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Immunology 2019 > Lecture 21 > Flashcards

Lecture 21 Flashcards

1
Q

Name 4 immunologically privileged sites

A

The Cornea

Heart Valves

Bone

Tendon

(Immunologically privileged: Immune cells cannot access it )

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2
Q

What discovery is credited to Peter Medawar?

A

Immunological basis of graft rejection

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3
Q

Define Autografts

A

Autografts: grafts exchanged from one part to another of the SAME individual

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4
Q

Define Isografts

A

Isografts: grafts exchanged between DIFFERENT individuals of IDENTICAL genetic constitutions (identical twins)

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5
Q

Define Allografts

A

Allografts: Grafts exchanged between NONidentical members of the SAME species

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6
Q

Define Xenografts

A

Xenografts: Grafts exchanged between members of DIFFERENT species

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7
Q

Explain what Xenografts are particularly susceptible to and a method that can somewhat remedy this issue

A

Xenografts are particularly susceptible to rapid attack by naturally occurring Abs and complement

Insertion of human genes into the genome of a pig, for example, increases the chances of a successful survival of the graft

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8
Q

Graft rejection shows ____ and _____, which are 2 key features of adaptive immunity

A

memory

specificity

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9
Q

Describe what it means when saying graft rejection is mediated by Lymphocytes and can be mediated by T lymphocytes. (use examples)

A

The ability to reject a graft rapidly can be transferred to a naive individual by lymphocytes from a sensitized individual

Depletion or inactivation of T lymphocytes by drugs or Abs leads to reduced graft rejection.

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10
Q

Between B and T cells, which plays a larger role in graft rejection

A

T cells

(experiments where T cells are depleted caused the graft to survive longer, whereas B cells being depleted did little to prolong the life of the graft)

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11
Q

How many HLA alleles do humans inherit? describe the method by which these HLA alleles are expressed (in terms of paternal and maternal inheritance)

A

Each person inherits 10-12 HLA alleles and they are expressed co-dominantly

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12
Q

Which Class of HLA Ags are particularly strong barriers to transplantation? (include the specific molecule type of HLA)

A

Class I HLA Ags: are particularly strong barriers to transplantation

HLA-A and HLA-B

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13
Q

Which Class of HLA Ags are the 3 most important pairs for transplantation? (include the specific molecule type of HLA)

A

Class II HLA Ags: are the 3 most important pairs for transplantation

HLA-DR, HLA-DP, and HLA-DQ

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14
Q

State the 3 specific cell types that express HLA Class II molecules. Only a few cells in the entire body can express class II.

A

Macrophage

DCs

B cells

(all APCs)

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15
Q

Compare direct and indirect allorecognition

A

Direct Allorecognition: The Graft APC’s MHC interacts with the recipient’s T cell
Recipient’s T cell recognizes Unprocessed allogeneic MHC molecules
(“D in direct is also in DC (an APC))

Indirect Allorecognition: Recipient’s APC cells uptakes and processes allogeneic MHC molecules of the graft tissue.
Recipient’s T cell then recognizes the processed MHC molecules of the Graft tissue, via an interaction with a Recipient APC

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16
Q

Which type of allorecognition occurs in a primary response to a graft? Which type occurs duirng chronic rejection?

A

Direct allorecognition occurs in a primary response to a graft

Indirect allorecognition occurs during chronic rejection

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17
Q

Define Chronic rejection in terms of the level of APCs

A

Chronic Rejection: when the number of donor professional APCs are low but still stimulate a direct immune response

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18
Q

Briefly explain the process by which Sensitization and ultimately rejection of a graft occurs.

A

Sensitization: make the body “aware” of the foreign Ags in the transplanted tissue
Either direct or indirect allorecognition causes the transport of alloAgs to the LN via the lymph

Once in the LN, T cells are activated and effector cells begin to be synthesized

Newly formed effector cells then travel through the blood back to the graft site, where they can cause graft rejection

(basically treats the new organ as if it were a pathogen)

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19
Q

For the following type of rejection, state its onset, type of hypersensitivity, its mechanism, and what symptoms it causes

Hyperacute

A

Hyperacute: Type II of hypersensitivity

Immediate onset

pre-existing Abs (usually IgM) against donor tissue, attack due to blood type incompatibility.
Causes thrombosis and occlusion of graft vessels

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20
Q

For the following type of rejection, state its onset, type of hypersensitivity, its mechanism, and what symptoms it causes

