Transplantation immunology Dr Adel Almogren.. Transfusion vs. Transplantation Transfusion transfer of blood Ab-mediated reactions Transplantation.

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).