: anti-62Qe

OK4F9: anti-142mI

slide25

Reactivity of mAb OK4F9 with 142mI-Carrying Alleles

Lymphocytotoxicity

Antigen-Binding

Allele

Triplets shared with HLA-A3

N

%Pos Rx

Rx Strength

Flow Beads

Elisa

142mI

62Qe,

,144tKr,151aHe,163dT

A*0301

79

99%

7.6

++

++

142mI

62Qe,

,144tKr

A*0101

48

100%

7.4

++

+

142mI

62Qe,

,144tKr

A*1101

68

97%

7.8

++

++

142mI

,151aHe

A*2601

37

97%

7.5

++

++

142mI

A*2902

16

100%

8.0

++

++

142mI

62Qe,

A*3001

13

100%

8.0

++

++

142mI

62Qe,

A*3002

12

92%

6.5

nd

nd

142mI

62Qe,

A*3101

29

97%

7.6

++

++

142mI

A*3301

13

92%

7.3

++

++

142mI

A*3303

12

75%

6.3

nd

++

142mI

,151aHe

A*3401

19

100%

8.0

++

nd

142mI

,151aHe

A*3402

7

100%

8.0

nd

++

142mI

,151aHe

A*6601

8

100%

8.0

++

++

142mI

62Qe,

A*7401

5

100%

8.0

++

++

142mI

A*2301

17

0%

1.0

Neg

Neg

142mI

,144tKr

A*2402

78

8%

1.6

nd

Neg

142mI

,144tKr

A*2403

4

25%

1.7

Neg

Neg

142mI

,144tKr

A*2407

5

0%

1.0

nd

nd

142mI

,151aHe

A*2501

9

0%

1.0

Neg

Neg

142mI

62Qe,

A*3201

22

0%

1.0

Neg

Neg

A2/A28

none

67

6%

1.3

Neg

Neg

slide26

The sequence 79G,80T,81L,82R,83G is shared between HLA-A3 and the 142mI-carrying alleles that react with OK4F9

slide27

Locations of 142mI-Defined Specificity and the 79GTLRG-Defined Critical Secondary Contact Sites on A*0301

Crtical

Second Contact Site

(Self Sequence)

Antibody

Specificity

Site

Distance between 142I and 82R is 13 Angstroms,

Sufficient for contact by two different CDRs

slide28

Residue Polymorphisms and Reactivity of Bw6-Reactive SFR8-B6 Monoclonal Antibody

Lutz et al. J. Immunol. 153: 4099, 1994

Studied the effect of single amino acid substitutions by mutagenesis of HLA-B7 molecules

  • Antibody Specificity site: 80N, 82R, 83G
  • Critical contact site: 90A (about 11 Angstroms away)
  • Permissive substitutions in 62 positions!
slide30

Permissive Residue Substitutions that Do Not Inhibit Reactivity of the 62Qe-Specific mAb

slide31

Locations of Permissive Polymorphic Residues for 62Qe-Specific mAb Reactivity

56G

62Qe

serological analysis of the hla a10 complex
Serological Analysis of the HLA-A10 Complex
  • “Monospecific” antisera against the HLA-A10 splits A25 and A26 (7th Int. Workshop)
slide34

Serological Analysis of the HLA-A10 ComplexDuquesnoy and Schindler: Tissue Antigens 7: 65-73, 1976Hackbarth and Duquesnoy: Transplant. Proc. 9: 43-45, 1977

  • Antisera against the HLA-A10 splits A25 and A26
  • Absorption studies:

Can HLAMatchmaker explain this?

slide35

Anti-A25 Serum

* Immunizing Antigen

slide36

Anti-A26 Serum

*Immunizing Antigen

slide37

Anti-A10 Sera

* Immunizing Antigen

slide38

Structural Basis of Cytotoxic Antibody Reactivity against A25 and A26

Anti-A26

Anti-A25

Critical Second Contact Site

:76An

Critical Second Contact Site

:82aLr

Antibody

Specificity

Site:

