L33: Transplantation Immunology

Question 1

Types of grafts (4)

Answer 1

1. Autograft: graft from one site to another site on the same individual (no histocompatability problems)
2. Isograft: graft from one individual to a genetically identical individual (inbred mouse, monozygotic twins)
3. Allograft: graft between genetically dissimilar individuals of the same species
4. Xenograft: graft from one species to another

Question 2

Graft type, tissue and genetic identity (4)

Answer 2

1. Autograft, autologous, total
2. Isograft, isologous, syngeneic or isogeneic
3. Allograft, homologous, allogeneic
4. Xenograft, heterologous, xenogeneic

Question 3

Graft Rejection

Answer 3

Both CD4+ and CD8+ are responsible for graft rejection. Other cells involved include macrophages, B cells and NK cells. Primary cells involved are CTL which directly kill the tissue graft

Question 4

Reasons for tissue transplant rejection (4)

Answer 4

Three classes of transplantation antigens

2. ABO blood groups
3. Minor histocompatibility antigens - coded by more than 30 minor loci
4. Major histocompatibility antigens (MHC antigens) - human leukocyte antigens (HLA) and major barrier to allograft survival

Question 5

HLA complex gene classes (3)

Answer 5

1. Class 1 Antigens: encoded by different loci (e.g. HLA-A/B/C); found in varying degrees on all nucleated cells, targets for CTL involved in graft rejection
2. Class 2 Antigens: encoded by HLA-DP/DQ/DR loci (all located on the HLA-D region of MHC complex); found on some macrophages and DCs, most B cells, some activated T cells and some epithelial cells, involved in the regulation of the immune response to most antigens
3. Class 3 antigens: encode various proteins with immune functions like complement proteins C4 and tumour necrosis factor

Question 6

MHC alleles

Answer 6

Polymorphic and expressed co-dominantly.
Polymorphism: variability at a gene locus where variants occur at a frequency of greater than 1%. The MHC is most polymorphic gene cluster in humans.
Co-dominant expression: occurs when both alleles at one locus are expressed in roughly equal amounts

Question 7

Co-dominant expression

Answer 7

When both alleles at one locus are expressed in roughly equal amounts

Question 8

Mixed Lymphocyte Reaction (MLR)

Answer 8

Both in vitro model of grafting and assay for donor/recipient compatibility and can predict if two sets of tissue are compatible. Lymphocytes from donor are irradicated and mixed with lymphocytes from recipient. Proliferation and cytotoxicity are induced when recipient T cells respond to MHC differences on donor cells. Assay is too slow for testing for compatibility from deceased donor.

Question 9

Hyperacute Rejection

Answer 9

Occurs within minutes/hours after transplantation. Antibody mediated (Type 2 hypersensitivity). Unresponsive to immunosuppressive treatment.

Question 10

Acute Rejection

Answer 10

Typical first set reject caused by CD8+ cytotoxic T cells specific for class 1 antigens on the transplanted organ and/or by CD4+ cells (TH1 cells) that induce macrophage-mediated damage. Can also happen months after transplant if recipients immune system is altered. Immunosuppressive therapy may prevent rejection.

Question 11

Chronic Rejection

Answer 11

Begins months after transplants and can proceed for months or years. Both cell and antibody-mediated processes are involved. Immunosuppressive treatment often fails. Essentially no improvement in long term losses due to chronic rejection.

Question 12

Haematopoietic stem cell transplants/bone marrow transplants

Answer 12

Effector cells are stem cells. Sources of stem cell in order of decreasing mature T cell contamination: blood, bone marrow, core blood. Many stem cell transplants are autologous, given after chemotherapy or radiotherapy and so they do not give rise to immunological problems

Question 13

Graft versus host (GVH) reaction

Answer 13

Occurs when mature T cells are injected into a non-identical immune-incompetent recipient. Cells from the donor respond to the HLA antigens of the recipient. Can occur in humans in allogeneic bone marrow grafts and reversed MLR can test for likelihood of GVH from marrow donor.
In HSC transcplant, recipient receives mature T cells. Alloreactive T cells activated by recipient DCs and cause widespread tissue damage called GVHD. If recipient DCs are absent, donor T cells no see only donor-derived DCs and are not activated to cause GVHD. Chances of GVHD are reduced by removing mature T cells from donor tissues.

Question 14

Treatment of rejection (3) - kidney transplant specific

Answer 14

Standard regime varies for different organs. For kidney transplants, combination therapy with 3 different sorts of drugs:

1. Steroids - complex immunosuppressive effects
2. Cytotoxic - leads to cell death and lack of entry into cell cycle. Hope is that CTL are more susceptible than other cells
3. Immunosuppressive - targets signalling pathway in T cells. Needs to be given indefinitely.

Question 15

Therapy consequences (4)

Answer 15

1. Steroids can cause long term tissue damage
2. Cytotoxic drugs can damage host tissue
3. Some immunosuppressive drugs can lead to nephritis
4. Microbial infection