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TI2 > Transplant and immunosuppressive drugs > Flashcards

Transplant and immunosuppressive drugs Flashcards

1
Q

Define transplantation

A

The introduction of biological material (e.g. organs, tissue, cells) into an organism

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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
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3
Q

What is a syngenic transplant?

A
  • Identical twins

- No immune response as they are genetically identical

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4
Q

What is an allogenic transplant?

A
  • Donors and recipients are from the same species, but genetically different
  • e.g. between family members
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5
Q

What is a xenogenic transplant?

A
  • Donor and recipient are different species

- e.g. pig or cow heart to human

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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
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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
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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
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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
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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
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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
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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
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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
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14
Q

What are the 3 types of graft rejection?

A
  • Hyperacute rejection
  • Acute rejection
  • Chronic rejection
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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
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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

TI2 (20 decks)

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