03/15d Transplant and Tumor Immunology

Question 1

What is an autologous graft?

Answer 1

A transplant from one individual to the same individual

Question 2

What is a syngeneic graft?

Answer 2

A transplant between two genetically identical individuals

Question 3

What is an allogeneic graft?

Answer 3

A transplant between two genetically different individuals

Question 4

What are alloantigens and alloreactivity?

Answer 4

Alloantigens are molecules that are recognized as foreign in allografts
Cells and antibodies that react with alloantigens are alloreactive

Question 5

How are alloantigens recognized?

Answer 5

By MHCs
Directly - donor MHCs directly activate many host T cells
Indirectly - donor MHCs are processed and presented by host MHCs and activate host T cells

Question 6

What are minor histocompatibility antigens?

Answer 6

Every other antigen besides MHCs

Question 7

What are the major effector functions of alloreactive T cells?

Answer 7

CD4 cells - damage grafts by cytokine-mediated inflammation (Th1 response)
CD8 cells - directly-stimulated cells kill grafts cells, indirectly-stimulated cells secrete cytokines and contribute to inflammation

Question 8

How do alloreactive B cells develop? What are their functions?

Answer 8

Naive B cells recognize foreign MHC, process these proteins, and present them to indirectly-activated allogeneic T cells
Generate alloantibodies - contribute significantly to graft rejection

Question 9

What are the three patterns of allograft rejection?

Answer 9

Hyperacute
Acute
Chronic

Question 10

What is the most common target of rejection? Why?

Answer 10

Graft blood vessels - first thing immune cells see when they encounter the graft

Question 11

What is hyperacute rejection?

Answer 11

Graft rejection mediated by preexisting antibodies in the host circulation that bind to graft endothelial cells
Severe systemic effects, including complement activation, endothelial damage, inflammation, and thrombosis
Presents minutes to hours after graft is complete

Question 12

What is acute rejection?

Answer 12

Graft rejection caused by CTL-mediated killing of graft cells, as well as injury caused by activated CD4 cells and cytokines
Characterized by infiltrates of lymphocytes and destruction of endothelial cells
Begins several days to a few weeks after transplantation - takes time to develop alloreactive cells and antibodies

Question 13

How can acute rejection be prevented?

Answer 13

Aggressive immunosuppression at the time of the tranplant

Question 14

What is acute antibody-mediated rejection?

Answer 14

Similar to hyperacute rejection, except that it present later because it takes time to develop alloantibodies
Histological hallmark - necrosis of grafts vessels with acute inflammation

Question 15

What is chronic rejection?

Answer 15

Graft rejection caused by proliferation of arterial smooth muscle cells, which is stimulated by growth factors and cytokines produced by alloreactive macrophages and lymphocytes
Arteries are occluded, and grafts fail due to ischemic damage
Develops over months or years

Question 16

What are the typical rejection pathologies of kidneys and hearts?

Answer 16

Vascular occlusion

Interstitial fibrosis

Question 17

What are the typical rejection pathologies of lungs?

Answer 17

Thickened small airways

Question 18

What are the typical rejection pathologies of livers?

Answer 18

Fibrotic and nonfunctional bile ducts

Question 19

How do you prevent and treat rejection?

Answer 19

Immunosuppression!
Reduce immunogenicity of allografts
Induce donor-specific tolerance

Question 20

How can you reduce the immunogenicity of allografts?

Answer 20

By minimizing alloantigenic differences between graft and host
Done through ABO blood typing, HLA allele tissue typing, and cross-matching (detection of pre-formed anti-graft antibodies)

Question 21

How do you induce donor-specific tolerance?

Answer 21

Pretreatment of potential hosts with blood transfusion with allogeneic leukocytes
Hematopoietic chimerism
Transfer or induction of Treg cells

Question 22

What is hematopoietic stem cell transplantation? What is it used for?

Answer 22

Transplantation of allogeneic pluripotent hematopoietic stem cells, in order to expand and reconstitute lymphocyte and innate cell populations

Question 23

What is graft-versus-host disease?

