Lecture 25 - Transplantation, Response to Tumors

Question 1

What is an autograft?

Answer 1

Self to self transplant

No rejection problems

Question 2

What is an isograft?

Answer 2

Transplant between identical twins

Question 3

What is an allograft?

Answer 3

Graft within the same species

Question 4

What is a xenograft?

Answer 4

Graft between different species

Ex: pig valve into human heart

Question 5

Learning Objective 1

Define the different types of tissue grafts

Answer 5

Autograft - self to self

Isograft - between identical twins

Allograft - between the same species

Xenograft - between different species

Question 6

How long does it usually take for graft rejection to occur?

Answer 6

10-14 days

Question 7

If an animal has rejected a graft in the past, how long will it take the animal to reject a second graft of the same tissue?

Answer 7

6-8 days

Suggests that memory is present

Question 8

Learning Objective 2

Describe how T cells recognize an allogenic graft and compare it to how T cells recognize foreign pathogens.

Answer 8

Cytotoxic T lymphocytes in the host recognize the forgeing MHC 1 in the graft. The lymphocytes are activated and induce apoptosis in the graft cells.

Note: this is a different process than recognition of endogenous peptides. Instead of recognizing foreign peptides, the cells recognize foreign MHC complexes themselves.

Question 9

What causes hyperacute tissue rejection?

Answer 9

Pre-existing antibodies to tissue antigens

Occurs within 24 hours of transplant

Example: natural antibodies against RBC antibodies cause hyperacute rejection of the blood transfusion.

Question 10

What kind of cellular infiltrate would you expect to see in a hyperacute tissue rejection?

Answer 10

Neutrophils

Antibody opsonizes cells, causing complement fixation, which causes vasodilation, increased vascular permeability, and neutrophil chemotaxis.

Question 11

How could you avoid a hyperacute transplant rejection?

Answer 11

Blood type and cross-match to insure that the tissue will not be rejected.

Question 12

Why is it that acute transplant rejection can happen without prior exposure to that transplant (i.e. no sensitization period)?

Answer 12

Cytotoxic T cells recognize foreign MHC molecules on the foreign tissue. Foreign tissue cells are present in high enough numbers to cause rapid clonal expansion of CTLs and memory cells. Results in tissue rejection within 10-14 days.

Question 13

Learning Objective 3

Explain the difference between hyperacute rejection and acute rejection – include timing and general immune mechanism in your explanation.

Answer 13

Hyperacute rejection

• Mediated by pre-formed antibodies and complement fixation
• Happens within 24 hours

Acute rejection

• Mediated by CD8+ T cells recognizing foreign MHC 1 molecules and inducing apoptosis
• Happens in 10-14 days

Question 14

How might Th1 cells become activated with a tissue graft?

Answer 14

Foreign cells are taken up by APCs and presented on MHC 2 molecules, stimulating Th1 cells.

This mechanism isn’t thought to play a big role in acute tissue rejection, but may play a role in chronic tissue rejection.

Question 15

What kinds of things could you do to insure a successful tissue transplant?

Answer 15

Test for matching MHC molecules

Administer immunosuppressive drugs like Cyclosporine

Question 16

What features of the developing fetus help to prevent it from being rejected by the mother?

Answer 16

Trophoblast layer acts as a nonimmunogenic barrier.

IgM cannot cross the barrier, barrier does not express MHC1 or 2, and barrier secretes molecules that help to suppress the mother’s immune system.

Question 17

Tumor Learning Objective 1

List the general categories of tumor antigens

Answer 17

• Mutated self antigens
• Virus particles in the case of oncogenic viruses
• Overproduction of self proteins
• Fetal proteins being produced by tumor cells that should not be produced in the adult

Question 18

Tumor Learning Objective 2

Describe the important innate and adaptive cellular immune response to tumor cells and their contribution to killing tumor cells.

Answer 18

Innate

• If a tumor stops expressing MHC 1, it will be killed by NK cells. Tumor cells expressing stress proteins will also be targeted by NK cells.
  
  • M1 macrophages kill tumor cells through cytokines, granule secretion, and oxidative burst.

Adaptive

• CTLs recognize tumor peptides on MHC 1 and induce apoptosis.
• APCs phagocytose tumor cells and present antigens on MHC 2. Causes activation of Th1 cells, which can activate CTLs and macrophages.

Question 19

Why are antibodies less important in defenses against tumors?

Answer 19

Antibodies can opsonize tumor cells and induce cell lysis. However, it is difficult for antibodies to enter the tissues, and foreign antigens are often not expressed on tumor cell surfaces.

Antibodies are most important in defense against oncoviruses, where the antigens of tumor-causing viruses are expressed on cell surfaces.

Question 20

Tumor Learning Objective 3

List three ways tumor cells evade being detected by the immune system

Answer 20

1. Tumor cells are self and do not appear foreign. Tolerance.
2. No costimulatory molecules that cause danger signals to the immune system.
3. Can produce immunosuppressive molecules.

Question 21

What protein tends to be over-expressed in canine melanoma?

Answer 21

Tyrosinase

Question 22

What is a xenogeneic DNA vaccine?

Answer 22

Vaccination of DNA from a different species.

DNA is inserted into a plasmid and injected into the patient. The DNA will be coded, producing a target protein. The immune system will respond to that protein. If the sequences are similar enough, the patient’s immune system will also respond to self proteins.

Using this method, you can target proteins that are being over-expressed by tumor cells.

Question 23

Can the canine melanoma vaccine be used preventatively?

Answer 23

Not really.

The vaccine is given to patients in early-stage malignant melanoma.

If it were given preventatively, you might expect to see problems with the dog’s native tyrosinase proteins. It’s best to give it when the dog has a tumor that is over-expressing tyrosinase.

Question 24

Tumor Learning Objective 4

Explain how the canine melanoma vaccine works – include the type of tumor antigen targeted, the type of vaccine and what the immune response is that attacks the tumor

Answer 24

• DNA coding for human tyrosinase is placed in a plasma and injected into the dog.
• The dog’s cells code for human tyrosinase. Presented on MHC 1 and 2 and also detected by B cells. Stimulates CTLs, Th cells, and antibody production.
• Human tyrosinase cross-reacts with canine tyrosinase, so the dog’s immune system will start targeting melanoma cells in its body that are overproducing tyrosinase.