Transplant Immunology Historical Perspective Histocompatibility Antigens Major Histocompatibility Complex Human Leukocyte Antigens (HLA) Genetics Structure Function HLA and Disease Transplantation Types of Transplants Rejection Mechanism Immunosuppressive Strategies
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Transplant ImmunologyHistorical Perspective
Histocompatibility AntigensMajor Histocompatibility Complex
Human Leukocyte Antigens (HLA)Genetics Structure Function
HLA and DiseaseTransplantation
Types of TransplantsRejection MechanismImmunosuppressive Strategies
Transplant ImmunologyHistorical Perspective
Histocompatibility AntigensMajor Histocompatibility Complex
Human Leukocyte Antigens (HLA)Genetics Structure Function
HLA and DiseaseTransplantation
Types of TransplantsRejection MechanismImmunosuppressive Strategies
primary graftprimary graft
regraft from same strain
regraft from same strain
regraft from new strain
regraft from new strain
first set rejection
(2 - 3 weeks)
first set rejection
(2 - 3 weeks)
second set rejection
(3 - 5 days)
second set rejection
(3 - 5 days)
first set rejection
(2 - 3 weeks)
first set rejection
(2 - 3 weeks)
Donor Strain X Recipient Strain Y
Donor Strain Z
Experimental Transplantation
Donor Strain X Recipient Strain Y
Recipient Strain Y
bi-directional primary grafts
bi-directional primary grafts
regrafts from offspring
regrafts from offspring
first set rejections
first set rejections
Strain X Strain Y
Inheritance of Histocompatibility Antigens
second set rejections
second set rejections
Strain XY ?
Major Histocompatibility Complex
Class II Class I
DP DQ DR B C A
Chromosome 6
Major Histocompatibility Gene Loci
Major Histocompatibility Complex
Class II Class I
DR B A
DR1, DR2, DR3, DR4, DR5 …..
DR1, DR2, DR3, DR4, DR5 …..
B5, B7, B8, B12, B13, B14, B15…
B5, B7, B8, B12, B13, B14, B15…
Chromosome 6
Example Antigens
A1, A2, A3, A9, A10, A11, …..
A1, A2, A3, A9, A10, A11, …..
Major Histocompatibility Gene Loci
variable domains
constant domains
(heavy) chain
-2-microglobulin
chain chain
antigen presentation grooves
Histocompatibility Antigen Structure
class I class II
Human Leukocyte Antigens
A locus B locus DR locus
A1 A30 B5 B35 B50 B63 DR1 DR10A2 A31 B7 B37 B51 B64 DR2 DR11A3 A32 B8 B38 B52 B65 DR3 DR12A9 A33 B12 B39 B53 B67 DR4 DR13
A10 A34 B13 B40 B54 B70 DR5 DR14A11 A36 B14 B41 B55 B71 DR6 DR15A19 A43 B15 B42 B56 B72 DR7 DR16A23 A66 B16 B44 B57 B73 DR8 DR17A24 A68 B17 B45 B58 B75 DR9 DR18A25 A69 B18 B46 B59 B76A26 A74 B21 B47 B60 B77A28 A80 B22 B48 B61 B78A29 B27 B49 B62 B81
Inheritance of HLA antigens
XPaternal Phenotype
Offspring Phenotype
Maternal Phenotype
A1, A2, B8, B12, DR3, DR7 A3, A9, B5, B7, DR1, DR2
A1, A3, B7, B8, DR2, DR3
Inheritance of HLA antigens
A1
DR3
A2
B12
A3A1
A9A3
B8
DR7
DR3
DR2 DR1
DR2
B7B8
B7 B5X
Paternal Chromosomes
Offspring
Maternal Chromosomes
HLA phenotype:A1, A2, B8, B12, DR3, DR7
HLA phenotype:A3, A9, B5, B7, DR1, DR2
HLA phenotype:A1, A3, B7, B8, DR2, DR3
Haplotype 1:A1, B8, DR3
Haplotype 2:A3, B7, DR2
Haplotype 1:A1, B8, DR3
Haplotype 2:A3, B7, DR2
Tc
Humoral and Cellular Immunity
APC Th
Tc
Tc
B
APC Tc
Tc
plasma cell
YYY
Y
Y
Y
Y
Tc
lymphokineslymphokines
lymphokineslymphokines
cell mediated immunity
cell mediated immunityTh Tc
MHC Molecules and Antigen Presentation
APC
antigen presentation via class II molecules
antigen presentation via class II molecules
antigen presentation via class I molecules
antigen presentation via class I molecules
lymphokines
HLA and Disease Associations
System Disease Associated Antigen(s)
Endocrine Insulin-Dependent Diabetes
Thyrotoxicosis
DR3, DR4
B8, DR3
Neurologic Narcolepsy
Multiple Sclerosis
Lupus erythematosis
Rheumatoid Arthritis
Ankylosing Spondylitis
Systemic
DR2
A3, B7, DR2
B8, DR3
DR1, DR4
B27
