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Host Defense > Lecture 18: Fetal Transplant > Flashcards

Lecture 18: Fetal Transplant Flashcards

1
Q

What is the biggest barrier igniting rejection?

A

MHC (system that allows us to discriminate between self and non self)

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2
Q

What tests can be done to determine donor/recipient compatibility?

A

detect recipient antibodies that might cause rejection of transplanted organs

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3
Q

What antibodies would you react with donor to test compatibility?

A

serum antibodies (lymphocytotoxic - would only have them if you were pregnant or had a prior transplant)

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4
Q

What is mixed lymphocyte culture?

A

basically a transplant in vivo (classic way to measure compatibility)

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5
Q

What are the best predictors of graft survival?

A

MHC Class 2 (DR) matches

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6
Q

What is the best way to determine whether potential organ recipients have MLC antibodies present in their serum?

A

incubate it with a panel of lymphocytes of known HLA specificity in individual wells. Then add complement so that the lymphocytes that have bound antibody will lyse

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7
Q

What are the steps of a mixed lymphocyte culture?

A

1) take cells from recipient and mix them with irradiated donor cells (so the donor won’t respond to recipient by multiplying)
2) mix the two lymphocyte cultures
3) Look to see if recipient cells proliferate (sign of INCOMPATIBILITY; not a good donor)

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8
Q

True or false: in graft rejection, both donor and host DCs get involved

A

TRUE

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9
Q

What are the 2 main ways the mammalian immune response prevents engraftment of tissue? (2 routes of allorecognition)

A

1) DIRECT: activation of the immune system by foreign MHC marker itself (w/o any MHC processing - HERESY)
2) INDIRECT: alloantigens are phagocytized, processed, and represented in context of Class II MHC by APCs

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10
Q

Why is the DIRECT allorecognition route considered a heresy?

A

It doesn’t obey the MHC restriction concept of antigen presentation since the recipient is recognizing MHC as antigen

(CD4+ T cells react with foreign MHC, treating it like peptide)

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11
Q

Which method of allorecognition involves recognizing grafted antigen presented by recipient MHC?

A

indirect (normal way)

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12
Q

Which method of allorecognition involves recognizing MHC as pathogen?

A

direct (HERESY)

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13
Q

What happens after direct and indirect activation of the immune system by allorecognition?

A

Classic CD4, Th1 response occurs

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14
Q

What are MANDATORY participants in ALL forms of cellular rejection?

A

CD4 T cells

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15
Q

What kind of Th response occurs during graft rejection?

A

TMMI (lots of IL-12 secretion)

leads to clonal expansion of CD8-alloantigen specific T cells (driven by IL-21)

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16
Q

True or false: donor dendritic cells take up alloantigen

A

FALSE, only host DCs do

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17
Q

What occurs in the lymph node after grafts?

A

Th1, Th2, and Th17 responses

APCs present peptide to T cells to generate a Th1 response

B cells present peptide to generate a Th2 response which will generate graft specific antibody

Th17 is generated and produces IL-17 for a chronic response (lots of IL-23 to promote this)

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18
Q

Which cytokines help promote the Th2 response in the lymph node?

A

IL4 and 21 - help produce alloantigen specific B-cell

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19
Q

What role do NK cells play in graft rejection?

A

try to kill graft right off the bat

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20
Q

What are the 4 important points summing up the cumulative effect of the graft rejection response?

A

1) activated macs mediate destruction
2) CD8 antigen specific graft cytolysis
3) Th17 mediated inflammation
4) antibody mediated, graft destruction by complement and/or Fc receptor activation of cell death mechanisms

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21
Q

What determines how severe the rejection to the graft is?

A

the ratio of Th1, Th2, Th17 cell activation countered by Tregs

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22
Q

Would a more dominant Th17 have a better or worse (more severe) response?

A

WORSE (recruits more neutrophils to the area)

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23
Q

Name 7 ways the immune system kills grafted tissue:

A

1) NK cytotoxicity against non-self MHC
2) NK antibody mediated cytotoxicity via Fc receptors (ADCC)
3) Th1 activated macrophage killing
4) Th1 amplified CD8 cytotoxicity
5) Th2 driven graft antibody
6) Complement mediated cytotoxicity
7) Th17 activation by DC

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24
Q

Hyperacute rejection is defined as __________ rejection, occurring within ___________ post transplantation.

A

accelerated; 48 hours

patient has pre-existing antibodies to graft (ex: antibodies to donor blood group antigens so antibodies bind vascular endothelium of graft, initiating inflammatory response that occludes blood vessel)

25
Q

What is the pathology of hyperacute rejection?

