18 - Immunology of Transplant

Question 1

Why does transplantation of cells or tissues from one individual to a genetically nonidentical individual invariably leads to rejection of the transplant

Answer 1

Due to adaptive immune response

Question 2

Rejection

Answer 2

• Failure of transplant caused by inflammatory reaction
• Shows characteristics of memory and specificity mediated by lymphocytes

Question 3

Autologous graft

Answer 3

A graft transplanted from one individual to the same individual

Question 4

Syngeneic graft / isologous transplant

Answer 4

graft transplanted between two genetically identical individuals (e.g. identical twin)

Question 5

Allogenic graft (allograft) / homologous transplant

Answer 5

Graft transplanted between two genetically different individuals of the same species

Question 6

Xenograft

Answer 6

Graft transplanted between individuals of different species

Question 7

Alloantigens (alloreactive)

Answer 7

Molecules that are recognised as foreign in allografts

Question 8

Xenoantigens (zenoreactive)

Answer 8

Molecules recognised as foreign in xenografts

Question 9

Basic rules of transplantation immunology

Answer 9

• Cells or organs transplanted between genetically identical individuals are not rejected
• Cells or organs transplanted between genetically non-identical people are almost always rejected
• The offspring of a mating between two different inbred strains of animal will not reject grafts from either parent.
• A graft derived from the offspring of a mating between two different inbred strains of animal will be rejected by either parent. In other words, a graft from an (A × B) F1 animal will be rejected by
  either an A or a B strain animal

Question 10

Molecules responsible for strong and rapid rejection reactions

Answer 10

MHC molecules that bind and present peptides to T cells

Question 11

Two different ways that allogenic MHC molecules of a graft can be presented for recognition by the recipients T cells

Answer 11

Direct and indirect

Question 12

Direct presentation (or recognition) of alloantigens

Answer 12

T cells of a graft recipient recognise intact, unprocessed MHC molecules in the graft

Question 13

Indirect presentation (or recognition) of alloantigens

Answer 13

Recipient T cells recognize graft (donor) MHC molecules only in the context of the recipient’s MHC molecules, implying that the recipient’s MHC molecules must be presenting peptides derived from allogeneic donor MHC proteins to recipient T cells

Question 14

Where does the initial T cell response to MHC alloantigens occur

Answer 14

Lymph nodes draining the graft

Question 15

Direct allorecognition

Answer 15

Seen as example of immunologic cross reaction in which a T cell that was selected to be self MHC restricted is able to bind structurally similar allogenic MHC molecules (without processing by host APCS) with high enough affinity to permit activation of the T cell

Question 16

Indirect allorecognition

Answer 16

MHC molecules are captured and processed by recipient APCs, and peptides derived from the allogeneic MHC molecules are presented in association with self MHC molecules

Question 17

Donor specific antibodies

Answer 17

• Antibodies against graft antigens that also contribute to rejection
• High-affinity alloantibodies are mostly produced by helper T cell–dependent activation of alloreactive B cells
• Antigens most frequently recognized by alloantibodies are donor MHC molecules, including both class I and class II MHC proteins

Question 18

Effector mechanisms engaged by alloreactive antibodies

Answer 18

• Complement activation
• Fc receptor mediated binding
• Activation of neutrophils, macrophages, and NK cells

Question 19

Hyperacute rejection

Answer 19

• Characterized by thrombotic occlusion of the graft vasculature that begins within minutes to hours after host blood vessels are anastomosed to graft vessels
• Mediated by preexisting antibodies in the host circulation that bind to donor endothelial antigens
• Also caused by wrong blood group donor

Question 20

Outcomes of hyperacute rejection

Answer 20

• Complement activation
• Endothelial damage
• Inflammation
• Thrombosis

Question 21

Acute cellular rejection

Answer 21

• CTL mediated killing of graft parenchymal cells and endothelial cells
• Inflammation caused by cytokines produced by helper T cells

Question 22

Major cause of the failure of vascularised organ allografts

Answer 22

Chronic rejection

Question 23

Graft vasculopathy / accelerated graft arteriosclerosis

Answer 23

• Caused by activation of alloreactive T cells and secretion of IFN-γ and other cytokines that stimulate
  proliferation of vascular smooth muscle cells.
• As the arterial lesions of graft arteriosclerosis progress, blood flow to the graft parenchyma is compromised, and the parenchyma is slowly replaced by nonfunctioning fibrous tissue

