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Immunology (aimen n) - use these > Transplantation & Immunosuppressive Drugs > Flashcards

Transplantation & Immunosuppressive Drugs Flashcards

1
Q

What is transplantation?

A

Transplantation is the introduction of biological material (eg organs, tissue, cells) into an organism

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2
Q

How does the immune system hinder transplantation?

A

The immune system has evolved to remove non-self

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3
Q

What are the different types of donor/recipient relationships?

A

-Autologous
-Syngeneic
(In these 2 donor/recipient relationships , donor and recipient is genetically identical = no immunological reactions)
-Allogeneic

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4
Q

What is an autologous transplantation?

A

Transplant biological material from one part of the organism into the same organism

e.g. skin graft - take skin from 1 part of the body and graft it onto another part of the body

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5
Q

Why is an immune response against autologous transplants unlikely?

A

May be inflammatory responses but no expected immune response as it is self transplant e.g. skin transplant

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6
Q

What is a syngeneic transplant?

A

Donor biological material is transplanted into recipient when donor and recipient are genetically identical e.g. twins

  • no immunological reaction
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7
Q

What is an allogeneic donor/recipient relationship?

A

Donor and recipient are from the same species but are genetically different e.g. relatives: close genetic match (e.g. brother/sister)

= immune system reacts to the donated biological material

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8
Q

What is a xenogeneic donor/recipient relationship?

A

Donor and recipient are different species

e.g. pigs/bovine heart valves into humans in heart valve transplantation

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9
Q

What is histocompatibility?

A

Histocompatibility = tissue compatibility (compatibility b/w donor tissue and the recipient)

MHC = major histocompatibility antigens

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10
Q

Why do immune responses occur against transplants?

A

Immune responses to transplant are caused by genetic differences (histocompatibility differences) between the donor and the recipient

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11
Q

What is the major cause of transplant rejection?

A

MHC incompatibility

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12
Q

What is the human MHC?

A

Human MHC = Human Leukocyte Antigen

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13
Q

Describe the diversity of HLA classes

A

3 class I HLA alleles: HLA A, B & C

3 Class II HLA alleles (dimers)

  • Thousands of Class I + Class II HLA alleles in a region of chr 6
  • Each individual has 2 HLA A alleles + 2 HLA B alleles, + 2 HLA C alleles
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14
Q

Which cells express the different MHC molecules?

A

All nucleated cells express MHC Class I but only immune cells express MHC II molecules

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15
Q

Describe HLA Class I expression frequency

A

Even most common (A2) HLA can be classified into dozens of subtypes - lots of variability despite same HLA

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16
Q

What epitopes are present on donor MHC molecules?

A

B-cell epitopes on donor MHC

T-cell epitopes derived from donor MHC

1000’s of HLA alleles but perhaps only 100’s of epitopes

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17
Q

What technique is used to identify differences b/w donor HLA(MHC) and recipient HLA(MHC) alleles?

A

Next generation sequencing

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18
Q

What is the role of T cells in MHC Interaction?

A

T cells recognise foreign (non-self) peptides that are bound to self-MHC

CD8+ T-cells (cytotoxic T-cell) TCR interacts w MHC I(HLA) + the epitope it is expressing
CD4+ T-cells (helper T-cells) TCR interacts w MHC II (HLA) + the epitope in its binding groove

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19
Q

How do APCs express MHC molecules?

A

APC will express MHC (I/II) molecules where peptides bind in their variable region grooves

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20
Q

How do T cells recognise MHC molecules?

A

TCR detects both peptide and MHC complex

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21
Q

What cells do MHC I molecules activate?

A

MHC I activates TCR CD8+ cells

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22
Q

What cells do MHC II activate?

A

MHC II activates TCR CD4+ cells

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23
Q

What molecules do T cells recognise by MHC I presentation?

A

T cells recognise short peptide fragments that are presented to them by MHC) proteins (intracellular pathogens) e.g. viral infection

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24
Q

How are viral proteins processed?

A

Viral proteins are degraded by proteasome into peptides

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25
Q

How do MHC bind to viral peptides?

A

Peptides attract and bind MHC molecules that are then transported to cells surface

CD8 T cells can now interact

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26
Q

How are external pathogens cross presented?

