Transplantation and immunosuppressive drugs

Question 1

What is transplantation?

Answer 1

= introduction of biological material into an organism

• But the immune system has developed to remove anything it regards as non-self

Question 2

What are the different donor/recipient relationships?

Answer 2

1. Autologous and syngeneic - Cells or tissues obtained from the same individual and are genetically identical and do not usually generate any immunological problems

• Eg. Skin from one part to another part
• One identical twin to another

2. Allogenic - same species but genetically different - immune system can react
   * Between brother and system
3. Xenogeneic - different species

Question 3

How are immune responses to transplant caused?

Answer 3

by genetic differences between the donor and the recipient

• Difference between the antigens forming the MHC
• There is huge variation in the proteins HLA on chromosome 6 - 6 combinations in each individual

Question 4

What is the basis of rejection of transplantation?

Answer 4

In transplants both the MHC protein and the peptide in its binding groove may be foreign to the TCR

Question 5

What is allorecognition?

Answer 5

When T-cells are activated to respond to transplanted material

• direct and non-direct

Question 6

What is indirect alloantigen?

Answer 6

Indirect alloantigen recognition occurs when allogeneic MHC molecules from graft cells are taken up and processed by recipient APCs and peptide fragments of the allogeneic MHC molecules and presented by recipient MHC molecules.

Donor-MHC-specific helper T cells are generated in this way can help B cells to produce donor-MHC-specific antibodies that can damage graft cells

Question 7

What is direct allo-recongition?

Answer 7

Direct alloantigen recognition occurs when alloreactive T cells bind directly to an intact allogeneic MHC molecule with bound peptide on a graft (donor) dendritic cell or other APC

Recipient CD4+ and CD8+ T cells can directly recognise donor Class 2 or Class 1 MHC molecules and will differentiate into helper T cells or kill these cells

In the case of direct recognition, intact MHC molecules displayed by cells in the graft are recognized by recipient T cells without a need for processing by host APCs

Question 8

What is a alloantigen?

Answer 8

= include histocompatibility antigens present in grafted tissues that stimulate an alloimmune response in the recipient in grafted tissues

Question 9

Compare direct and indirect alloantigen presentation

Answer 9

Question 10

How does graft failure come about?

Answer 10

Question 11

What are the types of graft rejection?

Answer 11

1. Hyperacute rejection
2. Acute rejection
3. Chronic rejection

Question 12

Describe hyperacute rejection

Answer 12

Within a few hours of transplant

Most commonly in highly vascularised organs

Requires pre-existing antibodies to ABO blood group antigens or MHC-1 proteins

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

Question 13

Describe acute rejection

Answer 13

1. Inflammation results in activation of organ’s resident dendritic cells
2. DC migrate to secondary lymphoid tissue where they encounter circulating effector T cells
3. Macrophages and CTL increase inflammation and destroy transplant

• T cell response develops as a result of MHC mismatch
• Results from direct allorecognition of foreign MHC

Question 14

Describe chronic rejection

Answer 14

Can occur months or years after

Blood vessel walls thicken and lumina narrow - loss of blood supply

Correlates with presence of antibodies to MHC-1

Occurs as a result from indirect allorecognition of foreign MHC/HLA

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

Question 15

What is Haematopoietic stem cell transfer (HSCT)?

Answer 15

Previously bone marrow transplant but now often source is blood

Autologous

HSCs can find their way to bone marrow after infusion and regenerate there after the patient’s own HSC are destroyed to restore normal blood cell production in the patient

The recipient is treated prior with chemotherapy, immunotherapy to kill the defective HSCs and to free up niches for the transferred stem cells

The donor and recipient must be carefully matched at all MHC loci to prevent rejection

Question 16

What is graft versus Host disease (GVHD)?

Answer 16

Caused by the reaction of grafted mature T cells in the HSC with alloantigen’s of the host

When transplanted tissue is immune cells themselves, there is a risk of the donor immune cells attacking the host

Can be lethal

Removing T cells from the transplant or suppressing their function reduces GVHD

It occurs when the host is immunocompromised and therefore unable to reject the allogenic cells in the graft

Question 17

What is graft verus leukaemia (GVL)?

Answer 17

Removing original leukaemia by mismatch and donor leukocytes

Decreases the relapse rate of leukaemia after allogeneic bone marrow transplantation

Question 18

What is cyclosporin?

Answer 18

breakthrough drug for transplant

• Blocks T cell proliferation and differentiation
• Improved patient and graft survival rates from 30-50%