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Host Defense Exam 2 > Fetal/Transplantation Immunology > Flashcards

Fetal/Transplantation Immunology Flashcards

1
Q

Define allogeneic

A

transplants between members of the same species who differ genetically

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2
Q

define allograft

A

a tissue transplant between allogeneic individuals

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3
Q

define xenograft

A

a tissue transplant between members of different species

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4
Q

discuss the general roles of the MHC

A

provides an immunological signature; used to demarcate self from non-self

provides effective immune surveillance

identify infected or altered host cells

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5
Q

what might the MHC system have evolved to do?

A

prevent parasitism

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6
Q

what is the strongest predictor of graft survival?

A

MHC DR (class 2)

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7
Q

what is the mixed lymphocyte reaction?

A

a transplant in vitro

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8
Q

What is the primary concept of the mixed lymphocyte culture (MLC)?

A

differences in HLA class I & II, particularly DR, antigens between donors of the cells will stimulate T lymphocytes to synthesize DNA and divide

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9
Q

what is the MLC designed to quantitate?

A

the amount of cell division as measured by newly synthesized DNA in responder lymphocytes when exposed to irradiated stimulator lymphocytes

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10
Q

in a solid organ transplant, who do the responder and stimulator lymphocytes correspond to?

A

stimulator lymphocytes are from the potential donor, responder cells are the cells from the recipient

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11
Q

During thymic maturation, T cells that react moderately to self-MHC:self-peptide are able to survive and mature. So why do T cells react strongly to non-self MHC?

A

this is called accidental resemblance: allogenic MHC:self-peptide resembles self MHC:foreign peptide

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12
Q

What does accidental resemblance cause?

A

Massive T cell response

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13
Q

What are three ways to do MHC typing?

A

Flow cytometry
ELISA
Genome Sequencing

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14
Q

What does the MHC of the donor function as, and what are the two ways that the recipient can recognize it?

A

MHC of the donor functions as an alloantigen, and can be recognized by a direct and indirect method

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15
Q

What is the direct method of recipient recognition of donor tissue?

A

Donor APC travel to the lymph node and activation the immune system by the foreign MHC marker itself without any form of MHC processing or presentation

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16
Q

What is the indirect method of recipient recognition of donor tissue?

A

alloantigens are phagocytized by recipient APCs, processed, and presented in the context of MHC class II molecules to CD4+ T cells

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17
Q

what kind of cells are mandatory players in all kinds of cellular rejection?

A

CD4 Th

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18
Q

discuss the cumulative effects of tissue rejection

A
  1. activated macrophage mediated graft destruction
  2. CD8 antigen specific graft cytolysis
  3. th17 mediated inflammation
  4. antibody mediated graft destruction either by activation of complement or Fc receptor activation of cell death mechanisms
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19
Q

are NK cells mandatory for successful rejection?

A

No, but participate to varying degrees

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20
Q

how is rejection defined clinically?

A

its temporal relationship to the actual transplantation

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21
Q

define hyperacute rejection

A

accelerated rejection, within 48 hours of transplantation

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22
Q

what is hyperacute rejection mediated by?

A

recipient alloantibody directed against donor antigens that were present prior to transplantation

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23
Q

when/how does hyperacute rejection normally occur?

A

A recipient has blood group O and has antibody directed against A and B antigens, which are present on the donated tissue (ABO Ag are not only on erythrocytes)

24
Q

How else can hyperacute rejection occur?

A

Ab with reactivity to MHC antigens can be present in some patients prior to transplantation, with sensitization occurring due to blood transfusions or multiple pregnancies

25
Q

what is the pathology of hyperacute rejection characterized by?

A

widespread vascular injury brought about by alloantibody mediated endothelial damage

26
Q

discuss some of the factors that lead to the pathological presentation of hyperacute rejection

A

binding of Ab to endothelial alloantigens results in the aggregation of platelets and the stimulation of the clotting cascade that leads to severe graft ischemia

neutrophils release granules that degrade the surrounding tissue

complement cascade is invoked which enhances intravascular clotting

27
Q

What is acute rejection defined by?

A

sudden appearance of anti-donor immune effector cells during the first three weeks after transplantation

28
Q

What does the vigor of the acute rejection depend on?

A

DR mismatch, gender, intensity of immunosuppression

29
Q

What is the rejection sequence of the acute rejection?

A

initiated by CD4 T cells reacting with alloantigens either directly or indirectly and mediating an TMMI response

SImultaneously, alloantigen specific CD8 cells attack the graft and Th17 cells mount an inflammatory response

after alloantigenic specific B cells take up residence in the graft they will produce alloantibody against the donor tissue

30
Q

What is chronic rejection?

A

diffuse, widespread arteriolar narrowing caused by intimal thickening of the vessel

31
Q

will anti-rejection therapy reverse chronic rejection?

A

No! It is a leading cause of retransplantation of hearts

32
Q

What are some strategies to prevent rejection?

