Transplantation And Immunosupressive Drugs

Question 1

What are the two types of donor-recipient relationships?

Answer 1

Autologous and Syngeneic — Donors and recipients are genetically identical

Allogenic — donors and recipients are from the same species but are genetically different

Xenogeneic - donor and recipient are different species

Question 2

What is histocompatibility?

Answer 2

Tissue compatibility between donor and organs

Immune responses are caused by genetic differences between the donor and recipient

Most important antigens are MHC

Question 3

What is the importance of epitopes on donor MHC?

Answer 3

B cell epitopes on donor MHC
T cell epitopes derived from donor MHC

Less variation of epitopes than HLAs

Next generation sequencing required

Question 4

Describe what occurs during MHC2 loading

Answer 4

Antigen is internalised by a phaglysosome

The antigen is lysed into peptides

These peptides then bind to MHC2 and are presented on the surface of the cell

Recognised by T helper cells and assistance from CD4

Question 5

What is the function of helper T cells?

Answer 5

Information no support for other immune cells via cytokine production

Question 6

what is the function of cytotoxic T cells?

Answer 6

Highly pacific killer cells

Question 7

What exactly is recognised as foreign in transplants?

Answer 7

both the MHC and peptide in its binding grove may be defined as foreign

Question 8

What occurs during indirect T cell activation?

Answer 8

Self HLA and self peptide will not activate T cells

Self HLA And NON Self peptide will activate T cells

Question 9

What occurs during direct T cell activation?

Answer 9

Matches HLA and peptide on the downpour cell - no T cell activation

Unmatched. (Non-self) HLA and peptide - T cell activation

Question 10

What is the correlation between HLA mismatch and graft survival?

Answer 10

Increased number of mismatches means a lower survival half life

Question 11

What is the difference between live and dead donors?

Answer 11

Organs from dead donors are likely to be inflamed condition due to ischemia and possibly having a history of disease

Transplant success is less sensitive too MHC mismatch for live donors

Question 12

What is hyper acute rejection?

Answer 12

Within a few hours of transplant.

Most commonly seen for highly vascularised organs (kidney)

Require pre existing antibodies (ABO blood group antigens OR MHC1 proteins)

Antibodies to MHC can arise from pregnancy, blood transfusion or previous transplants

Question 13

What is acute rejection?

Answer 13

Inflammation of donor organ results in activation of organs dendritic cells

T cell response developes as a response of MHC mismatch

Question 14

What is chronic rejection?

Answer 14

Can occur months or years after transplant

Blood vessel walls thickened, lumina narrowed - loss of blood supply

Correlates with presence of antibodies to MHC1

Question 15

How can antibodies cause damage to transplanted tissue?

Answer 15

Recognition of Fc region leading to

• complement activation
• antibody dependent cellular cytotoxicity (Fc receptors on NK cells)
• phagocytosis (Fc receptors on macrophages)

Question 16

Describe what occurs during hyper acute rejection

Answer 16

1. Antibodies bind to endothelial cells
2. Complement fixation
3. Accumulation of innate immune cells
4. Endothelial damage, platelets accumulate, thrombi develop - phagocytosis and lysis

Question 17

Describe what occurs in acute rejection?

Answer 17

1. Inflammation results in activation of organs resident DC
2. DC migrate to secondary lymphoid tissue - encounter circulating effector T cells
3. Macrophages and CTL increase inflammation and destroy transplant

Question 18

Describe what occurs during chronic rejection

Answer 18

1. Donor derived cells die
2. Membrane fragments containing donor MHC are taken up by host DC
3. donor MHC is processed into peptides which are presented by host MHC
4. T cell and antibody responses is generated to the peptide derived from processed donor MHC

Question 19

What is graft vs host disease (GVHD)?

Answer 19

When the transplanted tissue is immmune cells themselves (eg. Haematopoietic transplant), there is a risk of donor immune cells attacking the host

Can be lethal - best approach is prevention

Removing T ells from transplant or suppressing their function reduces GVHD

Question 20

What is graft versus leukaemia?

Answer 20

Sometimes mismatch and donor leukocytes can be beneficial - removing original leukaemia

May prevent relapse - as the graft sees leukaemia as non-self — stronger immune response to tumour cells

Question 21

What are the 3 phases of immunosupression?

Answer 21

Induction

Maintenance

Rescue phases of treatment

Question 22

What are 3 examples of immunosuppressants for transplant?

Answer 22

General immune inhibitors

Cytotoxic - kill proliferating lymphocytes

Inhibit T cell activation

IMMUNOSUPPRESSIVES MAY NEED TO BE MAINTAINED INDEFINITELY

Question 23

What is cyclosporin?

Answer 23

Breakthrough drug for transplantation

Blocks T cell proliferation and differentiation

Improves patient and graft survival rates

Question 24

What is included in combination immunosuppressive regimes?

Answer 24

1. Steroids
2. Cytotoxic
3. Immunosuppressive specific for T cells

Question 25

What occurs in the induction phase of immunosuppressants?

Answer 25

Antibody induction therapy
- lymphocyte depleting rabbit anti-thymocyte globulins (ATG) is the most commonly used antibody for induction therapy.

Triple drug regime
- calcineurin inhibited, a anti proliferative agent and corticosteroid

Question 26

What occurs in the maintenance phase of immunosuppressants?

Answer 26

Triple drug regime at lower doses

Question 27

What occurs in the rescue phase of immunosuppressants?

Answer 27

T cell mediated rejection is treated with ATG and steroids

B cell mediated rejection may be treated with intavenous immunoglobulin or anti-CD20 antibody and steroids

Question 28

What are the limitations of immunosuppressive therapy?

Answer 28

Currently no immmunosupressive that will prevent transplant rejection whilst maintaining other immune responses

Transplant patients are more susceptible to infection and malignancy

Immunosuppressive drug toxicity can lead to organ failure

Question 29

How can the intestinal microbiome be a effective anti cancer treatment for transplantation outcomes?

Answer 29

The microbiome and intestine is involved in regulating the adaptive immune response

FMT - feel material transplant in immunosupressed patients can promote effective anti-cancer immune responses

May be implicated in transplant outcomes