Tumor and Transplant

Question 1

Tumor and transplants - what is common

Answer 1

The immune response for the 2 are pretty similar

Question 2

Ipillimumab

Answer 2

Anti CTLA4 antibody

Question 3

Nivolumab

Answer 3

Anti PD-1 antibody

Question 4

When is Nivolumab used

Answer 4

Non small cell lung carcinoma and melanoma

Question 5

Adjuvents

Answer 5

Agents that cause inflammation

Question 6

Sipuleucal T

Answer 6

The idea over here is that patients with metastatic castrate resistant prostate cancer have their dendritic cells extracted from them, shipped to a company, the company incubates them in GM-CSF, exposes them to an antigen called the PAP (Prostate Acid Phosphatase). Then these dendritic cells are sent back and infused in the patient and this causes an immune response to develop against the cancer.

Question 7

Bi specific antibodies

Answer 7

These promote tumor immunity. In this antibody we have different light chains and heavy chains linked together such that one half of the antibody targets the tumor cell whereas the other half targets the T cell (specific for CD3 protein or NK marker like CD16). This causes the tumor cells and T cells to come in close proximity promoting tumor destruction.

You can also have trispecific so the FC region can be made to bind to NK cells and the tumor cell can be made to be surrounded with NK cell and T cell.

Question 8

Chimeric antigen

Answer 8

One of the problems when dealing with tumors is that tumors down regulate their MHC so the T cells cant identify them.

This problem can be solved by making single chain antibodies (scFv). Here the portion of the antibody that binds to antigen is fused with the zeta chain of the TCR. This whole complex is placed into the T cells to repalce TCR. This then allows the T cells to detect antigens without having to require MHC presentation and now they can go and kill cancer cells.

Very successful in lymphoma treatment.

Question 9

Syngenic

Answer 9

Genetically identical

Question 10

Congenic

Answer 10

Identical except for one locus

Question 11

Allogenic

Answer 11

Different members of the same species

Question 12

Xenogenic

Answer 12

Members of different species

Question 13

Autologous transplantation

Answer 13

Transplantation within the same individual like skin grafts, HSCTs

Question 14

Allotransplantation

Answer 14

Most common

Question 15

Xenogenic transplantation

Answer 15

Xenografts

Question 16

What is the antigen observed in organ transplant

Answer 16

MHC, there are minor histocompatibility complex - allelic forms of normal proteins that differ in people

Question 17

What are the mechanisms of organ rejection

Answer 17

Adaptive, T cells and antibodies

Question 18

What is the biochemical basis of transplant rejection

Answer 18

There is a change in the affinity of MHC-TCR interaciton these 2 interact more strongly now which leads to development of an immune response. Remember the low affinity model of thymic selection which requires that if T cells dont bind to MHC loosely so that they dont trigger an immune response

Question 19

What are the 2 ways body identifies the foreign organ after a transplant

Answer 19

1. Direct allorecognition: T cells go into the transplant organ, recognizes the transplanted organ and mount an immune response towards it
2. Indirect allorecogntion is when there is cross presentation so the APC goes into the transplant, engulfs one of the cells and presents the antigen to T cells. He called this process cross presentation.

Question 20

What 2 immune functions are significant in terms of cross presentation

Answer 20

1. Viral infections

2. Tissue rejection

Question 21

How can we predict transplant rejection

Answer 21

Mixed lymphocyte reaction: Mix the T cells of the recipient with the irradiated donor cells (we need to kill the donor cells so they dont start an immune response). If the recipient T cells are activated then there will be T cell infiltration and proliferate which can be checked for.

