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Immunology - Unit 4 - Zach H. > Transplantation Immunology > Flashcards

Transplantation Immunology Flashcards

1
Q

The discovery of what drug has allowed the widespread practice of transplantation?

A

Immunosuppressive drugs - steroids discovered in late 1940’s.

  • *steroids inhibit NFkappaB**
  • *immunosuppressants used now to target IL-2 gene inhibition**
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2
Q

What is the most important risk in patients that are taking immunosuppresive drugs?

A

developing cancer

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3
Q

The work of what scientist has led to the development of the immunological basis of graft rejection?

A

Sir Peter Medawar

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4
Q

How are transplant grafts classified?

A

On the basis of the genetic relationship between the host and the donor.

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5
Q

What are the 4 classifications of grafts?

A
  • autografts
  • isografts
  • allografts (allogeneic)
  • xenografts (xenogeneic)
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6
Q

What is an autograft?

A

Grafts exchanged from one part to another part of the same individual.

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7
Q

What is an isograft?

A

Grafts exchanged between different individuals of identical genetic constitutions (e.g., identical twins).

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8
Q

What is an allograft?

A

Grafts exchanged between non-identical members of the same species.

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9
Q

What is a xenograft?

A

Graft exchanged between members of different species.

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

** the insertion of human genes into the genomes of the donor animals (miniature swine) increases the chances of successful survival

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10
Q

List evidence that transplant rejection is an immune reaction.

A

> Prior exposure to donor MHC molecules leads to accelerated graft rejection - (conclusion) graft rejection shows memory and specificity - 2 key features of adaptive immunity.

> The ability to reject a graft rapidly can be transferred to a naive individual by lymphocytes from a sensitized individual - (conclusion) graft rejection IS mediated by lymphocytes.

> Depletion or inactivation of T lymphocytes by drugs or Abs leads to reduced graft rejection - (conclusion) graft rejection CAN be mediated by T lymphocytes.

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11
Q

How many allelic forms of HLA molecules does each individual inherit?

A

10 -12 alleles/person

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12
Q

True or False:

HLA Ags are co-dominantly expressed.

A

True

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13
Q

What class of HLA molecules are particularly strong barriers to transplantation?

A

Class-I HLA Ags (HLA-A and HLA-B) are particularly strong barriers to transplantation.

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14
Q

What are the three most important class II HLA molecules for transplantation pairs?

A

> HLA-DR
HLA-DP
HLA-DQ

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15
Q

What is the HLA system?

A

Human Lymphocytes Antigen (HLA) System

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16
Q

What is direct allorecognition?

A

> Primary response against graft.

the T cell receptors on recipient T cells directly recognize the donor MHC molecules

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17
Q

What is indirect allorecognition?

A

> the recipient T cells recognize donor MHC molecules that have been processed by recipient APCs.

> the donor MHC molecules are presented as peptides in the context of recipient MHC class II molecules.

> indirect pathway is important during chronic rejection (when the number of donor professional APCs is low to stimulate a direct immune response).

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18
Q

What are the 4 different types of rejection?

A
  • hyperacute
  • accelerated
  • acute
  • chronic
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19
Q

What causes hyperacute rejection?

A

Preformed antidonor Abs and complement.

because recipient has Abs against the Ags of the donor organ

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20
Q

What causes accelerated rejection?

A

Reactivation of sensitized T cells.

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21
Q

What causes acute rejection?

A

Primary activation of T cells.

typical primary exposure to Ag of organ

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22
Q

What causes chronic rejection?

A

Both immunologic and nonimmunologic factors.

it’s not manageable with immunosuppressant therapy

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23
Q

How long does it take for hyperacute rejection to occur?

A

minutes - hours

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24
Q

How long does it take for accelerated rejection to occur?

A

days

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25
Q

How long does it take for acute rejection to occur?

A

days - weeks

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26
Q

How long does it take for chronic rejection to occur?

A

months - years

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27
Q

Is hyperacute rejection due to humoral or cell-mediated immune response?

A

humoral immune response

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28
Q

Is accelerated rejection mediated by humoral or cell-mediated immune response?

A

Mostly humoral - but cellular involved a little bit.