A

Professional APCs (dendritic) can internalise external peptides and cross present onto MHC Class I pathway => CD8+ activation

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27
Q

Where does MHC II loading occur?

A

Only on professional APCs & WBCs

- immune cells

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28
Q

Describe the process of MHC II loading

A
  1. External antigens processed in phagolysosome into peptides
  2. Peptides interact with vesicles containing MHC and CLIP
  3. Vesicular complex transferred to surface
  4. CD4+ T cells activated
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29
Q

What is the role of the CLIP protein in MHC II loading?

A

Maintains HLA shape until peptide is ready to bind

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30
Q

What molecules do MHC I bind?

A

Fragments of intracellular proteins

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31
Q

Which molecules do MHC II bind?

A

Fragments of proteins which have been taken up by phagocytosis (APC)

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32
Q

What is the role of T helper cells (CD4+ T-cells)?

A

Helper T cells (CD4+ T-cells) are required to produce antibody and cytotoxic T-cell responses
CD4+ T-helper cells orchestrate the nature of the immune response

  • Provide information about the nature of the infection by presenting epitopes (peptides) on HLA II
  • Provides support to other immune cells via cytokine production = activates/inhibits B-cell responses, activates/inhibits cytotoxic T-cell responses (depending on cytokine production - IL2 / IFNgamma / IL10)
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33
Q

What is the role of cytotoxic T cells?

A

Highly specific killer cells

Lyse cells that present epitope (peptide) on their HLA I that the T-cell is specific to

Cytotoxic T-cells kill virally-infected cells/cancer cells/transplant(foreign) cells

34
Q

What is the ‘foreign’ proteins are detected in transplant rejection?

A

In transplants, both the MHC protein and the peptide in its binding groove may be foreign

detected by TCR or antibody binding = various mechanisms by which the recipient’s immune system can reject donor transplantation

35
Q

Describe how recipient cells may induce T cell activation

A

Recipient Cell:

No T-cell activation
- Self HLA + self peptide

T-cell activation
- Self HLA + non self peptide

36
Q

How may donor cells induce T cell activation?

A

Donor cell:

No T-cell activation
- Matched HLA + peptide

T-cell activation
- Unmatched HLA + peptide

37
Q

How are donors matched to recipients?

A 
Usually try to match 4/6 MHC class II loci, reduces likelihood of future transplants and problems with future transplants
- HLA mismatch reduces graft survival
38
Q

What is the inflammation state of transplant recipients?

A

Recipients will have a history of disease which will have resulted in a degree of inflammation

39
Q

What is the caution of using deceased donors?

A

Organs from deceased donors are also likely to be in inflamed condition due to ischemia

40
Q

How is transplant success affected by live / deceased donors?

A

Transplant success is less sensitive to MHC mismatch for live donors

41
Q

What are the 3 types of transplant rejection?

A
  1. Hyperacute rejection
  2. Acute rejection
  3. Chronic rejection
42
Q

How soon after transplant does a hyperacute rejection occur?

A

Within a few hours of transplant

43
Q

When is hyperacute rejection commonly seen?

A

Most commonly seen for highly vascularised organs (e.g. kidney)

(highly vascularised = greater immune system access)

44
Q

What causes a hyperacute rejection?

A

Pre-existing antibodies, usually to ABO blood group antigens or MHC-I proteins

(ABO antigens are expressed on endothelial cells of blood vessels in the transplanted tissue)

45
Q

Where do MHC antibodies come from?

A

Antibodies to MHC can arise from pregnancy, blood transfusion or previous transplants

46
Q

How do antibodies cause damage to transplanted tissues?

A

Antibody binds to the non-self MHC/ABO antigen = Fc antibody region(not bound) is recognised by Complement/NK cells

Recognition of Fc region leading to -

  1. Complement activation
  2. Antibody-dependent cytotoxicity (Fc Receptors on NK cells)
  3. Phagocytosis (Fc Receptors on macrophages)
47
Q

Describe how a hyperacute rejection occurs

A
  1. Antibodies bind to endothelial cells
  2. Complement fixation
  3. Accumulation of innate immune cells (NK cells, phagocytes) - phagocytose + lyse endothelial cells in transplanted tissue
  4. Endothelial damage, platelets accumulate, thrombi develop = tissue death, transplant failure
48
Q

What is acute rejection?