Question 24

Major strategy to reduce graft immunogenicity

Answer 24

To minimise alloantigenic differences between the donor recipient (e.g. the larger the number of MHC alleles that are marched between the donor and recipient, the better the survival)

Question 25

Clinical lab tests performed to reduce the risk for immunologic rejection of allografts

Answer 25

• ABO blood typing
• Tissue typing
• Detection of preformed antibodies in the recipient that recognize HLA and other antigens representative of the donor population
• Cross matching

Question 26

Tissue typing

Answer 26

Determination of HLA alleles expressed on donor and recipient cells

Question 27

Cross matching

Answer 27

Detection of preformed antibodies in the recipient that bind to antigens of an identified donor’s cells

Question 28

Tissue expression of Class 1 HLA antigens (A, B, C)

Answer 28

• On all nucleated cells
• Density varies from tissue to tissue

Question 29

Tissue expression of class 2 HLA antigens (DR, DQ, DP)

Answer 29

• APCs (DCs, macrophages)
• B lymphocytes
• Activated T lymphocytes

Question 30

MHC matching and graft survival

Answer 30

• HLA matching in renal
  transplantation is possible because donor kidneys can be stored and patients needing a kidney allograft can be maintained on dialysis
• In the case of heart and liver transplantation, organ preservation is more difficult, and potential recipients are often in critical condition

Question 31

Panel reactive antibodies

Answer 31

• Patients waiting for organ transplants are screened for the presence of preformed antibodies reactive with allogeneic HLA molecules prevalent in the population
• The presence of these antibodies, which may be produced as a result of previous pregnancies, transfusions, or transplantation, increases risk for hyperacute or acute vascular rejection

Question 32

HLA testing

Answer 32

• HLA antibody characterisation using bead based multiplex assay
• Complement dependent cytotoxicity crossmatch
• Flow cytometry crossmatch

Question 33

Complement dependent cytotoxicity crossmatch

Answer 33

• Recipient serum and exogenous complement are added to donor lymphocytes.
• If donor- specific anti- HLA antibodies are present in the recipient serum, they bind to HLA molecules on the surface of the donor lymphocytes and activate complement, leading to cell lysis.
• The lysed cells take up vital dye and can be detected using microscopy.
• Flow cytometry crossmatch uses flourphore instead

Question 34

Major immunologic barrier to xenogeneic transplantation

Answer 34

• The presence of natural antibodies in the human recipients that cause hyperacute rejection
• Antibodies are produced against species that are evolutionarily distant, but rarely produced in closely related species

Question 35

Delayed xenograft rejection / accelerated acute rejection / acute vascular rejection

Answer 35

• Characterised by intravascular thrombosis and necrosis of vessel walls
• Even when hyperacute rejection is prevented, xenografts are often damaged by a form of acute vascular rejection that occurs within 2 to 3 days of transplantation.

Question 36

Haematopoietic Stem Cell Transplant

Answer 36

• Procedure to treat lethal diseases caused by intrinsic defects in one or more hematopoietic lineages in a patient (e.g. CML)
• HSCs are obtained from the blood of donors, after treatment of the donor with colony-stimulating factors that mobilize stem cells from the bone marrow
• The recipient is treated before transplantation with a combination of chemotherapy, immunotherapy, or irradiation to kill the defective HSCs, and to
  free up niches for the transferred stem cells
• After transplantation, the injected stem cells repopulate the recipient’s bone marrow and differentiate into all of the hematopoietic lineages

Question 37

Autologous stem cell transplant

Answer 37

• Hematopoietic stem cells are harvested from the blood or bone marrow of a patient before the patient undergoes treatment for cancer
• In order to remove tumour
  cells that may have been collected with the stem cells, the sample is incubated with antibodies that bind only to stem cells
• The stem cells are then isolated and stored for later use, when they are reinfused into the patient.

Question 38

Graft versus host disease (GVHD)

Answer 38

• Caused by reaction of grafted mature T cells in the HSC inoculum with alloantigens of the host
• Principal cause of mortality among HSC transplant recipients