Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

Immunology > Lecture 17 - Fetal Transplant > Flashcards

Lecture 17 - Fetal Transplant Flashcards

1
Q

Define the following:

  1. Autograft
  2. Isograft
  3. Allograft
  4. Xenograft
A
  1. Autograft
    - self to self accepted
    (autologous)
  2. Isograft
    - identical twin to twin
  3. Allograft
    - person to person (not identical twins)
    - variable degree of rejection
  4. Xenograft
    (heterologous)
    - species to species
    - strong rejection (human to dog)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

What is the most prominent barrier to rejection?

What was it initially designed for?

A

MHC

  • designed for prevention of parasitism by other multicellular organism
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

What are ways that one can determine donor/recipient compatibility?

A

Detection of recipient antibodies that might cause rejection of a transplanted organ

Determination of the degree of compatibility between the recipient and the donor

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

What are 4 methods used to assess histocompatibility?

A
  1. Cell typing
  2. Lymphocytotoxic antibodies
  3. Tissue typing (using flow cytometry, ELISA and molecular methods)
  4. The mixed lymphocyte reactions (in vitro transplants)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

What matches are the most strongly predictive of graft survival?

A

MHC Class 2 (DR) matches

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

How does one use lymphocytic antibodies to perform a Complement- Dependent Assay?

A
  1. Incubate cells and antibody (antigen - antibody interaction)
    - lymphocytes of known HLA specificity in individual wells
    - if there are HLA antibodies in the serum they will bind to their MHC antigen on the lymphocyte cell surface
  2. Add rabbit serum
    (complement - mediated cell injury)
    - ** complement to the wells**
    - lymphocytes that have bound antibody n their MHC will be lysed
  3. Visualize cell membrane injury by adding vital dyes
    * * the exact anti-MHC specificity can be determined**
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

How does one perform MHC typing?

A
  1. take cells from the RECIPIENT and see if the cells will cause an immune reaction and reject the organ from the donor
  2. put the cells into culture
  3. mix the cells with the cells of the POTENTIAL DONOR (paralyze the cells so the donor cells go into the recipient culture)  donor still has its own MHC I and II but CANNOT MULTIPLY!!(which would give a false result)
  4. See it the recipient cells proliferate and set up cytotoxic CD8 reactions  if this occurs  REJECTION WILL OCCUR (need immunosupressants)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

What is the primary concept of the Mixed Lymphocyte Culture (MLC)?

A
  • differences in the HLA MHC Class I and II (particularly HLA DR) antigens between the donors of the cells used in the assay will stimulate T lymphocytes to synthesize DNA and divide.
  • MLC is used to quantitate the amount of cell division as measured by newly synthesized DNA in responder lymphocytes when exposed to IRRADIATED stimulator lymphocytes
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

What are “irradiated” cells?

A

Cells that look normal but are “paralyzed” cannot proliferate if activated

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

What happens in MLC mixed typing after the MHC T cells are mixed with irradiated MHC b non-T cells as APC’s?

A
  1. Measure proliferation of T cells by incorporation of H-thymidine
    - T cell proliferation depends largely on differences in MHC Class II Alleles
  2. Measure killing of Cr-labeled target cells to detect activated cytotoxic T cells
    - generation of cytotoxic T cells depends largely on differences in MHC Class I alleles
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

What are 3 new approaches to histocompatibility tests?

What do they decrease and increase?

A
  1. Flow cytometry
  2. ELISA
  3. Molecular Array

Decrease analysis time and Cost, increase sensitivity

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

Mechanisms of Rejection:

Both ____ and ____ DC get involved

Almost all, if not all, ______ will get involved

The intensity of the rejection will depend on multiple factors, including what 3 specific?

A
  1. DONOR and HOST Dc’s
  2. immune effector cells

1) MHC disparity
2) host immune response 3) genes
4) physician interventions

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

What happens after dendritic cells of donor and host origin become activated and migrate to T cell areas of secondary lymphoid organs?