A

widespread vascular injury brought about by alloantibody mediated endothelial damage

26
Q

When do acute rejections occur?

A

within 3 weeks (after a CD4 cell reaction to direct or indirect alloantigen response)

27
Q

What does a hyperacutre rejection look like?

A

ischemic and white (no blood flow, platelets agglutinate)

28
Q

What defines acute rejections?

A

sudden appearance of effector cells in the graft

29
Q

What determines the vigor of acute rejetion?

A

MHC Class II (DR)

30
Q

What technology helps with determination of acute rejection?

A

microarray (shows gene expression profile)

31
Q

What unknown fact have microarrays elucidated about predicting severe rejection?

A

if B cells are present

32
Q

What is chronic rejection?

A

repeated, slow attrition of graft

33
Q

Are chronic rejections caused by the same mechanisms acute rejections are?

A

NO; chronic via unknown mechanism

34
Q

What is the pathology of chronic rejection?

A

intimal thickening that leads to graft ischemia

35
Q

What is the ultimate goal to prevent graft rejection?

A

stimulate tolerance

36
Q

Name 4 strategies to prevent rejection:

A

1) optimally match MHC (especially DR)
2) block t-cell response to alloantigens
3) provide inhibitory second signals (CTLA-4), Tregs (CD4, 25) or cytokines (IL21, 23, 10, TGFb to override Th1, 17 and CD8)
4) INDUCE TOLERANCE BY MANIPULATING TREGS

37
Q

Graft vs. Host disease (GvH) is unique to what?

A

bone marrow transplantation (or inadvertent transfusion of immunocompetent cells into an immunodeficient host)

38
Q

What needs to happen before bone marrow transfusion occurs?

A

host needs to be essentially immunologically bankrupt (need to wipe out host’s T cells)

39
Q

How do you set up an assay to test for compatibility of bone marrow?

A

recipient cells are the stimulators and donor cells the responders —– effectively the opposite of how you would set it up for a solid organ transplant

40
Q

Why don’t xenotransplants work?

A

a 1,3 GT gene which higher primates develop antibodies against

41
Q

What can help blunt the autoreactivity to xenotransplants?

A

insert Human Decay Activating Factor (DAF) to activate complement and break it down so it wont cause inflammation

42
Q

What is the rate of first trimester failure?

A

30%

43
Q

True or false: trophoblast (fetal tissue) does not express HLA-A B or C

A

True (it is downregulated)

44
Q

What kind HLA is expressed on trophoblast tissue?

A

non classical HLA-G that expresses an inhibitory motif for maternal NK cells

45
Q

What is special about the HLA-G?

A

it expresses inhibitory motif for maternal NK cells

46
Q

What prevents the expression of cytokines that would promote cytotoxic T cells?

A

epigenetically silencing

47
Q

In the non-pregnant uterus, NK cells ___________ (increase or decrease)

A

increase

48
Q

In the gravid uterus, what happens to NK cells?

A

convert to markedly different NKs and make up 70% of all lymphocytes

49
Q

What is special about the NKs in the pregnant uterus?

A

they do NOT express CD16 (the Fc receptor necessary for antibody-directed cytotoxicity)

they have regulatory and tolerogenic functions that prevent immune cytotoxic attack

also help with angiogenesis

50
Q

what other immune cells are upregulated in the pregnant mom?

A

yd T cells, macs, paterna antigen specific CD4, 25 Tregs

these secrete IL10 and TGFb to tone down immune response

51
Q

What two cytokines strongly promote the presence of Tregs?

A

IL-10 and TGFb

52
Q

What does progesterone do in terms of maternal pregnancy?

A

suppresses Th1 type response

53
Q

The pregnant mom has suppressed _____ response but normal ____ response

A

Th1

normal Th2

54
Q

True or false: during pregnancy, mom has increased numbers of paternal MHC antigen specific maternal Tregs circulating

A

TRUE

55
Q

What else does progesterone do to the surface of the uterine endometrium to subdue immune response?

A

displays decay accelerating factor (DAF) to inhibit complement mediated death

56
Q

What is the best characterization of the mom’s immune system state during pregnancy?

A

dominant Th2 but suppressed Th1, Th17, and cytotoxic responses

57
Q

What happens if the dominant Th2 converts to Th1 bias with dominance of IFNy at the fetal/maternal interface?

A

inability for successful implantation or fetal resorption

58
Q

Why can the Th2 bias be harmful?

A

leads to exacerbation of maternal diseases dependent on TMMI (like Tb)

59
Q

What happens if fetus is infected in utero?

A

can develop tolerance to that and not handle it well the next time it sees that pathogen

Host Defense (21 decks)

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