A

Inflammation activates the transplant organ’s resident dendritic cells

DCs induce a T cell response due to MHC mismatch

49
Q

Outline how direct allorecognition of a foreign MHC occurs

A
  1. Kidney graft dendritic cells activated
  2. DC migrate to spleen and activate effector T cells
  3. Effector T cells migrate to graft via blood
  4. Graft destroyed by macrophages + CTLs
  5. Inflammation activates transplant organ’s DCs
  6. DCs migrate to secondary lymphoid tissue + encounter recipient T-cells
  7. T-cells recognise foreign MHC = induces direct allorecognition
  8. T-cells + macrophages target transplanted tissue + destroy transplant
50
Q

When does chronic rejection occur?

A

Occurs months/years after transplant

51
Q

What are the effects of chronic rejection?

A

Blood vessel walls thickened, lumina narrowed – loss of blood supply
Correlates with presence of antibodies to MHC-I

52
Q

How does chronic rejection arise?

A

Chronic rejection results from indirect allorecognition of foreign MHC/HLA

53
Q

Describe how indirect allorecognition occurs

A
  1. Donor-derived cells die
  2. Membrane fragments containing donor MHC are taken up by host DC
  3. Donor MHC is presented into peptides presented by host MHC
  4. T cell response generated to peptide derived from processed donor MHC
54
Q

What is HSCT?

A

Haematopoietic Stem Cell Transfer (HSCT)

Previously called bone marrow transplant, now renamed as source is often blood.

Often autologous

55
Q

What are the advantages of HSCT?

A

HSCs find their way to bone marrow after infusion and regenerate there

HSCs can be cryopreserved with little damage

56
Q

What is GVHD?

A

Graft Vs. Host Disease

When transplanted tissue is immune cells themselves, there is the risk of donor immune cells attacking the host

The host (transplant recipient) is seen as non-self = GVHD. Transplant is targeting the host (NOT THE HOST/RECIPIENT TARGETING THE TRANSPLANT)

57
Q

How to reduce GVHD?

A

Can be lethal – best approach is prevention

Remove T cells from transplant or Suppress T-cell function using immunosuppressive drugs

58
Q

What is GVL?

A

Graft Vs. Leukaemia

59
Q

Why is GVL sometimes a good thing?

A

Sometimes mismatch and donor leukocytes can be beneficial - removing original leukemia

Development of GVL may prevent disease relapse

(the graft can identify + kill leukaemia cells, which necessitated the graft in the first place)
graft sees leukaemia as non-self.
recipient’s original immune response partially sees leukaemia as self = weaker immune response against tumour cells.

60
Q

What is the significance of immunosuppression for transplants/?

A

Essential to maintain non-autologous (allogeneic) transplant.

3 phases of treatment:

  • Induction - Antibody induction therapy + Triple drug regimen(calcineurin inhibitor + antiproliferative agent + corticosteroid)(high doses)
  • Maintenance - Triple drug regimen at lower doses
  • Rescue - T-cell mediated rejection = treat with ATG + high dose steroids. B-cell mediated rejection = treat with IV Ig(derived from other ppl) OR anti-CD20 monoclonal antibodies(depletes B-cells by binding to CD20 on B-cells) + high dose corticosteroids(for both)

rescue phase if transplant rejection occurs

61
Q

What immunosuppressors are used for transplants?

A

General immune inhibitors:
- e.g. corticosteroids

Cytotoxic = specific:

  • kill proliferating lymphocytes
  • e.g. mycophenolic acid, cyclophosphamide, methotrexate

Inhibit T-cell activation:
- cyclosporin, tacrolimus, rapamycin

62
Q

What is a cost-effective drawback of using immunosuppressives?

A

Immunosuppressives may need to be maintained indefinitely

63
Q

What is cyclosporin?

A

Inhibits recipient immune response to donor transplant.

Blocks T cell proliferation and differentiation.

Breakthrough drug for transplant - enables transplants to survive for longer in recipients.

Next generation therapies developed are less toxic and effective at lower doses.