What are some “non-professional” APC’s that might be activated?

A
  1. Donor antigen bearing DC’s engage alloantigen-reactive naive T cells
    - may also trigger antigen experienced memory T and B cells or other non-professional APC such as endothelium of transplanted organ
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

What is the difference between DIRECT and INDIRECT ways that the MHC or antigen function as alloantigens?

Which one is a heresy and doe snot obey the MHC restriction concept of antigen presentation in the context of ones own MHC?

A

DIRECT:
activation of the immune system by the foreign MHC itself!!! without any form of MHC processing or presentation

INDIRECT:

  • standard recognition by the “indirect” method
  • aloo-antigens are phagocytose, processed and represented in contact of MHC Class II by APC’s to CD4 T cells
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

How does the direct mechanism of graft rejection occur?

A

Graft destroyed by defector T cells with only the DC activation (no MHC II used)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

What happens once either direct or indirect ulloantigen activation of the immune system occurs?

A

Classic Th1 CD4 amplifying pathways are activated –> ALL helper T cell subsets will most likely be involved

  • Th1 –> IFN - gamma
    Th2 –> B cells
    Th17 –> inflammation (IL-17) –> recruits neutrophils
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

Which cells are mandatory participants in all forms of cellular rejection?

What occurs early?

What follows this event?
(and which cytokine is most important)

What might cause SEVERE graft damage?

What provides the signals for alloantigen specific B cells to produce alloantibody?

A
  1. CD4 Th cells
  2. TMMI response driven by IL-12 driven
  3. Activation & clonal expansion of CD 8 ulloantigen specific T cells
    - driven by Th1 and IL-21
  4. Th17 and IL-23
  5. Th2 cells provide co-stimulatory signals IL-4 and IL-21
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

What cells might participate but are not mandatory in successful rejection of a transplanted organ?

A

NK cells

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

What are the 7 ways graft rejection can occur?

A
  1. NK cytotoxicity against non-self MHC
  2. NK antibody mediated cytotoxicity via Fc receptors
  3. TMMI macrophage mediated graft destruction (Th1)
  4. Th1 amplified CD8 antigen specific graft cytolysis(cytotoxicity)
  5. Th2 driven graft antibody
  6. Th17 mediated inflammation
  7. Complement mediated cytotoxicity ( or Fc receptor crosslinking causing cell death
  8. NK cytotoxicity
20
Q

What does the intensity of rejection depend on?

A

ratio of Th1, Th2, Th17 and cell activation counter-balanced by Treg inhibition

ex: if Th17 is dominant = rejection might be more destructive (more neutrophils) than if B cells were dominant

21
Q

What is hyperacute rejection?

What is the time frame?

When does it occur?

What is the therapy?

What mediates this type of rejection?

A

Accelerated rejection, usually within the first 48 hours after transplantation.

  • usually right after GRAFT EMPLACEMENT

Therapy: back up dialysis therapy for kidney, but ultimate disaster in heart and lung transplants

  • Mediated by recipient alloantibody directed against donor antigens that were present PRIOR TO TRANSPLANTATION

(also can occur if major mismatch between blood donor groups)

22
Q

What are 2 major examples of hyper acute rejection?

A
  1. transplant of A, B or AB organ into an “O” individual will result in immediate reaction between organ’s A or B determinants and recipient antibodies
  2. Antibodies with reactivity to MHC antigens
    - can be present PRIOR to transplant
    - sensitized by repeated blood transfusions or multiple pregnancies
23
Q

What is the clinical definition of hyper acute reaction? (pathology)

What type of damage ensues?

What is the result of fibrin deposition and coagulation cascade?

What gets attracted to the area?

What is activated?

A
  1. Widespread vascular injury brought about by alloantibody mediated endothelial damage
  2. initiates platelet aggregation, release vasoactive mediators that activate the coagulation cascade and initiate fibrin deposition
  3. SEVERE graft ischemia
  4. Neutrophils
  5. Complemeent is activated and escalates the clotting
24
Q

What happens to the graft if hyper acute rejection occurs?