Acute

A

Acute: Type IV of hypersensitivity

Weeks to months onset

T cell mediated response to foreign MHC.
Causes Inflammation and leukocyte infiltration of graft vessels. Endotheliitis.
(Most common type)

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21
Q

For the following type of rejection, state its onset, type of hypersensitivity, its mechanism, and what symptoms it causes

Chronic

A

Chronic: Type III and IV of hypersensitivity

Months to years onset

T cell mediated response from foreign MHC “looking like” a self MHC that is carrying an Ag.
Causes Intimal thickening and fibrosis of graft vessels (and atrophy)

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22
Q

For the following type of rejection, state its onset, type of hypersensitivity, its mechanism, and what symptoms it causes

Graft vs. Host

A

Chronic: Type IV of hypersensitivity

Varied onset

Donor T cells in the graft proliferate and attack the recipient’s tissue
Causes Diarrhea, rash, and jaundice
(most common in bone marrow transplants)

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23
Q

Which type of graft rejection is the most common? which is the most commonly occurring type in bone marrow transplants?

A

Most common = Acute

Most common in Bone Marrow Transplants = Graft vs. Host

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24
Q

For a Hyperacute graft rejection reaction, state the 3 potential causes for it.

A

ABO blood group incompatibility

The recipient has be sensitized to the donor MHC by previous transplants, multiple blood infusions, or pregnancy

Abs (IgM) bind to the endothelial cells which activates the classical pathway of complement activation
(Complement activation can lead to the death of the endothelium)

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25
Q

Which cell type (and from which tissue) plays an important role in Acute graft rejections? why?

A

Donor DCs (aka. passenger leukocytes in this case)

Donor DCs migrate to the lymph nodes, and stimulate the T cells that attack the donor tissue
Donor DCs will activate a T cell response in the LN regardless of what peptide they have, bc they are foreign and will express Class I MHC on their surface.

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26
Q

Acute graft rejection is initiated by _____T cells. Do CD4+ or CD8+ T cells react in Acute graft rejection?

A

alloreactive T cells

BOTH CD4+ and CD8+ T cells cause acute graft rejection

27
Q

_____immune responses recognize the MHC itself, NOT the peptide it is bound to. What type of immune response in terms of direct/indirect contributes to Acute graft rejection?

A

Direct

Direct contributes more bc the DC is foreign to the recipient’s body and expresses Class I MHC, but Indirect also contributes to acute graft rejection.

28
Q

What type of graft rejection occurs due to occlusion of blood vessels and subsequent ischemia of the organ? What pathway is the main immunologic mechanism of this type of rejection? Also state how this type of rejection responds to immunosuppressive therapy.

A

Chronic graft rejection

The indirect pathway is the main pathogenic mechanism of chronic graft rejection

Chronic graft rejection does NOT respond to immunosuppressive therapy

29
Q

State 3 non-immunologic factors in a chronic graft rejection

A

Ischemia-reperfusion damage

Recurrence of the disease that caused the failure of the original tissue (kidney for ex.)

The effects of Nephrotoxic drugs (ex. cyclosporine A, which is a chemotherapy drug)

30
Q

State the 4 key concepts that must be met in order to yield the best possible Transplant Outcome.

A
  1. Condition of the Transplant
  2. Donor-host antigenic disparity
  3. Strength of host anti-donor response
  4. Immunosuppressive regimen
31
Q

Mechanical trauma and ischemia-reperfusion injuries to graft tissue can release mediators that result in the rejection of the graft. State the following graft rejection mediators that the following may create and the mechanism by which these mediators operate.

Clotting cascade:

Kinin cascade:

A

Clotting cascade: generates fibrin and fibrinopeptides
Fibrinopeptides increase local vascular permeability, which serves as a chemoattractant for neutrophils and resident tissue macrophages

Kinin cascade: generates bradykinin
Bradykinin causes vasodilation, smooth muscle contraction, and increase vascular permeability (see above)

32
Q

When choosing a donor for a pt that needs a tissue graft, state the 4 characteristics that are considered.

A
  1. ABO blood group compatibility (bc these surface Ags are everywhere)
  2. Identify HLAs via “tissue typing”
  3. Test from preformed Abs via “cross matching” between the recipient and donor’s serum
  4. Test the level of lymphocyte proliferation via observation of the “mix lymphocyte reaction”
33
Q

In what blood types are Abs for A and Abs for B found?