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29
Q

What are the two types of acute rejections?

A
  • cellular

- vascular

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30
Q

Is acute, cellular rejections mediated by humoral or cellular immune responses?

A

> Mostly Th1 - cellular mediated.

> Slight humoral involvement.

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31
Q

Is acute, vascular rejections mediated by humoral or cellular immune responses?

A

> Mostly Th2 - humoral mediated.

> Slight cellular involvement.

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32
Q

is chronic rejections mediated by humoral or cellular immune responses?

A

> Mostly humoral.

> Slight cellular involvement - it contributes, but is not the major problem.

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33
Q

Does Th2 mediate acute vascular or acute cellular mechanism of rejection?

A

Th2 is humoral, acute (vascular) mechanism of rejection.

34
Q

Does Th1 mediate acute, vascular or acute, cellular mechanism of rejection?

A

Th1 is cellular, acute (cellular) mechanism of rejection.

35
Q

What causes hyperacute graft rejection?

A

Caused by the pre-existing Abs binding to the endothelial cells lining the blood within minutes to hours.

> recipient has pre-existing Abs that are reactive with the donor tissue.

> This may be caused by:

  • ABO blood group incompatibility.
  • The recipient has been sensitized to the donor MHC by previous transplants, multiple blood transfusions, or pregnancy.
  • Abs bind to endothelial cells which activates the classical pathway of complement activation.
  • Complement activation can lead to death of the endothelium.

a patient that has had several blood transfusions is very difficult to find a donor match for because they have been exposed to many different donor Ags

36
Q

What plays an important role in triggering acute rejection?

A

Donor DCs (also called passenger leukocytes).

after transplantation, donor DCs migrate to the lymph nodes draining the organ and stimulate a primary recipient response

37
Q

What initiates acute graft rejection?

A

Occurs in days to weeks and is initiated by alloreactive T cells.

38
Q

After transplantation, donor DCs migrate to the lymph nodes draining the organ and stimulate a primary recipient response. What happens next?

A

> Once activated the T cells migrate to the organ and lead to tissue damage by:

  • generation of cytotoxic T cells
  • induction of delayed-type hypersensitivity reactions

> Both CD4 and CD8 T cells can cause graft rejection.

> The indirect response can also contribute to acute rejection.

39
Q

What causes chronic graft rejection?

A

Occurs due to the occlusion of blood vessels and subsequent ischemia of the organ.

> macrophages infiltrate and smooth muscle cell proliferation is often seen.

> main pathogenic mechanism is the indirect pathway.

> Abs can also be involved in chronic rejection (the deposition of complement in graft tissues).

> non-immunologic factors in a chronic rejection may be:

  • ischemia-reperfusion damage
  • recurrence of the disease that caused failure of own kidney
  • the effects of nephrotoxic drugs (e.g., cyclosporine A)

Chronic rejection does not respond to immunosuppressive therapy.

40
Q

What are the non-immunologic factors in a chronic graft rejection?

A

> ischemia-reperfusion damage

> recurrence of the disease that caused failure of own kidney

> effects of nephrotoxic drugs (e.g., cyclosporine A)

41
Q

Does chronic rejection respond to immunosuppressive therapy?

A

No

42
Q

Is the main pathogenic mechanism of chronic graft rejection through the indirect or direct pathway?

A

Main pathogenic mechanism is the indirect pathway.

43
Q

Look over slide 15.

A

Figure of immune mechanisms.

44
Q

What are the 4 variables (key concepts) that determine transplant outcome?

A

(1) The condition of the allograft.
(2) Donor-host antigenic disparity.
(3) Strength of host anti-donor response.
(4) Immunosuppressive regimen.

45
Q

When transplanted, damaged graft tissues release mediators which trigger several biochemical cascades leading to immediate tissue damage. What are these mediators?

A

> Clotting cascade generates fibrin and fibrinopeptides.

> Fibrinopeptides increase local vascular permeability and serve as chemoattractant for neutrophils and macrophages.

> The kinin cascade produces bradykinin that causes vasodilation, smooth muscle contraction, and increased vascular permeability

> These early proinflammatory responses, if uncontrolled, can result in allograft rejection.