A

graft will turn pale and IMMEDIATELY due to loss of blood supply and never function

25
Q

What is ACUTE rejection?

What type or reaction is initiated? WHat follows?

A

Sudden (10-90 days) appearance of effector cells in the graft
** first 3 weeks***

  • vigor depends upon donor mismatch, gender, and intensity of immunosuppression
    2. TMMI reaction by CD4 T cells in the recipient reacting with alloantigens
  • CD8 cells attack the graft
    Th17 cells promote an inflammatory reaction and B cel alloantibody appears after alloantigen specific B cells take up residence within the graft
26
Q

What type of test is used to see if an acute reaction has occurred?

What cells are used in the control of rejection and can be used to detect it?

What if there are no T cells or cytotoxic CD 8 cells?

A
  1. Microarray
    - used in kidney transplant to see if T cells or B cells are reacting
  2. FoxP3 (and CD4,25 Tregs)
  3. Graft might be destroyed by drugs
27
Q

What is the hallmark of CHRONIC rejection?

A
  • leaves fibrosis behind
    INTIMAL THICKENING!!!

–> diffuse widespread arteriolar narrowing caused by intimal thickening of the vessel

  • insidious and caused by mechanisms probably different than acute rejection (mystery), usually caused by intimal thickening that leads to graft ischemia. (ex: coronary vessels  chokes the craft off from blood supply)

**The major problem in solid organ transplantation today

28
Q

What is the ultimate goal to prevent rejection?

4 ways?

Which cytokines specifically?

Which reactions should be prevented?

A

TOLERANCE

  1. optimal MHC II (D) matching
  2. Blunt T cell responses to alloantigens by immunosuppression
  3. Provide inhibitory second signals –> CTLA -4 or IL - 10 & TGF- B to override Th1 and CD8 reactions
  4. INDUCE SPECIFIC TOLERANCE
    - CD4, 25, FoxP3 regulatory cells to enforce tolerance
29
Q

Hyperacute, acute, and chronic rejection are all examples of what?

Which disease is unique to bone marrow transplantation?

A
  1. HOST versus Graft disease

2. GRAFT versus HOST disease

30
Q

What cytokines are necessary to prevent rejection?

A

IL-21
Il- 23
IL - 10
TGF - B

  • to override Th1 Th17 and CD8
31
Q

State the 6 strategies to prevent rejection

A
  1. Optimal MHC matching, especially DR (MHC II especially)
  2. Block T-cell responses to alloantigens
  3. Provide inhibitory second signals(CTLA-4)
  4. T regulatory cells(CD4,25)
  5. cytokines(Il-21, IL-23, IL-10 & TGF- to override Th1,Th17 and CD8 responses
  6. Induce tolerance by manipulating Tregs
32
Q

How does T reg based therapy work?

A
  1. Potential donor
  2. incubate with cells from potential recipient by using TGF – B
  3. Induce T reg cells to the antigen from this donor
  4. Transplant kidney into patient
  5. Reintroduce Tregs into patient
  6. Tregs will suppress it
33
Q

The following describes what type of transplant:

When ______ is transplanted the T cells in the transplant attack the recipients tissues

What is a situation that this occurs in and is often forgot about?

A

bone marrow***
GRAFT VERSUS HOST DISEASE

Please remember that this situation can occur when an
Immunoincompetent host receives a BLOOD TRANSFUSION*
(if it is not depleted of lymphocytes first!!!!)

** mature T cells from graft recognize host cells as foreign**

34
Q

Xenotransplants undergo ____ rejection

If they survive hyperacute, they are subject to standard ___ and ______ rejection.

A
  1. Hyperacute
  2. ACUTE
  3. CHRONIC

anti-alpha-1,3GT

35
Q

Why do primates (humans/apes) form hyperacute reaction?

Why can’t we pigs and other non-primates for xenotransplant?