150tAhe

Antibody

Specificity

Site:

150tAhe

Immunizing A26 antigen

Immunizing A25 antigen

The Critical Second Contact Site is a Non-Self Sequence

and is Necessary for Complement Binding

emerging concepts
Emerging Concepts
  • The HLA antibody specificity site consists of a cluster of few polymorphic amino acids on the molecular surface
    • This site would be contacted by CDR-H3
  • Antibody reactivity may require a second contact site which is about 7-15 Angstroms away from the antibody specificity site
    • This site would be contacted by a different CDR
interpretations of negative reactions of a serum with hla antibodies

Interpretations of Negative Reactions of a Serum with HLA Antibodies

The mismatched HLA antigen has a different epitope not recognized by patient antibody: Acceptable mismatches are identified through sharing of epitopes not recognized by patient’s antibodies

interpretations of negative reactions of a serum with hla antibodies41

Interpretations of Negative Reactions of a Serum with HLA Antibodies

The mismatched HLA antigen has a different epitope not recognized by patient antibody: Acceptable mismatches are identified through sharing of epitopes not recognized by patient’s antibodies

The mismatched HLA antigen carries the antibody specificity site but lacks the Critical Contact Site (CCS) for antibody binding: Acceptable mismatches are more difficult to identify

interpretations of negative reactions of a serum with hla antibodies42

Interpretations of Negative Reactions of a Serum with HLA Antibodies

The mismatched HLA antigen has a different epitope not recognized by patient antibody: Acceptable mismatches are identified through sharing of epitopes not recognized by patient’s antibodies

The mismatched HLA antigen carries the antibody specificity site but lacks the Critical Contact Site (CCS) for antibody binding: Acceptable mismatches are more difficult to identify

Hidden polymorphisms may affect the conformation of surface residues in the antibody specificity site and/or critical second contact site

hlamatchmaker analysis of antibody reactivity patterns with luminex single hla alleles
HLAMatchmaker Analysis of Antibody Reactivity Patterns with Luminex Single HLA Alleles

Example: Screening for antibodies against HLA-DP

slide45

Anti- HLA-DP Reactivity of Serum Group B Pt 43 Patient types as DPB1*0201,-

Questions:

Do the antibodies react with DPB or DPA or both ?

What are the antibody specificities ?

Which DP antigens are acceptable mismatches ?

Which DP antigens are unacceptable?

slide55

Predominant Eplets Reacting with anti-HLA-DP Antibodies

* 55DE is similar to the 57DE eplet on DR11

All 55DE-reactive sera reacted also with DR11

slide56
Retransplant Candidates Have Donor-Specific Antibodies that React with Structurally Defined HLA-DR,DQ,DP Epitopes

Duquesnoy et al. Transplant immunology, 18:352-360, 2008

three groups of hla sensitized patients
Three Groups of HLA-Sensitized Patients

A. Sensitizing tissue is absent

Previous transplant has been removed

Prior transfusion and pregnancy

B. Sensitizing tissue is present

Transplanted organ still in place No evidence of pre-transplant sensitization

C. Combination of A and B

slide58

Incidence of Anti-HLA-DR, -DQ and -DP Antibodies in HLA Class II Sensitized Patients with or without a Transplant Present

* p=0.001 ** p<0.0001

slide59

Effect of eplet mismatching and the Incidence of antibodies to donor DRB1, DRB3, DRB4 and DRB5 mismatches

slide64

SERUM ANALYSIS AFTER TRANSPLANT NEPHRECTOMY REVEALS RESTRICTED ANTIBODY SPECIFICITY PATTERNS AGAINST STRUCTURALLY DEFINED HLA CLASS I MISMATCHES

Adeyi et al. Transplant Immunology, 14: 53-62, 2005

slide65

Thirty Patients With Rejected Kidney Transplants Underwent Allograft Nephrectomy

100%

80%

PRA

60%

40%

20%

0%

Before Tx Pre-AlloNx. Post-AlloNx

Adeyi et al. Transplant Immunology, 14: 53-62, 2005

slide66

Donor Epitopes:  