HLA and Disease Mechanisms
Defective Immune Regulation
HLA molecule contributes to the disease process through the presentation of self-peptides
Molecular Mimicry
HLA molecule cross-reacts with microbial antigens
Pathogen Receptor
HLA molecule serves as a receptor for viruses that may be associated with certain diseases
Coincidental Association
The disease gene is located near or within the MHC
Types of Transplants
Classification Description Histocompatibility
Autologous (autograft)
Within the same individual or organism
Antigens are always identical
Syngeneic (isograft)
Between genetically identicalmembers of the same species
Between members of the same species not genetically identical
Between members of different species
Allogeneic (allograft)
Xenogeneic (xenograft)
Antigen are always identical
Antigens may be similar but usually are not
Antigens are always dissimilar
Graft Rejections
Classification Description Immunology
Hyperacute Occurs within minutes or hours after transplantation
Caused by high levels of
preexisting antibodyAccelerated Usually occurs within 3 to 5
days after transplantation
Occurs approximately 2 to 3 weeks after transplantation
May occur months or years after transplantation
Acute
Chronic
May be due to low-level antibody or memory T cells
Usually due to T cells but may involve antibody
May involve antibodies and T cells
Antibody Mediated Graft Rejection
Y YC
C
Y
Y
Y
YY
Y
Damaged endotheliumcauses platelet accumulation
and thrombus formation
Complement fixation leadsto neutrophil recruitment
and endothelial destruction
Antibody reacts with theendothelial lining of the
blood vessel wall
A B C
Cytotoxin production and graft destructionCytotoxin production and graft destructionDirect antigen recognitionDirect antigen recognition
Indirect antigen recognitionIndirect antigen recognition
Tc
Cell Mediated Graft Rejection
Th
APCTc Y
YY
YTc
B
Th
graftcell
graftcell
Lymphokine network
Lymphokine network
I II
K
Pre-Transplant Immunological Evaluations
Evaluation Objective
ABO blood group ABO compatibility between donor and recipient avoids hyperacute rejection
HLA phenotype
HLA antibody and crossmatch test
HLA matching delays the onset of chronic rejection and may avoid
accelerated rejection in regraft patients
Avoiding those donors against whom recipient antibodies are reactive prevents
hyperacute and accelerated rejections
Immunosuppression Strategies
Immune Suppressant Immunological Effects
Corticosteroids Decrease the availability and activity oflymphocytes and antigen presenting cells
T cell antisera
Cyclosporin A, FK506
Eliminate naïve and memory T cells
inhibits helper T cell associated functions, e.g. IL-2 production and interaction
Antimetabolites Inhibit T cell activation and proliferation
Case Study 1. Recipient selection for a cadaveric kidney transplant
PotentialRecipients
ABOblood group
HLA-Aantigens
HLA-Bantigen
HLA-DRantigens
HLAantibodies
1 B A1, A9 B7, B8 DR1, DR3 none
2 A A2, A3 B7, B8 DR2, DR3 anti-A1
3 O A1, A10 B5, B12 DR6, DR7 anti-B14
4 A A1, A3 B7, B15 DR1, DR9 none
5 A A2, A9 B13, B21 DR1, DR4 none
6 O A9, A19 B7, B8 DR3, DR6 none
7 A A1, A11 B8, B17 DR2, DR3 anti-A9
8 B A2, A9 B5, B18 DR3, DR7 anti-A10
9 A A2, A10 B7, B22 DR2, DR3 anti-B12
10 A A1, A3 B5, B8 DR1, DR3 none
Donor A A1, A3 B7, B8 DR2, DR3
Case Study 2. Living donor selection for a kidney transplant
PotentialDonors
ABOblood group
HLA-Aantigens
HLA-Bantigen
HLA-DRantigens
HLAantibody
Father A A11, A31 B35, B51 DR1, DR4
Mother O A9, A29 B16, B44 DR6, DR7
Sibling #1 O A9, A11 B16, B35 DR1, DR6
Sibling #2 O A29, A31 B44, B51 DR4, DR7
Sibling #3 O A9, A31 B16, B51 DR4, DR6
Sibling #4 A A11, A29 B35, B44 DR1, DR7
Patient O A11, A29 B35, B44 DR1, DR7 Anti-A9
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