Genetic engineering can insert _____ into pigs to BLUNT hyperacute rejection

A

alpha 1,3 – Antibodies

  • react to PRE-FORMED antibodies!!!
  1. Non-primates have rich endothelial displays of the alpha-gal epitope
    - transplanting these organs into humans = HYPERACUTE rejection
  2. Human Decay Activating Factor
36
Q

What has a similar blood supply to cancer?

What is evoked by both the fetus and the mother?

A
  1. PLACENTA (spiral arteries)

2. TOLERANCE

37
Q

What are the strategies of TOLERANCE to protect the fetus in utero?

a) what is down regulated
b) what MHC is expressed and what specific signal does this have?
c) local epigenetic silencing of what?

A
  1. fetus (trophoblast) does NOT display classic HLA - A,B,C because the MHC is DOWN REGULATED (no MHC I and II)
  2. HLA - G which has an inhibitory signal for maternal NK cells
  3. CHEMOKINE genes
38
Q

MATERNAL NK cells:

In the non-pregnant uterus they increase when?

They are inhibited by _____, they do NOT express the _____ and promote regulatory effects by producing what 2 cytokines?

They produce _____ to support the placenta

  1. What 2 things promote differentiation of T regulatory cells that suppress regional immune responses?
A
  1. Towards the end of the menstrual cycle, and appear to be somewhat similar but not identical to peripheral NK cells
  2. HLA-G
  3. FcR ( no CD16 for ADCC)
  4. TGF-B & IL-10
  5. angiogenic factors
  6. HLA-G & TGF - B
39
Q

More strategies to protect the uterus:

Maternal ____ cells also home to the uterus and are presumed to be promoting tolerance to the fetus

The fetal trophoblast upregulates a gene complex that prevent _____ activation by anti-fetal antibodies

Lastly, when maternal T lymphocytes (ly) come in contact with fetal ly (maternal & paternal MHC) at the placental interface maternal ly or in the fetus itself, they are converted by fetal _____ to paternal specific T-regs.

A
  1. GAMMA DELTA T cells!!!
  2. complement
  3. TGF-B
    - PATERNAL ANTIGEN SPECIFIC Tregs are unregulated by TGF - B!!!!
40
Q

Maternal gamma delta T cells, macrophages, and paternal antigen specific CD4, 25 Treg cells secrete what cytokines?

What else secretes these cytokines?

What does it strongly promote?

A

IL- 10 and TGF - B

FETAL tissue also produces IL-10 and TGF - B

Strongly promotes the continued presence of Treg cells

41
Q

Pregnancy induced hormones, especially _____, strongly suppress uterine and systemic Th1 reactions

Placenta produces _____ which acts globally

Progesterone also promotes increased display of _____ on uterine cells which further inhibits complement reactions

______ generated locally in the uterus circulate systemically

WHAT IS THE NET RESULT?

A
  1. progesterone
  2. IL-10
  3. DAF
  4. T regs!!!!

(Infiltrating maternal cells are converted to these also)

NET: suppressed Th1 responses but normal Th2 responses

42
Q

Maintenance of a Th2 bias during gestation is associated with success but…….increases the risk of what?

Maintenance of a local Th1 bias during the implantation phase decreases the possibility of what?

Promotion of maternal ___ or _____ could enhance the chance of a successful pregnancy

Conversely, failure of maternal lymphocyte conversion to _______ at the placental interface might lead to spontaneous abortion

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

  1. successful pregnancy
  2. Th2, T regs
  3. PATERNAL specific T regs
43
Q

What happens if there is a Th1 response early in the pregnancy?

A

Spontaneous abortion

44
Q

WHat 3 reactions are suppressed in the mother due to Th2 bias/dominance?

A
  1. Th1
  2. TMMI
  3. Cytotoxic responses
45
Q

Clinical implications for the fetus.

Infection of the fetus could lead to what?

How would this affect the baby’s ability to respond to future infections?

A

tolerance to the pathogen and could lead to subsequent inability to respond appropriately to a future infection!

Immunology (26 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions