03/15d Transplant and Tumor Immunology Flashcards Preview

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Flashcards in 03/15d Transplant and Tumor Immunology Deck (42)
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1
Q

What is an autologous graft?

A

A transplant from one individual to the same individual

2
Q

What is a syngeneic graft?

A

A transplant between two genetically identical individuals

3
Q

What is an allogeneic graft?

A

A transplant between two genetically different individuals

4
Q

What are alloantigens and alloreactivity?

A

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

5
Q

How are alloantigens recognized?

A

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

6
Q

What are minor histocompatibility antigens?

A

Every other antigen besides MHCs

7
Q

What are the major effector functions of alloreactive T cells?

A

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

8
Q

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

A

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

9
Q

What are the three patterns of allograft rejection?

A

Hyperacute
Acute
Chronic

10
Q

What is the most common target of rejection? Why?

A

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

11
Q

What is hyperacute rejection?

A

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

12
Q

What is acute rejection?

A

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

13
Q

How can acute rejection be prevented?

A

Aggressive immunosuppression at the time of the tranplant

14
Q

What is acute antibody-mediated rejection?

A

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

15
Q

What is chronic rejection?

A

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

16
Q

What are the typical rejection pathologies of kidneys and hearts?

A

Vascular occlusion

Interstitial fibrosis

17
Q

What are the typical rejection pathologies of lungs?

A

Thickened small airways

18
Q

What are the typical rejection pathologies of livers?

A

Fibrotic and nonfunctional bile ducts

19
Q

How do you prevent and treat rejection?

A

Immunosuppression!
Reduce immunogenicity of allografts
Induce donor-specific tolerance

20
Q

How can you reduce the immunogenicity of allografts?

A

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)

21
Q

How do you induce donor-specific tolerance?

A

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

22
Q

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

A

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

23
Q

What is graft-versus-host disease?

A

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

24
Q

What are the symptoms of acute GVHD?

A

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

25
Q

What are the symptoms of chronic GVHD?

A

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

26
Q

How is GVHD prevented and treated?

A

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

27
Q

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

A

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

28
Q

How do normal proteins become tumor antigens?

A

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

29
Q

What are some examples of oncogenic viral tumor antigens?

A

Papillomavirus - E6 and E7 proteins

EBV - EBNA-1 protein

30
Q

What are oncofetal antigens?

A

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

31
Q

What tumors express high levels of altered glycolipids and glycoproteins?

A

Neuroblastomas, melanomas, and many sarcomas

32
Q

What are the innate immune responses to tumors?

A

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

Macrophages - kill tumor cells by phagocytosis

33
Q

What are the adaptive immune responses to tumors?

A

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?

34
Q

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

A

Prostate-specific antigen

CD20 on B cells

35
Q

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

A

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

36
Q

By what intrinsic mechanisms do tumors evade the immune system?

A

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

37
Q

By what extrinsic mechanisms do tumors evade the immune system?

A

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

38
Q

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

A

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

39
Q

How do tumor vaccines work?

A

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

40
Q

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

A

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

41
Q

How does the immune system promote tumor FORMATION?

A

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

42
Q

How does the immune system promote tumor GROWTH?

A

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