64
Q

T-cells and MHC I

Cell processes the protein and cell’s MHC I presents the peptide to T-cells

A
  1. T-cells recognise short peptide fragments that are presented to them by cell
  2. In the cell, the protein is internalised in the cell - acts as a viral protein/is MHC protein itself
  3. Proteasome degrades the protein into peptides
  4. ER transports these peptides to MHC I
  5. MHC I travels to cell surface
  6. TCR recognises MHC I + the peptide it presents

2-6 occur in the cell

65
Q

T-cells and MHC II

A
  1. Antigen is internalised from extracellular spaces by phagolysosome
  2. Protein is lysed into peptides
  3. These peptides are transferred to MHC II
  4. MHC II-peptide complex is presented on APC cell surface

MHC II , CD4 , Extracellular antigens (e.g. antibody-bound viral particles/dead cells

66
Q

What is allorecognition?

A

Allorecognition = T-cells are activated to respond to transplanted material

  • Direct allorecognition
  • Indirect allorecognition
67
Q

Recipient Cell

A

Self-HLA presents self-peptide to self-TCR = no immune response.
If immune response occurs here = autoimmunity
Self-HLA + self-peptide = no T-cell activation

Self-HLA presents foreign peptide to self-TCR.
Self-HLA + non-self peptide = T-cell activation.

68
Q

Indirect allorecognition

A

Partial matching b/w donor + recipient HLA

1 HLA which does match (self) could present a foreign peptide which does not match. Immune system recognises as foreign.

The T-cells activated to this self-HLA, non-self peptide then find this same combination on transplanted cells

69
Q

Donor cells

A

If the donor cell has matched HLA + self-peptide , no T-cell activation
If matched donor HLA presents a foreign peptide(from an unmatched HLA) = targeting of transplant in indirect allorecognition

Unmatched donor HLA presents non-self epitope from the HLA itself = TCR binding/antibody binding of unmatched HLA = causes direct allorecognition

70
Q

The more donor/recipient HLA mismatches =

A

The more donor/recipient HLA mismatches = the less successful the transplant will be, lower graft survival

71
Q

What happens in chronic rejection?

A

Alloantibodies bind to antigens + endothelial cells of the transplanted organ and recruit other immune effector cells - macrophages, cytotoxic T-cells, which induce damage + reduce blood supply to the organ.

Alloantibodies to MHC I of the transplanted organ

For chronic rejection, the MHC protein + its peptide in the binding groove may be foreign

In chronic rejection, the Anti-transplant immune responses are induced from a type of indirect allorecognition

Donor-derived cells die (e.g. donor HLA) + the dying cells are internalised by recipients’ DCs = donor HLA is presented on recipient HLA = recipient HLA induces T-cell + antibody responses generated from the peptides derived from donor’s MHC

72
Q

What do HSCs do when they reach the bone marrow after infusion?

A

produce common precursors for lymphocytes = B-cells, T-cells, activated effector T-cells, plasma cells that produce Abs, granulocyte progenitors, basophils, neutrophils, eosinophils, monocytes, DCs, macrophages, mast cells, RBCs

73
Q

Combination immunosuppressive regimes

A

1 - Steroids
2 - Cytotoxic
3 - Immunosuppressive specific for T-cells

74
Q

What does calcineurin inhibitor inhibit?

A

Calcineurin inhibitor inhibits IL2 production

75
Q

What do antiproliferatives do?

A

antiproliferatives inhibit B-cell/T-cell proliferation

76
Q

what do corticosteroids do?

A

corticosteroids = anti-inflammatory

77
Q

what do monoclonal antibodies do?

A

monoclonal antibodies = costimulation blockers

78
Q

what do antithymocyte globulins do?

A

antithymocyte globulins inhibit/deplete T-cells

79
Q

What are the negative consequences of immunosuppression?

A

Immunosuppression to prevent transplant rejection also reduces recipient ability to fight infection/tumorigenesis.
-Transplant patients are more susceptible to CMV infection

Immunosuppressive drug toxicity causes organ failure e.g. cyclosporin induces nephrotoxicity in kidney transplant

80
Q

What new area has been found to be involved in transplant immunity?

A

The microbiome of the intestine is involved in regulating adaptive immune responses

= may be useful in transplantation outcomes

81
Q

Summary

A

• Transplant rejection results from genetic differences
between donor and recipient – variability between MHC
proteins is the major genetic difference in transplant
rejection
• Host attacks transplant – rejection (hyperacute, acute,
chronic)
• Transplant attacks host – GVHD
• Immunosuppression can prolong the survival of
transplanted organs

Immunology (aimen n) - use these (14 decks)

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