Tumor and Transplant Immunology

Question 1

What is “rejection”?

Answer 1

When T-cells and antibodies are produced to attack antigens on the new (donated) tissue/graft.

Question 2

What is the main cause of the difference between the donated tissue and the patient? (aka what causes the immune response against the donated tissue?)

Answer 2

The major antigenic differences between the host and the graft cause the attack… These differences are the result of different HLA genes

Question 3

What is an allograft?

Answer 3

When tissue is recieved from a member of the same species

Question 4

What is a xenograft?

Answer 4

When tissue is received from a different species ( ie pig vasculature used in humans)

Question 5

What are the two types of immune reactions to a graft?

Answer 5

1) direct pathway of allorecognition

2) indirect pathway of allorecognition

Question 6

What is the direct pathway of allorecognition?

Answer 6

Antigen Presenting cells (APCs like dendritic cells) from the donor directly present antigens to the host CD4+ and CD8+ t-cells… (theres always gunna be some transfer of donor dendritic cells with transfer of tissue)

**think of this one as mostly CD8+ cells that get stimulated!!*

Summary: Direct = CD8 (mostly), Donor APCs, Acute Rejection (DAD8)

Question 7

What is the indirect pathway of allorecognition?

Answer 7

When HOST APCs up-take some of the donated tissue and present to CD4+ only cells… not unlike the normal immune response… DCs pick up foreign material and present to T-cells. (note there is NOT CD8+ activation in this case… ONLY CD4+)

*Chronic Rejection

Summary: Indirect = CD4, host APCs, chronic rejection (IHC4)

Question 8

What are the 3 types of allograft rejection?

Answer 8

1) Hyperacute
2) Acute
3) Chronic

Question 9

What is a hyperacute rejection?

Answer 9

Occurs when preformed anti-donor antibodies are present in the circulation of the recipient!

Occurs within minutes/hrs of transplantatino and is NOT cell-mediated but rather a HUMORAL response of pre-formed antibodies. Patient likely has had previous transplantations or prior blood transfusions, or multiparous women (cuz these all give the opportunity to make the antibody)

Question 10

What is acute rejection? (recall 2 different types!)

Answer 10

Occurs a few days after transplantation… may occur after stopping immunosuppressive therapy!

Is either humoral OR Cell-mediated!!!

Mostly CD8+ cells doing the work with some CD4+

Acute cellular rejection (T-cell mediated) usually presents with interstitial and infiltration into the tubules of the kidney and vasculitis!

Acute antibody-mediated rejection usually presents with damage to the glomeruli and small blood vessels

Question 11

What is chronic rejection? (also 2 types)

Answer 11

Occurs months to years after transplantation

Also either humoral or cell-mediated but its mostly mediated by CD4+ (NOT CD8+)

Question 12

What is an autograft?

Answer 12

graft from within the same person

Question 13

What is an isograft?

Answer 13

graft from an individual to a syngenetic recipient (aka monozygotic twins)

Question 14

What is an allograft?

Answer 14

Graft from a member of the same species

Question 15

What is xenograft?

Answer 15

Graft between members of different species

Question 16

When do you try to match HLAs and what HLAs do you want to match when looking for a transplant?

Answer 16

ONLY with a kidney transplant, do you acutally try to match HLAs… and you want to match HLA-A HLA-B and HLA-DR

With liver, lung, and heart transplants HLA matching is usually not even done!

Question 17

What are the HLA genes for professional APCs and every other cell?

Answer 17

Professional APCs have both MHC class 1 & 2… every nucleated cell has MHC 1.

MHC class 1 genes = HLA-A, HLA-B, HLA-C
MHC class 2 genes = HLA-DR, HLA-DP, HLA-DQ

Question 18

Talk to me about MINOR histocompatibility complex

Answer 18

Coded by genes outside of HLA and NOT detectable by standard tissue typiing.

Causes rejection in up to 1/3 of transplants!!!

Question 19

What are 2 potential immune responses to a transplant?

Answer 19

1) Recipient rejects donor stem cells (HVGD)

2) Donor cells respond against recipients MHC antigens (GVHD) (Major Problem!)

Question 20

How do you prepare a donor for stem cell transplant?

