Greenfield.33.TransplantImmunology Flashcards Preview

B. Rotation 2 > Greenfield.33.TransplantImmunology > Flashcards

Flashcards in Greenfield.33.TransplantImmunology Deck (108)
Loading flashcards...
1
Q

how does hypoxia cause ischemic-reperfusion injury?

A

hypoxia-inducible factor

2
Q

how does complement cause ischemic-reperfusion injury?

A

senses injury, activates endothelium and leukocytes

3
Q

how do natural antibodies contribute to ischemic-reperfusion injury?

A

activate complement

4
Q

how do oxidants contribute to ischemic-reperfusion injury?

A

activate endothelium, damage cells

5
Q

how does apoptosis contribute to ischemic-reperfusion injury?

A

disrupts endothelium

6
Q

how do toll-like receptors contribute to ischemic-reperfusion injury?

A

activate endothelium and leukocytes

7
Q

how do cell-adhesion molecules contribute to ischemic-reperfusion injury?

A

facilitate leukocyte migrations

8
Q

how do T-cells contribute to ischemic-reperfusion injury?

A

unknown

9
Q

Name tow mechanisms of ishcemic-reperfusion injury that can occur during organ harvesting?

A

failed anastomosis can result in immediate transplant failure. Mild injury of the organ during the harvest can –> activated endothelium –> inflammation

10
Q

what is the “no reflow” state in transplant?

A

severe injury to small blood vessels –> no reflow –> tissue necrosis

11
Q

what three solid organs are more susceptible to ischemic-reperfusion injury than the kidney?

A

lungs, liver, heart

12
Q

Define “histocompatibility”

A

The genetic relationship between donor and recipient

13
Q

what does MHC stand for?

A

major histocmompatibility complex

14
Q

can you still have rejection if MHC is matched?

A

yes, but its slower

15
Q

do you have to match minor histocompatibility complexes between donors and recipients?

A

sometimes

16
Q

Do antibodies have more effects on organ grafts or cell/tissue grafts?

A

organ grafts

17
Q

what are the four fundamental characteristics of the antibody-mediated immune response?

A

1) systemic reaction. 2) specific reaction (second set reaction doesn’t affect third party grafts); 3) generalizable (same rxn aroused by tumor is aroused by skin); 4) exhibits memory

18
Q

Briefly, how do T-cells and B-cells respond to transplantation

A

T-cells attack cells and tissues without Ab. B-cells and T-cells both attack organs, B-cells use Ab

19
Q

What is TAP and which type of MHC is it associated with?

A

Transporter a/w Antigen Processing. Major transporter a/w MHC-I, determines immunogenicity of the peptide

20
Q

What is the peptide loading complex and what type of MHC is it associated with?

A

MHC-I, promotes exchange of bound peptides, loaded in ER, further determines immunogenicity

21
Q

What are the origins of TAP and peptide loading complex of MHC-I? (3)

A

endogenous proteins, virus-produced proteins, other intracellular origins

22
Q

Define cross-presentation and what it is used for

A

Fusion of endosomes containing phagocytosed proteins / cell fragments to the ER. Cross-presentation is essential to develop cytotoxic responses to tumor cells, allogeniec treatment, and virus-infected cells

23
Q

Which cells present MHC-I?

A

all nucleated cells

24
Q

Which cells present MHC-II?

A

specialized, antigen-presenting cells. Macrophages, dendritic cells, endothelial cells.

25
Q

Where do the peptides that bind to MHC-II originate from?

A

intact cells, cell debris, and proteins taken up by phagocytosis into phagosomes

26
Q

are MHC-II lacking a bound peptide expressed on cell surfaces and why?

A

No they arent to ensure that extracellular peptides are not inadvertently presented

27
Q

Describe the roles of positive and negative selection in development of T-cell receptors

A

ensure that TCRs recognize self-MHC but do not bind too tightly (positive selection –> negative selection)

28
Q

What type of peptides do T-cells bind to (free or bound)?

A

Do not bind to free Ag, only bind peptides bound to MHC-I / II

29
Q

What are the three coreceptor proteins for T-cell receptors?