A3: 62Qe,66rNv,70aQs,76Vd,80gTl,144tKr,149aAh,151aHe,163dT

A31: 56R,62Qe,66rNv,74iD,76Vd,80gTl,193Av  

B55: 131S  

B63: 45Ma,66rNm,70aSa,74Y,131S

Adeyi et al. Transplant Immunology, 14: 53-62, 2005

slide67

Donor Epitopes (serum-reactive epitopes are shown in underlined bold font)

A3: 62Qe,66rNv,70aQs,76Vd,80gTl,144tKr,149aAh,151aHe,163dT

A31: 56R,62Qe,66rNv,74iD,76Vd,80gTl,193Av

B55: 131S

B63: 45Ma,66rNm,70aSa,74Y,131S

Adeyi et al. Transplant Immunology, 14: 53-62, 2005

slide68

Donor Epitopes (serum-reactive epitopes are shown in underlined bold font)

A3: 62Qe,66rNv,70aQs,76Vd,80gTl,144tKr,149aAh,151aHe,163dT

A31: 56R,62Qe,66rNv,74iD,76Vd,80gTl,193Av

B55: 131S

B63: 45Ma,66rNm,70aSa,74Y,131S

Unacceptable epitopes identify unacceptable antigens

e.g. 45Ma is present on B13, B46, B57,B62, B63. B75, B76, B76

Adeyi et al. Transplant Immunology, 14: 53-62, 2005

slide69

Donor Epitopes:

B13: 41T,45Ma,76En,80rTa,82aLr,144tQl,163E

82aLr is expressed by all Bw4-associated HLA-B antigens +A23, A24, A25 and A32

144tQl is unique for HLA-B13

After six months: the anti-76En and anti-82aLr antibodies have disappeared,

Only anti-144tQl antibodies are detected

Adeyi et al. Transplant Immunology, 14: 53-62, 2005

relative immunogenicity of eplets

Relative Immunogenicity of Eplets

How often do mismatched eplets induce specific antibodies?

14th International HLA Workshop Project

Analysis of donor-specific antibodies in patients whose rejected kidney transplants had been removed

preliminary results eplet immunogenicity in 62 cases
Preliminary Results: Eplet Immunogenicity in 62 Cases

Duquesnoy, RJ and Claas FHJ: Progress Report of 14th International Histocompatibility Workshop Project on the Structural Basis of HLA Compatibility, Tissue Antigens, 69 (Suppl. 1): 1-5, 2007

15 th international workshop project on epitope immunogenicity
15th International Workshop Project on Epitope Immunogenicity
  • Analyze post-allograft nephrectomy sera for antibodies against donor class I and class II epitopes
  • Serum screening with single alleles (Luminex) and by CDC
  • So far, 40 laboratories worldwide will contribute informative cases
  • For more information go to

http://www.15ihiws.org/project.php?n=13

hla mismatch immunogenicity73
HLA Mismatch Immunogenicity
  • Mismatched HLA antigens have different epitope loads
  • HLA epitopes have different degrees of immunogenicity

A better understanding of HLA immunogenicity will permit a permissible mismatch strategy for non-sensitized transplant patients

slide75

HLAMatchmaker-Driven Analysis of Responses to HLA Typed Platelet Transfusions in Alloimmunized Thrombocytopenic Patients

Ashok Nambiar, Rene J. Duquesnoy, Sharon Adams, Yingdong Zhao, Jaime Oblitas, Susan Leitman, David Stroncek and Francesco Marincola

Department of Transfusion Medicine, National Institutes of Health

Blood 107: 1690-1697, 2006

slide76

T R A N S F U S I O N P R A C T I C E

Structural epitope matching for HLA-alloimmunized

thrombocytopenic patients: a new strategy to provide more

effective platelet transfusion support?

