Download 12-Transplantation

Transplantation immunology
Dr Adel Almogren.
Transfusion vs. Transplantation
Transfusion
transfer of blood
Ab-mediated
reactions
Transplantation
transfer of any other
tissue/organ
T cell mediated
reactions
Transplant Immunology Outline
•
•
•
•
Introduction
Graft compatibility
Graft rejection
Types of organ transplantation
Transplant Immunology Outline
• Introduction
Introduction
Transplantation
the moving of cells, tissues, and
organs from one site to another
Graft
the transplanted organ
Donor
person from whom graft is taken
Recipient (host)
person who gets the graft
• 1954 - first transplant (living kidney)
• 1960s - liver, heart transplants
Introduction
Transplantation problems
• Surgical difficulties
• Graft rejection
• Organ shortage
Transplant Immunology Outline
• Introduction
• Graft compatibility
Compatibility
Rejection = recipient recognizes graft as foreign,
and destroys it
Autograft
within same person
Isograft
between identical twins
Allograft
between genetically different people
Xenograft
between different species
Compatibility
Histocompatibility
• Histocompatible: antigenically similar to the host
• Histoincompatible: antigenically different from the host
• MHC antigens are the most important
• ABO antigens are also important
• Minor histocompatiblity antigens are less important
Compatibility
HLA complex
• Gene collection on chromosome 6
• Three regions: class I, class II, class III
• Class I gene products
• HLA-A, HLA-B, HLA-C
• expressed on nearly all cells
• present antigen to TC cells
• Class II gene products
• DP, DQ, DR
• expressed on antigen-presenting cells
• present antigen to TH cells
Compatibility
MHC class
I
II
III
Region
A
B
C
DP
DQ
DR
C4, C2, BF
Gene
products
HLAA
HLAB
HLAC
DP
DQ
DR
TNF-
proteins TNF-
C'
Compatibility
HLA inheritance
• HLA genes sit very close to each other
• Inherited as a set (“haplotype”)
• Everyone has two sets, one on each ch. 6
• Genes are codominantly expressed
(both maternal and paternal gene products
are expressed in the same cell)
Compatibility
HLA inheritance
• The more matching alleles between donor and
host, the better!
• Matching the class II antigens is more important
than matching the class I antigens.
• One or two class I mismatches = no big deal
• One or two class II mismatches = big deal
• Mismatches in both class I and II = very big deal
number of mismatches
graft survival, %
100
50
3
6
12
time after transplant, months
Class I
Class II
0
0
1 or 2
0
3 or 4
0
0
1 or 2
1 or 2
1 or 2
3 or 4
1 or 2
Transplant Immunology Outline
• Introduction
• Graft compatibility
• Graft rejection
1st set versus 2nd set reactions
1st set versus 2nd set reactions
Role of cell mediated responses
Unprimed syngeneic
recipient
Rejection
• Any two people (except identical twins) will express
some HLA proteins that are different.
• Every recipient will recognize, and react against, at
least some foreign antigens in the graft
• Rejection is complex, with lots of killing mechanisms.
Rejection
How do recipient cells know which cells to kill?
• Direct pathway of recognition
• Indirect pathway of recognition
Direct Pathway
Indirect Pathway
Rejection
Two mechanisms of rejection
• T-cell-mediated rejection
• Antibody-mediated rejection
Rejection
T-cell mediated rejection
• CD8+ CTLs kill graft cells directly
• CD4+ cells trigger a delayed hypersensitivity reaction
Role of CD4+ versus CD8 T+ cells
Injecting recip. mice with monoclonal
Ab against CD8, CD4 or both to
deplete one or both types of T cell
Rejection
Clinical types of rejection
• Hyperacute rejection
• Acute rejection
• Chronic rejection
Clinical manifestations of graft rejection
I.
Hyperacute rejection: very quick
II.
Acute rejection: about 10 days (cell mediated)
III. Chronic rejection: months-years (both)
Rejection Response
Transplant Immunology Outline
•
•
•
•
Introduction
Graft compatibility
Graft rejection
Types of organ transplantation
Types of Organ Transplantation
Kidney
• Most common transplanted organ
• Diabetes, glomerulonephritis,
congenital disorders
• Problems:
• host sensitization
• post-transplant malignancy
Types of Organ Transplantation
Heart
• Cardiomyopathy, myocarditis, congenital
defects, ischemic disease
• Must use heart-lung machine
• Problems:
• organ shortage
• maintaining graft before transplant
• atherosclerosis
• post-transplant lymphoma
Types of Organ Transplantation
Bone marrow
• Leukemia, lymphoma
• Find living donor (easy) that matches (hard)
• Massive chemo/radiation first
• Problem: GVHD
Types of Organ Transplantation
Bone marrow
• Leukemia, lymphoma
• Find living donor (easy) that matches (hard)
• Massive chemo/radiation first
• Problem: GVHD
• Donor T cells see recipient as foreign!
• Attack skin, GI, liver
• Treat with immunosuppressives
• Or, partially deplete donor marrow of T cells
Tissue Matching
General
Immunosuppressio
n Therapy
Problem 1
A 40 years old man who require a kidney graft
due to end-stage renal disease. His HLA genotype was
as follows: HLA-A3/A6.B27/B44,CI/C8,DR1/DR4.
He brought 5 donors .and tissue typing was
performed. Which one of them is the best choice ?
Donor no.1 HLA type: HLA-A3/A8, B7/B28, C4/C8, DRI/DR4.
Donor no.2 HLA “
: HLA-A6/A6, B27/B24, C12/C1, DR1/7.
Donor no.3.HLA “ “ : HLA-A27/A44, B1/B8, C3/C6, DR3/DR14.
Donor no.4 HLA “ ‘ : HLA-A3/A6, B24/B7,C2/C9, DR4/DR7.
Donor no.5 HLA “ “ : HLA-A3/A3, B27/B44, C1/C8, DR4/DR4.
Problem 2
A 5-months old boy who was diagnosed with severe
combined immunodeficiency (SCID ) received a bone
marrow transplantation from an HLA-matched donor.
He was doing well until 2 weeks after transplantation
when he developed a skin rash. Subsequently he
developed diarrhea, an enlarged liver & spleen and
jaundice.
What immunological process might be involved
in his problem ?
Problem 3
A 45-year- old woman with end-stage renal disease due
to diabetes mellitus, underwent renal transplantation.
She received a kidney from a living, unrelated donor.
Approximately one month after transplantation, the
patient’s urine output and kidney function decreased.
She developed tenderness, pain, and swelling at the
graft site. In addition, she had nonspecific symptoms
that included fever, decreased appetite, and myalgia
(muscle pain).