A

Abs to A: B, O

Abs to B: A, O

34
Q

If I have type B blood, explain how my immune system will have anti-A Abs, despite having never encountered the A Ag on a RBC from type A blood. Which specific IgM class are we dealing with here?

A

normal bacterial flora of my body has carbohydrate-containing molecules that are similar enough to A Ags so that my immune system can develop anti-A Abs, without exposure to someone else’s blood.

(anti-B Abs are not allowed to survive via self tolerance mechanisms)

IgM antibodies (makes sense bc it happens so quickly)

35
Q

True or False:

In humans, HLA Ags and MHC class I and class II are the exact same thing. explain.

A

True

HLA = human leukocyte antigen complex
not much to explain.

36
Q

How are HLA antisera and Lymphocytes for HLA typing usually harvested? What happens to a cell once the Ag-Ab complex forms between the HLA antisera and the HLA molecules on the cell surface? (include a crucial step to detecting whether or not this occurs)

A

HLA antisera: harvested from from multiparous women or volunteers who get immunized a certain way

Lymphocytes for HLA typing: spleen and LNs of cadavers

Once the Ag-Ab complex forms, the classical complement cascade occurs and causes lymphocyte lysis of the cell
This is detected by staining cells

37
Q

Describe the 3 steps performed when conducting a microcytotoxicity test to choose an organ donor. What are you looking for in terms of finding a satisfactory donor?

A
  1. Abs are added
  2. Complement is formed (or not formed if the Abs don’t react to one/both of the tissues)
  3. Dye is added and the results are compared

The result you want is for the donor and recipient cell to reacts identically to the various types of Abs that can be added in step 1.
(only identical twins will perfectly match, usually you just find a donor with as similar HLA as possible)

38
Q

Are women or men preferred donors? explain why or why not.

A

Men bc they will not have preformed Abs to the HLA type of their sexual partner(s)

Women will have these preformed Abs for sexual partners bc of her immune system’s exposure to HLA-containing sperm

39
Q

The presence of preformed Abs that are reactive to HLA molecules in the Donor’s tissue can cause what? What testing is conducted in order to avoid this?

A

Hyperactive graft rejection

Microcytotoxicity test between the donor and recipient’s cells

40
Q

What does it mean if you find that donor cells are not stained after conducting a microcytotoxicity test?

A

That there are not any preformed Abs in the serum that bind to the HLA composition of the cell (aka. this is a good donor)

41
Q

Compare the tests conducted to test for Class I HLAs and Class II HLAs.

A

Class I HLAs are tested via Tissue typing

Class II HLAs are tested via MLR (mixed leukocyte reaction)

42
Q

When conducting MLR to choose a donor, lymphocytes from the donor are irradiated and called ____ cells. Lymphocytes from the recipient are intact and called ____ cells. Which of these functions basically as an APC during this test?

A

Lymphocytes from donor = Stimulator cells

Lymphocytes from recipient = Responder cells

Stimulator cells basically act as APCs

43
Q

What does it mean if responder cells proliferate after conducting MLR? How is this proliferation measured?

A

Responder cells only proliferate if they are activated by mismatched Class II MHC (HLA) molecules

Measuring the incorporation of tritiated thymidine allows the level of proliferation to be quantified

44
Q

High levels of radiation in an MLR serum means what? Where is this radiation coming from?

A

There is a large disparity between the donor and the recipient’s MHC (HLA) so they will not be an ideal donnor

H-thymidine (Tritiated Thymidine) is a radioactive substance added during MLR so you can easily measure the level of proliferation of responder cells
(don’t confuse this with the radiation applied to the donor cells prior to mixing with donor cells. That radiation is just to ensure they will not proliferate and disguise the level of proliferation)

45
Q

Give examples of HVG and GVH diseases.

A

HVG: when a kidney is transplanted and the recipient’s T cells attack the new kidney

GVH: when bone marrow is transplanted and the Donor’s T cells attack the recipient’s body

46
Q

Up to __% of host T cells are able to recognize foreign MHC of a graft. This explains why HVG disease is such a strong reaction when compared to reactions to pathogens. What is something that may occur and allow T cells to enter the allograft, which would further stimulate what is already bout to be a strong immune reaction?

A

2% (apparently thats a lot compared to the % of T cells that can recognize pathogens)

Non-immune injury to the graft will allow T cells to enter the allograft and activates endothelial cells by releasing DAMPs

47
Q

Humoral and Cellular rejections are both effector mechanisms of HVG disease. What Th cell types fit these 2 effector mechanisms?

