Transplantation immunology

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Transplantation immunology Dr Adel Almogren.
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Transfusion vs. Transplantation

• Transfusion
• transfer of blood
• Ab-mediated reactions
• Transplantation
• transfer of any other tissue/organ
• T cell mediated reactions

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Transplant Immunology Outline

• Introduction
• Graft compatibility
• Graft rejection
• Types of organ transplantation

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Transplant Immunology Outline

• Introduction

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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

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Introduction
Transplantation problems

• Surgical difficulties
• Graft rejection
• Organ shortage

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Transplant Immunology Outline

• Introduction
• Graft compatibility

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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

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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

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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

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Compatibility
MHC class I I I II II II III III
Region A B C DP DQ DR C4, C2, BF C4, C2, BF
Gene products HLA-A HLA-B HLA-C DP DQ DR C' proteins TNF-? TNF-?
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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)

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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

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number of mismatches
Class I
Class II
100
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
50
graft survival,
6
3
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time after transplant, months
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Transplant Immunology Outline

• Introduction
• Graft compatibility
• Graft rejection

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1st set versus 2nd set reactions
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1st set versus 2nd set reactions
Role of cell mediated responses
Unprimed syngeneic recipient
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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.

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Rejection
How do recipient cells know which cells to kill?

• Direct pathway of recognition
• Indirect pathway of recognition

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Direct Pathway
Indirect Pathway
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Rejection
Two mechanisms of rejection

• T-cell-mediated rejection
• Antibody-mediated rejection

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Rejection
T-cell mediated rejection

• CD8 CTLs kill graft cells directly
• CD4 cells trigger a delayed hypersensitivity
  reaction

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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
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Rejection
Clinical types of rejection

• Hyperacute rejection
• Acute rejection
• Chronic rejection

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Clinical manifestations of graft rejection

1. Hyperacute rejection very quick
2. Acute rejection about 10 days (cell mediated)
3. Chronic rejection months-years (both)

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Rejection Response
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Transplant Immunology Outline

• Introduction
• Graft compatibility
• Graft rejection
• Types of organ transplantation

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Types of Organ Transplantation
Kidney

• Most common transplanted organ
• Diabetes, glomerulonephritis, congenital
  disorders
• Problems
• host sensitization
• post-transplant malignancy

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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

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Types of Organ Transplantation
Bone marrow

• Leukemia, lymphoma
• Find living donor (easy) that matches (hard)
• Massive chemo/radiation first
• Problem GVHD

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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

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Tissue Matching
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General Immunosuppression Therapy
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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.
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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 ?
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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 patients 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).