46
Q

What are the 4 steps in the donor-recipient work-up?

A

(1) ABO blood group compatibility is first established.
> very strong cell surface Ags found on may other tissues.

(2) Tissue typing to identify class I HLA typing is then performed.
(3) Cross-matching is used to test the recipient serum for preformed Abs against donor’s HLAs.
(4) The mixed lymphocyte reaction may be used to determine if the donor cells stimulate proliferation of the recipient’s lymphocytes (class II HLA typing).

47
Q

What is a barrier to transplantation of solid organs?

A

ABO (blood group antigens)

48
Q

What type of patient has Abs to A and B?

A

Abs to A and B are in individuals without these antigens on their RBCs.

49
Q

ABO matching is not important for what type of transplants?

A
  • Corneal transplantation
  • Heart valve transplantation
  • Bone and tendon grafts
50
Q

True or False:

ABO incompatibility is not a contraindication to stem cell transplantation.

A

True

51
Q

List examples of tissues that express blood group Ags.

A
  • renal

- endothelium

52
Q

What Abs are present in people with A blood type?

A
  • Anti-B Abs

- Ag A present

53
Q

What Abs are present in people with B blood type?

A
  • Anti-A Abs

- Ag B present

54
Q

What Abs are present in people with A/B blood type?

A
  • no Abs

- Ags A/B present

55
Q

What Abs are present in people with O blood type?

A
  • Anti-A/B Abs

- no Ags present

56
Q

What kind of ABO blood can a patient with type A receive?

A

A or O

57
Q

What kind of ABO blood can a patient with type B receive?

A

B or O

58
Q

What kind of ABO blood can a patient with type AB receive?

A

A, B, AB, and O

59
Q

What kind of ABO blood can a patient with type O receive?

A

O

60
Q

What is the success of transplantation dependent on?

A

matching of the MHC Ags

these Ags are encoded by the major histocompatibility complex, MHC class-I and class-II

61
Q

Why is the HLA compatibility between donor and recipient required for a successful transplant?

A

Required due to the extreme polymorphism of HLA.

62
Q

What convenient sources are lymphocytes for HLA typing taken from?

A

> spleen and LN (from cadaver)

> HLA antisera are mostly obtained from multiparous women or from planned immunization of volunteers.

the antisera contain antibodies to HLA Ags

63
Q

Serological Class I HLA Typing

A

> HLA antisera are mostly obtained from multiparous women or from planned immunization of volunteers.

> Antisera contain Abs to HLA Ags.

> Abs bind to HLA Ag on the surface of lymphocytes.

> The Ag-Ab complex formed activates the classical complement cascade and this will result in lymphocytes lysis.

> The lymphocytes lysis can be detected by staining the cells with acridine orange, ethidium bromide, or hemoglobin stain.

64
Q

Look over slides 27-29.

A

Microcytotoxicity Test

65
Q

Why is it important that cross-matching is used to test the recipient serum for preformed Abs against donor’s HLAs?

A

Needed to prevent hyperactive Ab-dependent rejection of graft!

66
Q

How can the presence of preformed Abs cause hyperactive graft rejection?

A

The presence of preformed Abs reactive with various allogeneic HLA Ags can cause hyperactive graft rejection.

recipients are screened for the presence of such Abs by using a microcytotoxicity test with complement-activated cell damage

67
Q

How is the test for preformed Abs performed?

A

Recipient’s serum is mixed with cells of a donor - if there is no cell damage, then a potential donor is identified.

68
Q

Mixed lymphocyte response (class II HLA typing)

A

> Leukocytes from two unrelated individuals are mixed.

> Lymphocytes from the donor are irradiated to stop their proliferation and called stimulator cells.

> Stimulator cells are used for presentation of class II MHC Ags.

> Lymphocytes from the recipient are intact and called responder cells.

> Responder cells will be activated by mismatched class II MHC and proliferate.

> Proliferation (the response) is measured by incorporation of tritiated thymidine.

If class II MHC Ags are the same, no proliferation will occur

69
Q

Give an example of host-versus-graft disease.

A

When a kidney is transplanted the recipient’s T cells attack the transplant.

donor T cell come and expand after exposure to Ag

70
Q

Give an example of graft-versus-host disease.