A

CD3, CD4, CD8

30
Q

how do Antigen-presenting cells (APCs) interact with T0cell receptors for immune response

A

APCs activate with cytokines –> APCs process and present antigens –> APCs migrate to LNs and activeate T-cells –> increased T-cell presentation + increased MHC-I/II expression + increased peptide stability

31
Q

Name the two basic steps of T-cell activation

A

T-cell receptor bind to MHC, costimulatory receptors enhance binding to MHC (CD8 - MHC-I / CD4 - MHC-II)

32
Q

what is the role of total level of signaling on T-cells

A

survival, activation, and apoptosis of T-cells depend on total level of signaling, therefore lotso low levels of signaling = big signals

33
Q

what is the relative amount of T-cell stimulation required in blood vs. LNs

A

T-cells in blood require more stimulus than T-cells in LNs

34
Q

how does immunologic memory compare to innate immunity?

A

immunologic memory is more rapid, specific, and effective than innate immunity

35
Q

how long does immunologic memory take to be effective after first encounter with Antigen?

A

several weeks to respond

36
Q

What type of cell retains cellular immunity?

A

Memory T-cells

37
Q

Name the three characteristics of cellular immunity mediated by memory T-cells and how is this related to transplant immunology

A

migrate through the body, activated by little/no costimulation, hang around for a long time - therefore difficult to overcome in transplant pationetns. Basically, stronger, faster, more intense immune response

38
Q

What part of the transplanted organ is the immunologic reaction directed at?

A

Mainly directed at blood vessels that feed the transplant (recipient vessels)

39
Q

How do T-cells interact with allograft MHC?

A

T-cells directly recognize allografts and MHC on foreing allograft cells, which can engage a large percentage of T-cells. Heightened immunogenicity of MHC-derived peptide can cause allografts MHC to load efficiently on host MHC.

40
Q

How does the interaction of T-cells with allograft MHC affect immunologic memory?

A

the speed/intensity of the T-cell response to MHC is associated with the speed/intensity of immunologic memory

41
Q

Describe the step of positive selection in development of central tolerance in T-cells

A

T-cells that bind to MHC survive, T-cells that bind to anything else die

42
Q

Describe the step of negative selection in development of central tolerance in T-cells

A

T-cells that bind too tightly to MHC die

43
Q

What do receptor-binding do B-cells require to be activated?

A

need activation with Antigen-receptor and second-receptor

44
Q

How do antigen-presenting cells respond to tissue injury?

A

increase MHC and peptide expression with exposure to tissue injury

45
Q

Name the four types of Peripheral Tolerance

A

peripheral deletion, anergy, regulatory T-cells, accommodation

46
Q

What is the MOA of peripheral deletion?

A

shapes repertoire to eliminate reactive lymphocytes, part of peripheral tolerance

47
Q

what is the MOA of Anergy?

A

conditional responses

48
Q

what is the MOA of reglatory T-cells

A

suppression of immune response

49
Q

what is the MOA of accommodation

A

prevents immune-mediated injury via resistance to complement and Ab

50
Q

What histocompatibilty genes can be matched between transplant donors and recipients and how does this affect outcomes?

A

HLA A/B/DR can be matched, improved outcomes with match

51
Q

why are MHC-compatible grafts sometimes rejected?

A

b/c MHC is not fully sequenced between donors and recipients, so there still may be a mismatch

52
Q

how does donor viral infection affect recipient immune response?

A

if the donor has a virus (ex: CMV), this virus may be recognized as an alloantigen –> alloimmune response

53
Q

Describe how crossmatch works in context of transplant immunology

A

recipient serum is applied to donor cells to test for C’-mediated lysis and binding by activated cell sorting

54
Q

what does a positive crossmatch indicate in terms of transplant compatibility

A

positive crossmatch predicts hyperacute reaction therefore absolute CI to transplant

55
Q

How does panel-reactive antibody test work in the context of transplant?