Rene J. Duquesnoy

Transfusion, 48: 221-227, February 2008

alloimmunization induced refractoriness to random donor platelet transfusions
Alloimmunization-Induced Refractoriness to Random Donor Platelet Transfusions
  • Antibody reactivity with
    • HLA Class I antigens
    • Platelet-specific antigens
    • Other antigens (MICA?, HLA class II?, blood groups)
  • Refractory patients
    • Hematological defects (e.g. aplastic anemia)
    • Malignancies (e.g. leukemia)
    • Highly sensitized liver transplant candidates
alloimmunization induced refractoriness to random donor platelet transfusions78
Alloimmunization-Induced Refractoriness to Random Donor Platelet Transfusions
  • Antibody reactivity with
    • HLA Class I antigens
    • Platelet-specific antigens
    • Other antigens (MICA?, HLA class II?, blood groups)
  • Refractory patients
    • Hematological defects (e.g. aplastic anemia)
    • Malignancies (e.g. leukemia)
    • Highly sensitized liver transplant candidates
treatment of hla alloimmunization induced refractoriness
Treatment of HLA Alloimmunization-Induced Refractoriness
  • Platelet transfusions from HLA matched donors (Yankee et al. N Eng J Med 281:1208, 1969)
  • Platelet transfusions from donors mismatched for cross-reacting HLA antigens (Duquesnoy et al. Amer J Hematol 2: 219, 1977)
serological cross reactivity between hla antigens
Serological Cross-Reactivity Between HLA Antigens
  • HLA antigens carry “private” and “public” epitopes
  • Cross-Reacting Groups (CREGs) of HLA antigens share the same public epitope

Rodey and Fuller: Crit Rev Immunol 7:229, 1987

slide84

Responses to Platelet Transfusions with Different HLA Match Grades

Duquesnoy et al. American Journal of Hematology. 2:219-226, 1977

limitations of the cross reactivity based hla match grade system
Limitations of the Cross-Reactivity Based HLA Match Grade System
  • Many BX matches are unacceptable epitope mismatches
  • A and BU match groups may have incompatible epitopes revealed by 4-digit DNA typing
  • CREG matching considers only HLA-A and HLA-B; how important is HLA-C?
many bx matches have incompatible epitopes
Many BX Matches Have Incompatible Epitopes
  • Cross-Reacting Matches and Bw4/Bw6 mismatches
  • Eplet differences between Cross-Reacting Antigens

Effect of BW4/6 incompatibility on responses to BX matched platelet transfusions

Patients 1-8: lower increments

Patients 9-21: comparable increments

McElligott et al Blood 59: 971, 1982

limitations of the cross reactivity based hla match grade system88
Limitations of the Cross-Reactivity Based HLA Match Grade System
  • Many BX matches are unacceptable epitope mismatches
  • A and BU match groups may have incompatible epitopes revealed by 4-digit DNA typing
  • CREG matching considers only HLA-A and HLA-B; how important is HLA-C?
limitations of the cross reactivity based hla match grade system90
Limitations of the Cross-Reactivity Based HLA Match Grade System
  • Many BX matches are unacceptable epitope mismatches
  • A and BU match groups may have incompatible epitopes revealed by 4-digit DNA typing
  • CREG matching considers only HLA-A and HLA-B. How important is HLA-C?
    • Not Important (Duquesnoy et al Transplant. Proc. 9: 1827, 1977)
    • Low expression on platelets (Mueller-Eckhart et al Tissue Antigens 16: 91, 1980)
    • Important for some patients (Saito et al Transfusion 42: 302, 2002)
example of luminex screen for antibodies specific for hla c 1
Example of Luminex Screen for Antibodies Specific for HLA-C (1)

What is the cut-off point to distinguish between positive and negative reactions?

example of luminex screen for antibodies specific for hla c 2
Example of Luminex Screen for Antibodies Specific for HLA-C (2)

Antibody react with Cw*0102 of donor

Reactivity with donor’s Cw*0701?

What HLA-C epitopes are recognized?