Answer 20

No longer need to actually poke through the bone… Now you can simply mobilize the HSCs out of the marrow via stem cell growth factors to push into peripheral blood

Question 21

What is the mechanism of damage in Graft vs Host Disease? and what is particularly vulnerable in chronic vs acute GVHD?

Answer 21

When donor T-cells recognize recipients MHC antigens resulting in activated DONOR T-cells –> cytokines –>inflammation –> tissue destruction!

Epithelia is particularly vulnerable to acute GVHD (epi of skin –> skin rash, epi of liver –> jaundice, epi of GI tract –> bloody butt pee)
Solid organs are more vulnerable in chronic GVHD

Question 22

So if T-cells are the cause the damage with transplantation… why not just remove them prior to putting the organ in the patient?

Answer 22

It made things WORSE! The incidence of graft failures INCREASED when they removed the T-cells suggesting that they have some sort of protective effect.

Question 23

So if immunosuppressive therapy helps to tone down the immune response in GVHD… why not just put them on a shitload of steroids indefinitely?

Answer 23

Infections are a big problem with those receiving immunosuppressive therapy… Specifically cytomegalovirus… CMV-induced pneumonitis can be fatal!

Question 24

What is the biggest problem with xenografts (ie getting a transplant from a pig)?

Answer 24

Actually… humans do not have a strong T-cell response to pig (or any foreign) MHC antigen!…

However, people often have natural or pre-formed antibodies to carbohydrates expressed on the donor’s (pigs) endothelial cells which leads to complement activation and HYPERACUTE rejection.

There is also the possibility of introducing weird viruses and shit

Question 25

What are serological detection methods for HLA matching?

Answer 25

1) immunofluorescence (flow cytometry or IHC)

2) Lymphotoxicity test

Question 26

What is the lymphotoxicity test?

Answer 26

Plate with wells that have different HLA antigens in them, then expose patient leukocytes… bottom line is if there are antibodies, they will bind, fix complement and cause cell membrane damage which will allow dye to enter…

Thus… presence of dye = bad news bears

Question 27

Mixed leukocyte reaction… what does that do?

Answer 27

So… mix donor T-cells, and recipient T-cells in a culture… label pts with a radio-tracer and treat donor’s with mitomycin c (so they don’t divide)… if the patient’s cells divide (ie large radio signal…) then thats bad news bears cuz the patient is mounting a response

Question 28

What are 5 normal cellular gene products that are tumor antigens?

Answer 28

3 Oncofetal antigens (ie present early in life then only in cancer)

1) Melanoma-associated antigen (MAGE)
2) Carcinoembryonic Antigen (CAE) - GI/Colon cancer
3) alpha-fetoprotein - hepatocellular carcinoma & testicular teratocarcinomas

4) Normal intracellular enzymes (Prostate Specific antigen, PSA)
5) Oncoproteins (HER2/neu)

Question 29

What are 3 tumor antigens that are mutant cellular gene products (ie mutated genes caused by somatic mutations)

Answer 29

1) CML : Philadelphia chromosome
2) Familial Melanoma : mutation reduces CDK4 from binding to its inhibitor (p16INK-4 tumor suppressor)
3) many cancers : p53 mutation

Question 30

Bence-Jones protein in the urine is suggestive of what cancer?

Answer 30

Multiple Myeloma (or any other plasma cell cancer)

Question 31

high levels of alpha-fetoprotein is associated with what cancers?

Answer 31

hepatocellular carcinoma (also just liver cirrhosis as well)
ovarian
testicular embryonal carcinoma

Question 32

Carcinoembryonic antigen (CEA) in the blood is suggestive of what cancer?

Answer 32

Colon and GI cancers

Question 33

Is a high prostate specific antigen test confirmatory of prostate cancer?

Answer 33

NOPE! High PSA can also be seen in prostatitis and benign prostatic hyperplasia

Question 34

What marker is helpful for diagnosis and monitoring ovarian cancer?

Answer 34

Cancer antigen 125 (CA-125)

Question 35

What immunotherapy is particularly useful for treating B-cell leukemias and lymphomas?

Answer 35

Rituximab! (anti-CD20!)