A

When bone marrow is transplanted the T cells in the transplant attack the recipient’s tissues.

memory B and T cells in bone marrow also expand after exposure to Ag

71
Q

Host versus Graft Responses

A

> The host immune system attacks the donor tissue.

> It is an adaptive immune response against a graft.

> The immune response against a graft is much more vigorous and strong than the response seen against a pathogen.

> This is due to higher frequency of T cells that recognize the graft as foreign:

  • unimmunized individual has The immune memory of previous encounters with donor Ags is important:
  • from animal experiments - if a second graft is performed from the same donor, it is rejected more rapidly.

> Up to 2% of the host T cells are capable of recognizing and responding to single foreign MHC.

> Non-immune injury of the graft (danger signals) activates endothelial cells, and T cells enter the allograft.

> Ag-specific T cells interact with APC and become simulated (activated).

> The inflammatory cytokine/chemokine field is created and causes further activation of APC, endothelium and leukocyte traffic.

> Effector mechanisms of graft rejection:

  • Humoral rejection Th2 (IL-4, IL-5, and IL-10)
  • Cellular rejection Th1 (IL-2, IFN-gamma)
72
Q

Graft-Versus-Host Disease (GVHD)

A

> Hemopoietic-cell transplantation (HCT) is used to treat high-risk hematological malignant disorders and other life-threatening hematological and genetic diseases.

> The main complication of HCT is GVHD, and immunological disorder that affects many organ systems, including the GI, liver, skin, and lungs.

> Many patients with GVHD require continued treatment with immunosuppressive drugs that increases their risks for serious infections.

73
Q

What is given to donors that are donating hematopoietic stem cells (HSCs)?

A

Donors receive granulocyte colony-stimulating factor (G-CSF) to mobilize hematopoietic stem cells (HSCs), which are collected by leukapheresis.

74
Q

How are recipients treated prior to HSC transplant?

A

> The recipients receive chemotherapy (and radiotherapy), which is designed to:

  • prevent immunological graft rejection
  • reduce the number of tumor cells when stem cells are used to treat cancer
  • create niches for HSC engraftment
75
Q

Minor Histocompatibility (miHAs) in HSC Transplantation

A

> In MHC-matched transplants, peptide recognition by donor T cells is equivalent to the recognition of pathogen-derived Ags.

> In MHC-mismatched transplants, the MHC molcule is likely to contribute more to the TCR binding energy than in allorecognition in MHC-matched interactions.

> Because of this, there is greater promiscuity in the identity of peptides that can support TCR recognition of allogeneic MHC molecules.

76
Q

Look over slide 44.

A

Figure showing the initiation phase of GVHD.

77
Q

After the initiation phase of GVHD, what happens next?

A

> Donor APCs can activate donor CD8 T cells by cross-presenting exogenously acquired Ags (through the uptake of apoptotic recipient or shed proteins) on MHC class I molecules.

> In this case, donor APCs could re-prime donor CD8 T cells previously activated by recipient APCs against the same antigens expressed by recipient APCs.

> Alternatively or in addition, donor APCs could activate naive donor CD8 T cells against new, non-hematopoietic Ags (epitope spreading).

78
Q

Besides in bone marrow transplants, what other transplants can GVHD often occur after?

A
  • small bowel
  • lung
  • liver
79
Q

What causes GVHD?

A

Caused by the reaction of grafted mature T cells in the tissue transplant with allo-Ags of the host.

Reaction is directed against miHAs of the recipient (HLA Ags are usually matched).

Occurs in the immunocompromised recipients because their immune system is unable to reject the allogeneic cells in the graft.

80
Q

For solid grafts, what are the classifications of GVHD?

A

> Acute GVHD -> epithelial cell death in the:

  • skin
  • liver
  • GI
  • clinical presentation: rash, jaundice, diarrhea, and GI hemorrhage.

> Chronic GVHD -> fibrosis and atrophy of affected organ.

  • clinical: may lead to complete dysfunction of the affected organ (or two of the same).
  • may produce obliteration of small airways.

Immunology - Unit 4 - Zach H. (5 decks)

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