A
  1. Optimal MHC, especially MHC-II (D) loci
  2. Blunt T cell responses to alloantigens by immunosuppression
  3. Provide inhibitory secondary signals (CTLA-4) or cytokines (IL-10 & TGF-beta) to override Th-1 and CD8 response
  4. Induce specific tolerance to the organ: enforce tolerance via CD4, 25, & FoxP3
33
Q

What kind of transplantation is graft versus host (GvH) disease specific for?

A

bone marrow transplantation or inadvertent transplantation of immunocompetent cells into an immunocompromised host

34
Q

What rejection can GvH present with?

A

Acute or chronic

35
Q

How would you set up an MHC assay for a stem cell transplantation?

A

recipient cells are the stimulators, donor cells are the responders (this is the reverse of a solid organ transplant)

36
Q

What is the difficulty in xenotransplantation, and what kind of rejection does it result in?

A

higher primates stopped expressing alpha-1,3-GT ~2.8 mil years ago, and have since developed anti-GT Ab after exposure to alpha-GT epitopes on intestinal bacteria

other species have endothelial display of alpha-gal on endothelial cells, and thus a transplantation into humans would result in hyperacute rejection

37
Q

What is the pregnancy paradox?

A

the fetus is semi-allogeneic but survives in utero

38
Q

What is unique about the maternal-fetal interface in the context of MHC?

A

trophoblastic (fetal) tissue does not display the classic HLA-A, B, or C molecules as the molecules are downregulated

instead, the trophoblastic tissue only displays a non-classical HLA, HLA-G, that has an inhibitory motif for maternal NK cells

39
Q

How are cytokines prevented from promoting an immune response?

A

Local epigenetic silencing of cytokines prevent cytotoxic T cell homing to the uterus

40
Q

describe NK cell activity in the non-pregnant women

A

increase towards the end of the menstrual cycle and appear similar (but not-identical) to peripheral NK cells

41
Q

describe NK cell activity in the pregnant woman

A

In the gravid uterus under the influence of progesterone and uterine produced TGF-beta, they convert to a markedly different NK cell and comprise about 70% of all lymphocytes in the endometrium during pregnancy

42
Q

What is different about NK cells in the pregnant woman?

A

do NOT express CD16 (the Fc receptor necessary for Ab directed cytotoxicity)

cytotoxic receptors inhibited by HLA-G, and their cytokine profile becomes inhibitory

produce angiogenic factors that increase blood supply to the fetal tissue

43
Q

What is found in increased number in the uterine wall during pregnancy, and what do they do?

A

maternal gamma-delta T cells and macrophages, and paternal Ag specific CD4 & 25 regulatory cells

these cells secrete large amounts of IL-10, TGF-beta and therefore suppress CD4 and CD8 attack on the fetus

fetal trophoblast tissue also produces large amounts of IL-10 and TGF-beta and therefore promote the continues presence of Treg cells

44
Q

What is a major pregnancy induced immunoregulatory hormone, and what does it do?

A

Progesterone and placenta-derived factors strongly suppresses local and systemic Th-1 responses

IL-10 is also increased in the uterine blood during pregnancy

45
Q

What is the result of anti-inflammatory hormones and cytokines?

A

suppressed Th1 response, but relatively normal Th2 response

46
Q

What kind of cells (against what?) can be found in higher concentrations in the uterine blood during a pregnancy?

A

Paternal MHC Ag specific maternal Treg cells - these cells can become memory T cells and proliferate again if there is a subsequent pregnancy with the same male

47
Q

How does progesterone prevent complement fixation?

A

progesterone stimulates the surface cells of the endometrium to display DAF which inhibits complement mediated cell death

48
Q

How can you describe the maternal immune state during pregnancy?

A

systemically, the maternal immune state can be characterized as Th2 dominant with a strong humoral response but with suppressed TMMI, Th17 and cytotoxic responses

49
Q

What does conversion of a maternal Th2 to Th1 dominance do?

A

increase INF-gamma at the fetal-maternal interface, and is associated with inability for successful implantation and/or fetal resorption

50
Q

What diseases does Th1 suppression predispose the mother to?

A

TB, influenza, toxoplasmosis, leprosy

51
Q

What happens if the mother is unable to produce Tregs?

A

fetal loss

52
Q

What else uses the mechanisms that the immune system has developed for fetal survival?

A

Tumors

53
Q

What can happen with infection of the fetus?

A

this can lead to tolerance against the invading pathogen (rather than immunity), and prevent the child/adult from later developing an immune response against an infection by the same pathogen (zika!)

54
Q

What is a problem with bone marrow transplantation?

A

Bone marrow is a good niche for memory T cells, which can attack the recipient after implantation –> GvH

55
Q

What is a result of Th2 bias during gestation?

A

Increases the risk of disseminated intracellular infections that require TMMI and CD4 help (think H1N1maternal mortality) and Th17 responses to fungi and other pathogens

56
Q

maintenance of a Th1 bias during implantation phase is associated with what?

A

decreases the possibility of successful pregnancy

57
Q

What can enhance the chance of a successful pregnancy?

A

Promotion of maternal Th2 or T regs

Host Defense Exam 2 (11 decks)

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