A

recipient serum is applied against a panel of cells/antigens that represents lots of donors –> tests for antibodies –> predicts degree of difficulty in finding a negative crossmatch donor

56
Q

How does ABO blood type affect transplantation between donor and recipient

A

you match it when possible

57
Q

what is the MOA of induction therapy for transplant and when is it administered?

A

administered at the time of transplant, its antibodies to deplete / block T-cells (thymoglobulin, anti-CD3, anti-CD25)

58
Q

what does induction therapy for transplant accomplish?

A

reduces ischemic / reperfusion injury, increases susceptibility to bacteria / fungi

59
Q

Name three agents used for maintenance therapy

A

glucocorticoids, calcineurin inhibitors, and antimetabolites

60
Q

what is the MOA of glucocorticoids in maintenance immunosuppression for transplant and give an example

A

regulates gene transcription, ex: prednisone

61
Q

what is the MOA of calcineurin inhibitors in maintenance immunosuppression for transplant and give an example

A

inhibit protein kinase / phosphatase. ex: cyclosporine (Gengraf), tacrolimus (Prograf, FK-506), rapamycin (Rapamune)

62
Q

what is the MOA of antimetabolites in maintenance immunosuppression for transplant and give an example

A

reduced de nove nucleic acid synthesis. ex: azathioprine, mycophenolate mofetil (Cellcept), leflunomide (Arava)

63
Q

How do you treat rejection?

A

treat with increased steroids and Ab

64
Q

why don’t calcineurin inhibitors work to treat rejection?

A

b/c they prevent differentiation of naive T-cells, so not relevant in the case of rejection

65
Q

What are the two effects of induction of tolerance in transplant patients (experimental)?

A

1) eliminates mature lymphocytes and other hematopoetic cells by providing stem cells from transplant source = no allogeneic immune response. Downside - you would knock out immunologic memory. 2) inhibit costimulatory molecules (CD80, CD86, CD40)

66
Q

What are the locations of B-cell development in the fetus?

A

fetal liver

67
Q

what is the location of B-cell development in the adult?

A

bone marrow

68
Q

when does B-cell development occur in the human lifespan?

A

continually develops through life

69
Q

what is the MOA of B0cell activation

A

B0cell receptors are immunoglobulins that activate by binding to target and then secreting antibodies –> somatic hypermutation and isotype class switch recombination

70
Q

what are the two types of B-cells a naive B-cell can differentiate to?

A

memory B cell and plasma cell

71
Q

how do memory B-cells interact with T-cells

A

T-cell dependent, interact with CD40/CD40L to increase IgM and IgG. Also interact with CD8 to reduce antipolysaccharide response.

72
Q

How do plasma cells interact with T-cells?

A

Naive B cells can be activated by T-cells to differentiate into plasma cells. Otherwise they are T-cell independent and react to ABO Ag.

73
Q

How is immune response in plasma cels activated?

A

They are initiated by polyclonal activators (LPS) which stimulate B-cells through toll-like receptors

74
Q

what patients have anti-ABO Ab and what is their presumed origin?

A

anti-ABO Ab are “natural” and universally present possibly 2/2 exposure to commensal bx with polysaccharide walls

75
Q

what type of sequential B-cell activation takes longer - T-cell dependent or independent?

A

T-cell dependent takes longer b/c of sequential activation, therefore cant usu treat primary infection but creastes long-lasting Ab and memory

76
Q

What are two mechanisms of B-cell memory?

A

relies on long-lived plasma cells in bone marrow or de novo generation of short-lived plasma cells from long-lived memory cells.

77
Q

name four postulated mechanisms of long-lived humoral immunity

A

2/2 plasma cell differentiation from memory B-cells responding to: 1) persistent Ag; 2) polyclonal stimuli; 3) noncognate T-cells; 4) cross-reactivity to self

78
Q

Define B-cell tolerance

A

absence of humoral immune response following adequate stimulus

79
Q

What is the role of clonal deletion in development of B-cell tolerance?

A

eliminates self-reactive B-cells

80
Q

What is the role of clonal deletion in development of B-cell tolerance?

A

eliminates self-reactive B-cells

81
Q

What is the role of receptor editing in development of B-cell tolerance

A

low affinity self-Ag binding on immature B-cells, induces rearrangement of Ig genes from self to nonself

82
Q

what is the host immune response directed at cellular transplants?

