18 - Immunology of Transplant Flashcards
Why does transplantation of cells or tissues from one individual to a genetically nonidentical individual invariably leads to rejection of the transplant
Due to adaptive immune response
Rejection
- Failure of transplant caused by inflammatory reaction
- Shows characteristics of memory and specificity mediated by lymphocytes
Autologous graft
A graft transplanted from one individual to the same individual
Syngeneic graft / isologous transplant
graft transplanted between two genetically identical individuals (e.g. identical twin)
Allogenic graft (allograft) / homologous transplant
Graft transplanted between two genetically different individuals of the same species
Xenograft
Graft transplanted between individuals of different species
Alloantigens (alloreactive)
Molecules that are recognised as foreign in allografts
Xenoantigens (zenoreactive)
Molecules recognised as foreign in xenografts
Basic rules of transplantation immunology
- 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
Molecules responsible for strong and rapid rejection reactions
MHC molecules that bind and present peptides to T cells
Two different ways that allogenic MHC molecules of a graft can be presented for recognition by the recipients T cells
Direct and indirect
Direct presentation (or recognition) of alloantigens
T cells of a graft recipient recognise intact, unprocessed MHC molecules in the graft
Indirect presentation (or recognition) of alloantigens
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
Where does the initial T cell response to MHC alloantigens occur
Lymph nodes draining the graft
Direct allorecognition
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
Indirect allorecognition
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
Donor specific antibodies
- 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
Effector mechanisms engaged by alloreactive antibodies
- Complement activation
- Fc receptor mediated binding
- Activation of neutrophils, macrophages, and NK cells
Hyperacute rejection
- 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
Outcomes of hyperacute rejection
- Complement activation
- Endothelial damage
- Inflammation
- Thrombosis
Acute cellular rejection
- CTL mediated killing of graft parenchymal cells and endothelial cells
- Inflammation caused by cytokines produced by helper T cells
Major cause of the failure of vascularised organ allografts
Chronic rejection
Graft vasculopathy / accelerated graft arteriosclerosis
- 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
Major strategy to reduce graft immunogenicity
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)
Clinical lab tests performed to reduce the risk for immunologic rejection of allografts
- 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
Tissue typing
Determination of HLA alleles expressed on donor and recipient cells
Cross matching
Detection of preformed antibodies in the recipient that bind to antigens of an identified donor’s cells
Tissue expression of Class 1 HLA antigens (A, B, C)
- On all nucleated cells
- Density varies from tissue to tissue
Tissue expression of class 2 HLA antigens (DR, DQ, DP)
- APCs (DCs, macrophages)
- B lymphocytes
- Activated T lymphocytes
MHC matching and graft survival
- 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
Panel reactive antibodies
- 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
HLA testing
- HLA antibody characterisation using bead based multiplex assay
- Complement dependent cytotoxicity crossmatch
- Flow cytometry crossmatch
Complement dependent cytotoxicity crossmatch
- 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
Major immunologic barrier to xenogeneic transplantation
- 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
Delayed xenograft rejection / accelerated acute rejection / acute vascular rejection
- 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.
Haematopoietic Stem Cell Transplant
- 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
Autologous stem cell transplant
- 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.
Graft versus host disease (GVHD)
- 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
