Transplant and immunosuppressive drugs Flashcards
1
Q
Define transplantation
A
The introduction of biological material (e.g. organs, tissue, cells) into an organism
2
Q
What is an autologous transplant?
A
- A transplant of a part of a patient’s body to another part
- e.g. skin graft from thigh to face
- No immune response as they recognise it as self
3
Q
What is a syngenic transplant?
A
- Identical twins
- No immune response as they are genetically identical
4
Q
What is an allogenic transplant?
A
- Donors and recipients are from the same species, but genetically different
- e.g. between family members
5
Q
What is a xenogenic transplant?
A
- Donor and recipient are different species
- e.g. pig or cow heart to human
6
Q
What causes the genetic differences in transplant?
A
- MHC genes are the most variable genes in our genome
- Immune responses to transplant are caused by genetic differences between the donor and recipient
- The most important are differences between the MHC antigens
7
Q
Why is there diversity between people’s HLA?
A
- 2 main groups of HLA alleles
- class 1 HLA alleles (A,B,C)
- Class 2 HLA alleles (DR, DP, DQ)
- HLA class I is a single protein liked to betaIIM, found on the surface of all nucleated cells
- The frequency of Class I expression varies between different ethnic groups
- HLA Class II is comprised of 2 proteins each - A and B subunit - typically expressed on immune cells, but not normal somatic cells
8
Q
How do T cells recognise foreign peptides bound to self-MHC?
A
- HLA I interact with the TCR on CD8 cell. The CD8 co-receptor interacts with MHC on the side
- This is involved with CTL immunity, clearing macrophages etc
- HLA class II has 2 protein chains, and interacts with the TCR of CD4 T-cells
- These activate CD4 T-cell immunity - T helper cells (Th1 cytotoxic responses or Th2 Ab responses
9
Q
How are antigens presented in MHC class I?
A
- Endogenous proteins are broken down into peptides in the proteasome
- They are sent to the ER and then loaded into MHC molecules - happens in all somatic nucleated cells
10
Q
How are antigens presented in MHC II?
A
- requires various receptors
- protein taken up from EC spaces into immune cells by phagocytosis
- This can break the protein into peptides, which are then presented on the surface
11
Q
What is the major difference between Th cells and CTL?
A
- Helper - information and support for other immune cells via cytokine production
- CTL - highly specific killer cells
- Th are required to produce antibody and CTL responses
12
Q
How does HLA mismatch affect graft survival?
A
- The more mismatches between the HLA of the recipient and the donor, the shorter the half-life of the graft
- Usually try to match 4/6 MHC class II loci, reducing the likelihood of probs with future transplants
13
Q
What differences are there between live and dead donors?
A
- Recipients will have a history of disease which will have resulted in a degree of inflammation
- organs from dead donors are also likely to be inflamed due to ischaemia - can activate innate and adaptive immune responses
- Transplant success is less sensitive to MHC mismatch for live donors
14
Q
What are the 3 types of graft rejection?
A
- Hyperacute rejection
- Acute rejection
- Chronic rejection
15
Q
What is hyperacute rejection?
A
- Occurs within a few hours of transplant
- Most commonly seen for highly vascularised organs (e.g. kidney)
- Requires pre-existing Abs, usually ABO Ags, or MHC-1 proteins
- ABO Ags are expressed on endothelial cells of vessels
- Abs to MHC can arise from pregnancy, blood transfusion or previous transplants
16
Q
How can Abs cause damage to transplanted tissue?
A
- Very quick because they can quickly identify mismatches and give quick response
- Recognition of Fc region leads to complement activation; Ab dependent cellular toxicity (Fc on NK); and phagocytosis (Fc on macrophages)
17
Q
Why does hyperacute rejection cause problems?
A
- Abs bind to endothelial cells
- Complement fixation
- Accumulation of innate immune cells - attract adaptive immune cells
- Endothelial damage, platelets accumulate, thrombi develop
18
Q
Give an example of a hyperacute rejection
A
- Healthy kidney grafted into patient with defective kidney and preexisting Abs against donor blood group antigens
- Abs against donor blood group antigens bind vascular endothelium of graft, initiating an inflammatory response that occludes blood vessels
- Graft becomes engorged and purple due to haemorrhage
19
Q
What happens in acute rejection?
A
- T cell response develops as a result of MHC mismatch
- Inflammation results in activation of organ’s resident dendritic cells
- DC migrate to secondary lymphoid tissue, where they encounter circulating effector T cells
- Macrophages and CTL increase inflammation and destroy transplant
20
Q
What happens in chronic rejection?
A
- Can occur months or years after transplant
- Abs to MHC recruits inflammatory cells to blood vessel walls of transplanted organ
- Increasing damage enables immune effectors to enter the tissue of the vessel wall and to inflict increasing damage
- Vessel walls thickened, lumen narrowed, loss of blood supply
21
Q
What is indirect allorecognition?
A
- Donor-derived cells die
- Membrane fragments containing donor MHC are take up by host DCs
- Donor MHC is presented into peptides which are presented by host MHC
- T cell response generated - eventually destroy it
22
Q
What is haematopoietic stem cell transfer?
A
- “Bone marrow transplant”
- Often autologous
- HSCs can find their way to the bone marrow after infusion and regenerate there
- From these cells you can get all of the leukocytes involved in immune responses - lymphoid and myeloid progenitors
- They can be cryopreserved with little damage
23
Q
What is GVHD?
A
- Graft versus host disease
- When transplanted tissue is immune cells themselves, there is a risk of donor immune cells attacking the host (GVHD)
- Can be lethal
- Removing T cells from the transplanted reduces GVHD
- Because immune cells have been grafted, the graft attacks the host. The new immune system has been transplanted into the recipient - identifies the recipient as foreign
24
Q
How can mismatch be beneficial?
A
- Sometimes mismatch and donor leukocytes can be beneficial - removing original leukaemia
- Graft versus leukaemia response
- Development of GVL may prevent relapse
25
Q
How can we induce immunosuppression?
A
- Essential to maintain non-autologous transplant
- Immunosuppressants can be: general immune inhibitors (corticosteroids); cytotoxic - kill proliferating lymphocytes (eg methotrexate); inhibit T cell activation (eg cyclosporin)
- May need to be maintained indefinitely
26
Q
What are the stages of immunosuppression?
A
- Induction phase - the chances of generating an immune response are highest because of the surgery and the inflammatory environment generated. Strong medication required
- Maintenance - recipient has to regularly take immunosuppresants - can be toxic
- If these drugs fail/ are too toxic, or an immune response is generated = rescue phase. More suppressive therapy to stop the transplant to be rejected entirely
27
Q
What is cyclosporin?
A
- Breakthrough drug for transplant
- Blocks T cell proliferation and differentiation (IL-2), but is toxic and has to be taken at relatively high doses
- Next generation therapies less toxic and effective at lower doses
28
Q
What combination of immunosuppressants is good?
A
- Steroids e.g. prednisolone
- Cytotoxic e.g. mycophenolate motefil
- Immunosuppressive specific for T cells e.g. Cyclosporin A
- Try to give the best anti-immune effect with the lowest dose
29
Q
Why do we monitor immunosuppressive therapy?
A
- Currently no immunosuppressive that will prevent transplant rejection whilst maintaining other immune responses
- Transplant patients are more susceptible to infection and malignancy
- Immediate risk e.g. CMV
- Immunosuppressive drug toxicity can lead to organ failure eg cyclosporin nephrotoxicity in kidney transplant