A

fed by recipient blood vessels therefore there is reduced Ab/C’-mediated injury

83
Q

what is the host immune response directed at tissue transplants?

A

recipient Ab bind to donor blood vessels. Recipient vascularization can help shield graft. Ischemia can occur.

84
Q

what is the host immune response directed at organ trasnplants

A

recipient Ab bind to donor vessels to a much greater extent than cell/tissue transplants

85
Q

what is the timeline of hyperacute rejection?

A

occurs within 24 hours of transplant

86
Q

how does hyperacute rejection present and what is its MOA?

A

p/w inflammation, interstitial hemorrhage, and thrombosis secondary to preformed antidonor antibodies binding to blood vessels and complement activation

87
Q

what role do anti-ABO Ab have in hyperacute rejection

A

hyperacute rejection with ABO-Ab can depend on Ab-level and affinity/susceptibility to injury

88
Q

how do livers, kidneys, and heart transplants compare in terms of susceptibility to hyperacute rejection and why?

A

livers are less susceptible than kidneys and hearts, possibly 2/2 differences in the sizes of vascular beds

89
Q

what is the role of complement in hyperacute rejection?

A

complement activation mediates it, can sometimes be 2/2 unidentified lectin/alternative pathways reacting to endothelial antigens

90
Q

how can you get hyperacute rejection WITHOUT preformed antibodies?

A

classic/lectin/alternative complement reacting to endothelial antigens

91
Q

Describe the steps of crossmatch prior to transplant

A

1) combine donor lymphocytes with recipient serum; 2) if donor specific lymphocytoxic Ab present in recipient, will attack donor cells; 3) damage to donor cells will cause uptake of dye = positive crossmatch

92
Q

what is the timeline of Ab-mediated rejection?

A

without immunosuppresion, can begin within 24 hours of transplant

93
Q

how can Ab-mediated rejection occur in the abscence of Ab?

A

does not exclude Ab-mediated rejection b/c donor organ can absorb lotso Ab

94
Q

how do pathologiests identify Ab-mediated rejection in transplant?

A

rely on C4d deposition in peritubular capillaries as evidence of Ab-mediated rejection

95
Q

what is the pathophys a/w Ab-mediated rejection?

A

activated endothelial cells shed thrombomodulin and heparin sulfate –> express tissue factor and plasminogen activator inhibitor –> coagulation –> focal ischemia, endothelial cell injury, intravascular coagulation

96
Q

how do you treat Ab-mediated rejection?

A

plasmapheresis, sometimes anti B-cel Ab

97
Q

What is the MOA of chronic rejection?

A

2/2 repeated immune and non-immune injury and inflammation of graft

98
Q

What is the name of chronic rejection in the kidney?

A

chronic allograft nephropathy

99
Q

What is the name of chronic rejection in the liver?

A

vanishing bile duct syndrome

100
Q

What is the name of chronic rejection in the lungs?

A

bronchiolitis obliterans

101
Q

What is the name of chronic rejection in the heart?

A

accelerated arteriosclerosis

102
Q

what should you suspect as the MOA of chronic rejection if you see C4d deposition?

A

humoral immunity

103
Q

what is the treatment of chronic rejection?

A

no tx

104
Q

Define accommodation in terms of transplant immunology

A

acquired resistance of an organ graft to humoral immunity

105
Q

what is the MOA of accommodation in transplant?

A

healthy organs can absorb anti-donor Ab. Xenografts/allografts with accomodation have protective/anti apoptotic agents

106
Q

What types of transplants are susceptible to cellular rejection?

A

all allografts are susceptible therefore need to reduce cell immune responses

107
Q

what is cellular rejection directed against and what cells mediate it?

A

directed against small blood vessels –> thrombosis. Mediated by cytotoxic T-cells (CD8), helper T cells, and delayed-type hypersensitivity (CD4)

108
Q

what effect do CD4 cells have on blood vessels in the transplant?

A

causes edema in relatively uninjured blood vessels