Do HLAMatchmaker analysis

What are the mismatched eplets?

example of luminex screen for antibodies specific for hla c 3
Example of Luminex Screen for Antibodies Specific for HLA-C (3)

These are the eplets on HLA-C alleles of donor and the panel

Cw*1203 has no mismatched eplets for this patient

One or more eplets on donor’s Cw*0102 must react with antibody

Any reactivity with 65QNR of donor’s Cw*0701?

example of luminex screen for antibodies specific for hla c 4
Example of Luminex Screen for Antibodies Specific for HLA-C (4)

No reactivity with 65QNR of donor’s Cw*0701

No reactivity with the eplets of the negative alleles

Cw*0202, Cw*0401, Cw*0501, Cw*1502, Cw*1701 and Cw*1801

Record these negative alleles in the HLAMatchmaker program

example of luminex screen for antibodies specific for hla c 5
Example of Luminex Screen for Antibodies Specific for HLA-C (5)

The 77TVS eplet of donor’s Cw*0102 is present on all reactive alleles

77TVS is an unacceptable mismatch

proposed hla epitope based matching protocol steps 1 and 2
Proposed HLA Epitope-Based Matching Protocol (steps 1 and 2)
  • Perform HLA-A, B, C typing of patients and donors by DNA methods at the high-resolution (4-digit allele) level.
  • Screen patient sera with HLA typed panel
    • Complement-dependent methods: direct and/or antiglobulin-augmented lymphocytotoxicity
    • Antigen-binding assays such as Luminex, Flow Cytometry and ELISA preferably with single HLA class I alleles
    • HLAMatchmaker-based analysis of serum reactivity pattern to identify acceptable mismatches
proposed hla epitope based matching protocol step 3
Proposed HLA Epitope-Based Matching Protocol (step 3)

3. Conduct a platelet donor search

  • Establish a computerized platelet donor registry that incorporates an HLAMatchmaker-based search engine
  • Enter the HLA type of the patient and the non-reactive mismatched alleles in this database and the computer will generate a list of donors with matches and acceptable mismatches at the eplet level
  • No need for platelet cross-match testing for HLA incompatibility
proposed hla epitope based matching protocol step 4
Proposed HLA Epitope-Based Matching Protocol (step 4)

4. Evaluate the outcome of the platelet transfusion, if increment is low then:

  • Determine whether serum reactivity patterns have improperly been interpreted in terms of HLA mismatch acceptability
  • Look for antibodies against platelet-specific antigens and blood groups, or autoimmune phenomena and drug reactions
  • Consider clinical conditions such as coagulopathy, infection and hepatosplenomegaly
prevention or delay of hla alloimmunization
Prevention or Delay of HLA Alloimmunization
  • HLAMatchmaker-based selection of apheresis platelets with minimal numbers of mismatched eplets
    • From existing inventories of stored platelets
    • Do a computer search for compatible platelet donor
    • Avoid immunogenic eplets
  • Leukoreduction of platelet preparations prior to transfusion
prevention or delay of hla alloimmunization102
Prevention or Delay of HLA Alloimmunization
  • HLAMatchmaker-based selection of apheresis platelets with minimal numbers of mismatched eplets
    • From existing inventories of stored platelets
    • Do a computer search for compatible platelet donor
    • Avoid immunogenic eplets
  • Leukoreduction of platelet preparations prior to transfusion
prevention or delay of hla alloimmunization103
Prevention or Delay of HLA Alloimmunization
  • HLAMatchmaker-based selection of apheresis platelets with minimal numbers of mismatched eplets
    • From existing inventories of stored platelets
    • Do a computer search for compatible platelet donor
    • Avoid immunogenic eplets
  • Leukoreduction of platelet preparations prior to transfusion
conclusions
Conclusions
  • The serological cross-reacting antigen matching system introduced in 1977 should be replaced by a system that incorporates modern concepts of epitope reactivity with antibody.
  • The proposed HLA epitope matching protocol is expected to benefit platelet transfusion outcome and increase the number of compatible donors for refractory patients.
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