Transplantation immunologyDr Adel Almogren.
Transfusion vs. Transplantation
Transfusion transfer of bloodAb-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
• Surgical difficulties
• Graft rejection
• Organ shortage
Introduction
Transplantation problems
Transplant Immunology Outline
• Introduction
• Graft compatibility
Compatibility
Rejection = recipient recognizes graft as foreign, and destroys it
Autograftwithin same person
Isograft between identical twins
Allograft between genetically different people
Xenograft between different species
• 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
Histocompatibility
• 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
HLA complex
Compatibility
MHC class I II III
Region A B C DP DQ DR C4, C2, BF
Gene products
HLA-A
HLA-B
HLA-C
DP DQ DRC'
proteins
TNF-
TNF-
• 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
Compatibility
HLA inheritance
graf
t su
rviv
al,
%
50
100
63 12
time after transplant, months
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
number of mismatches
Class I Class II
Transplant Immunology Outline
• Introduction
• Graft compatibility
• Graft rejection
1st set versus 2nd set reactions1st set versus 2nd set reactions
1st set versus 2nd set reactions1st set versus 2nd set reactions
Unprimed syngeneic recipient
Role of cell mediated responses
• 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
• Direct pathway of recognition
• Indirect pathway of recognition
Rejection
How do recipient cells know which cells to kill?
Direct Pathway Indirect Pathway
• T-cell-mediated rejection
• Antibody-mediated rejection
Rejection
Two mechanisms of rejection
• CD8+ CTLs kill graft cells directly
• CD4+ cells trigger a delayed hypersensitivity reaction
Rejection
T-cell mediated rejection
Role of CD4Role of CD4++ versus CD8 T versus CD8 T++ cells cells
Injecting recip. mice with monoclonal Ab against CD8, CD4 or both to
deplete one or both types of T cell
• Hyperacute rejection
• Acute rejection
• Chronic rejection
Rejection
Clinical types of rejection
Clinical manifestations of graft rejectionClinical manifestations of graft rejection
I. Hyperacute rejection: very quick
II. Acute rejection: about 10 days (cell mediated)
III. Chronic rejection: months-years (both)
Rejection ResponseRejection Response
Transplant Immunology Outline
• Introduction
• Graft compatibility
• Graft rejection
• Types of organ transplantation
• Most common transplanted organ
• Diabetes, glomerulonephritis, congenital disorders
• Problems:
• host sensitization
• post-transplant malignancy
Types of Organ Transplantation
Kidney
• Cardiomyopathy, myocarditis, congenital defects, ischemic disease
• Must use heart-lung machine
• Problems:
• organ shortage
• maintaining graft before transplant
• atherosclerosis
• post-transplant lymphoma
Heart
Types of Organ Transplantation
• Leukemia, lymphoma
• Find living donor (easy) that matches (hard)
• Massive chemo/radiation first
• Problem: GVHD
Bone marrow
Types of Organ Transplantation
• 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
Bone marrow
Types of Organ Transplantation
Tissue MatchingTissue Matching
General General ImmunosuppresImmunosuppres
sion Therapysion 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 3A 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).