Answer 23

Reaction of graft mature T cells against alloantigens of the host, usually minor histocompatibility antigens
May be acute or chronic

Question 24

What are the symptoms of acute GVHD?

Answer 24

Epithelial cell death in the skin, liver, and GI tract
Causes rash, jaundice, diarrhea, and GI hemorrhage
Can be fatal

Question 25

What are the symptoms of chronic GVHD?

Answer 25

Fibrosis and atrophy of the skin, liver and GI tract
Obliteration of small airways in the lungs
No evidence of acute cell death

Question 26

How is GVHD prevented and treated?

Answer 26

Prevented by eliminating mature T cells from the graft; any new T cells are educated by the host
Treated with intense immunosuppression

Question 27

How do mutated genes produce tumor antigens? List a few examples

Answer 27

Oncogenes, mutated tumor suppressor genes, and randomly mutated gene produce abnormal proteins
Examples - Ras and p53 mutations, products of Bcr/Abl rearrangments,

Question 28

How do normal proteins become tumor antigens?

Answer 28

When they are abnormally or excessively expressed, or expressed in the wrong places
Example - HER2/Neu

Question 29

What are some examples of oncogenic viral tumor antigens?

Answer 29

Papillomavirus - E6 and E7 proteins

EBV - EBNA-1 protein

Question 30

What are oncofetal antigens?

Answer 30

Proteins that are expressed in normal developing fetal tissues and cancer cells, but not in adult tissues
Examples - CEA, AFP

Question 31

What tumors express high levels of altered glycolipids and glycoproteins?

Answer 31

Neuroblastomas, melanomas, and many sarcomas

Question 32

What are the innate immune responses to tumors?

Answer 32

NK cells - kill tumors cells that lose expression of MHC I

Macrophages - kill tumor cells by phagocytosis

Question 33

What are the adaptive immune responses to tumors?

Answer 33

Cross-presentation of tumor antigens by dendritic cells, and subsequent killing of tumor cells by CD8 CTLs
Production of antibody against tumor antigens - not very effective?

Question 34

List two tissue-specific differentiation antigens, one from a solid cancer and one from a blood cancer

Answer 34

Prostate-specific antigen

CD20 on B cells

Question 35

By what general categories of mechanisms do tumors evade the immune system?

Answer 35

Intrinsic - activity of tumors themselves
Extrinsic- immune responses that are normal, but inappropriate for tumors
Myeloid-derived suppressor cells (MDSCs)

Question 36

By what intrinsic mechanisms do tumors evade the immune system?

Answer 36

Lose expression of immunogenic antigens, due to mutation
Make tumor antigens inaccessible to the immune system - antigen masking
Secrete products that suppress anti-tumor responses - TGF-beta, FasL

Question 37

By what extrinsic mechanisms do tumors evade the immune system?

Answer 37

Act like self, and thus induce peripheral self-tolerance
Tumor-associated macrophages may promote growth
Treg cells may suppress T cell responses, due to self-mimicry

Question 38

What are MDSCs? What are their functions and roles in tumor immunity?

Answer 38

Myeloid-derived suppressor cells
Immature myeloid cells normally recruited from the bone marrow to sites of chronic inflammation
Suppress T cell responses, induce development of Tregs and Th2 cell responses
May suppress anti-tumor innate and T cell responses

Question 39

How do tumor vaccines work?

Answer 39

Antigens are found by identification of peptides recognized by tumor-specific CTLs
Induce active immunization by stimulating CTLs against tumor antigens

Question 40

Besides vaccines, how else can the immune system be stimulated against tumors?

Answer 40

Systemic cytokine therapy to boost immune responses
Blocking inhibitory pathways
Nonspecific stimulation

Question 41

How does the immune system promote tumor FORMATION?

Answer 41

Through chronic inflammation as a result of fighting an infection
Generation of free radicals by innate immune cells, which can damage DNA and lead to malignant transformation

Question 42

How does the immune system promote tumor GROWTH?

Answer 42

Tumor-associated macrophages produce growth factors and other substances which help tumors grow