A

Humoral rejection via Th2 (IL-4, IL-5, and IL-10)

Cellular rejection via Th1 (IL-2, and IFN-gamma)

48
Q

State 3 tissues that often induce GVHD bc of their high number of T cells. Explain how GVHD can still happen, despite matching donor and recipient HLA Ags. What type of patients are these types of reactions commonly seen in?

A

GI, Lung, or Liver

GVHD can occur directed against miHAs (minor histocompatibility antigens)

This is commonly observed in immunocompromised pts (makes sense bc it takes them too long to make an immune response, so the immune response from the graft is what attacks)

49
Q

Compare the symptoms and clinical presentation of Acute and Chronic GVHD.

A

Acute GVHD: epithelial cell death in skin, liver, and GI
Clinically: rash, jaundice, diarrhea, and GI hemorrhage

Chronic GVHD: fibrosis and atrophy of affected organ (this makes the organ dysfunctional)
Clinically: may produce obliteration of small airways

50
Q

Patients on immunosuppressive drugs are more prone to _____ ______ and have a raised incidence of _____.

A

opportunistic infections

Malignancy

51
Q

Briefly describe the mechanism of the following immunosuppressive drug.

Steroids:

A

Steroids: Anti-inflammatory

52
Q

Briefly describe the mechanism of the following immunosuppressive drug.

Cyclosporin A:

A

Cyclosporin A: Inhibits IL-2 gene transcription

53
Q

Briefly describe the mechanism of the following immunosuppressive drug.

Tacrolimus:

A

Cyclosporin A: Inhibits IL-2 gene transcription

54
Q

Briefly describe the mechanism of the following immunosuppressive drug.

Anti-CD25 monoclonal Abs:

A

Anti-CD25 monoclonal Abs: inhibits IL-2 function

55
Q

Briefly describe the mechanism of the following immunosuppressive drug.

Sirolimus:

A

Sirolimus: Inhibits Cytokine-mediated signals

56
Q

Briefly describe the mechanism of the following immunosuppressive drug.

Anti-CD3 monoclonal Abs:

A

Anti-CD3 monoclonal Abs: Inhibits T cell activation, opsonization, and depletion

57
Q

What group of medications do prednisolone and methylprednisolone fall under? What are their 3 modes of action?

A

prednisolone and methylprednisolone = glucocorticosteroids

  1. Inhibition of T cell proliferation
  2. Transcriptional inhibition of proinflammatory genes
  3. Induction of lymphocyte apoptosis
58
Q

What is another name for OKT 3? where in the cell does it carry out it’s function?

A

OKT 3 = Anti-CD3 mAb (mAB = monoclonal antibody)

OKT3 blocks the function of CD3 on the membrane of human cells

59
Q

OKT3 is used to treat which 2 types of graft rejection? OKT3 is used in a prophylactic or treatment method of allograft rejection in all types of_____ _____ transplants

A

Acute or steroid-resistant rejection

solid organ

60
Q

State the 4 mechanisms of OKT 3 action

A
  1. Coating: Once a lot of Abs bind, the cell prevents the T cell from conducting any cell-to-cell signalling
  2. Depletion: Either activating complement or opsonizing the T cell to be destroyed by Macrophages
  3. TCR down-modulation: “boxing out” the TCR molecules from causing too large of an immune response
  4. Cell signalling: If it’s a pathogenic T cell this induces anergy. If it’s a regulatory T cell, it stimulates an immune response
61
Q

What is CsA (Cyclosporin) and where does it come from? Describe its 2 mechanism

A

CsA is a peptide that is isolated from fungus species

CsA inhibits the Calcium-dependent pathway of T cell activation by preventing calcineurin from activating NFAT (keeps it phosphorylated and outside of the nucleus)

With NFAT remaining phosphorylated, it cannot induce the production of Cytokines that would otherwise stimulate an immune response

62
Q

What types of organ transplants is CsA used for and in what manner?

A

CsA is used for ALL types of organ transplants

It is used in an immunoprophylaxis manner

(Tacrolimus is used for the exact same situations, it just does less damage to the kidneys)

63
Q

Describe the mechanism of Tacrolimus

A

inhibits T cell activation in the same way CsA does, by inhibiting the translocation of NFAT into the nucleus via an interruption in the Calcineurin-calmodulin complex

(This prevents the transcription of IL-2, IL-3, IL-4, IL-5, IFN-gamma, TNF-Beta, and GM-CSF)

Immunology 2019 (22 decks)

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