Question 22

What are the 3 types of rejections

Answer 22

1. Hyperacute
2. Acute
3. Chronic

Question 23

Hyperacute

Answer 23

Malpractice, very fast response.
The immune response is adaptive, however the immune response is pretty damn fast that suggests there are pre existing antibodies.
1. Antibodies could exist from prior trasnfusion
2. Activates compliment and blood clothing mechanisms

Question 24

Acute

Answer 24

CD8 T cell mediated:

1. Targets graft or blood vessels within the graft
2. Antibodies also contribute to vascular rejection, role of antibodies is unclear in chronic and acute

Question 25

Chronic

Answer 25

From hyperactue to chronic we move from more of a type II reactions to a type IV reaction. So here the T cells kick in: 1. Th1 mediated response 2. Antibodies and compliment system activation, role is unclear 3. Progressive loss of graft tissue 4. Fibrosis and arteriosclerosis of graft tissue (narrowing of the vessels to the graft). Chronic in inevitable, happens over the years.

Question 26

Therapy for graft rejection

Answer 26

Immunosuppression: 1. GCs. 2. Cyclosporin 3. Mycophenolate 4. Rapamycin 5. Thymoglobulin - cocktail of antibodies, target T and B cell and also attacks the antibodies.

Question 27

What is HSC transplantation used for

Answer 27

Used for primary immunodeficiencies and after chemotherapy for cancer

Question 28

What markers does HSCs have

Answer 28

CD34

Question 29

Describe HSCs transfer

Answer 29

1. Space created before injection - maybe by high dose chemotherapy 2. Isolate CD34 cells 3. Treat the donor with G-CSF so CD34 cells become immobilized into the blood, then we can harvest them from the blood

Question 30

Risks of HSC transplant

Answer 30

1. Graft failure 2. Delayed engraftment; hemorrhage and anemia 3. Opportunistic infections - reactivation of CMV, EBV, bacterial pneumonias and fungal infections 4. Tumor reoccurence 5. GVHD - Graft versus Host disease, the major problem, mortality is 50%

Question 31

How do we consider the directions of immune response in solid tissue transplant and HSC transplant

Answer 31

In solid tissue transplant the recipient's immune system attacks the graft whereas in HSC the donor's immune system attack's the body, this is called graft vs host disease. When evaluating the MHC's considering the directionality is critical

Question 32

Requirements for graft versus host disease (GVHD)

Answer 32

Billingham's postulates: 1. Graft must contain immunologically competent cells. There can be special circumstance where this has to be understood well as in liver trasnplants this can happen as live has many macrophages in there to protect it (kupfer cells) 2. Recipients must have tissues and antigens that are not expressed in the donor 3. Recipient must be not be able to mount an effective immune response to the graft to destroy the transplanted cells

Question 33

What are these relevant to

Answer 33

HSCT and blood products in infants, thats why the blood is irradiated before given to infants

Question 34

Categories of GvHD

Answer 34

Acute and Chronic

Question 35

Acute

Answer 35

Phase 1: We destroy the CD34 cells of the recipient to make room for the new CD34 cells to come in and thrive. in order to do this there is myloablative therapy given which is highly toxic and triggers release of cytokines such as TNF and IL-1 Phase 2: Some of the donor's CD4 cells are also given to the recipient to prevent reactivation of EBV, CMV and prevent opportunistic infections even though these CD4 cells are going to cause GVHD. Phase 3: The donor's CTL, NK cells and monocytes respond to the cytokines and cause GVHD

Question 36

What is the time frame for acute and chronic

Answer 36

More than 100 days is chronic

Question 37

Chronic

Answer 37

3 phases: 1. Progressive - continuation of GVHD 2. Quiescent - presence of continued GVHD with previosuly resolved GVHD 3. De novo - New onset of GVHD

Question 38

What is the MOA of chronic GVHD

Answer 38

1. Th1 cell mediated immune response 2. B cell are also involved. 3. Organs involved are GI, Skin, thymus, BM, lung and bone

Question 39

Treatment for gvhd

Answer 39

1. Steroids 2. methotrexate 3. cyclosporin 4. mycophenylate 5. Anti CD25 which is Daclizumab