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BC4022 AM > Lecture 3 > Flashcards

Lecture 3 Flashcards

1
Q

Key developments in drugs that allowed us to develop organ transplantation

A
  • Sandimmune (cyclosporine)
  • OKT3 Abs (bind to CD3 to deplete T cells)
  • FK506 (Tacrolimus): calcineurin inhibitor
  • CellCept (mycophenolate mofetil): IMPDH inhibitor
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2
Q

What technology had a major influence in creating transgenic pigs?

A

CRISPR

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3
Q

Tissue graft between genetically identical individuals

A

Isograft (syngeneic)

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4
Q

Tissue graft from one individual to another of the same species

A

Allograft (allogeneic)

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5
Q

Tissue graft between individuals of different species

A

Xenograft (xenogeneic)

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6
Q

How is organ rejection genetically controlled?

A

through MHC matching

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7
Q

The MHC in humans

A

HLA (human leukocyte antigen)

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8
Q

MHC Class I genes

A

HLA-A, -B and -C

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9
Q

MHC Class II genes

A

HLA-DR, -DP and -DQ

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10
Q

Typically, a person expresses __ different MHC Class I and __ different Class II molecules on their cell surface

A

6 Class I
8 Class II

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11
Q

Example of disease resistance being linked to MHC

A

HLA-B53 strongly associated with recovery from malaria

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12
Q

Example of autoimmune disease susceptibility being associated with MHC

A

HLA-DR4 associated with an increased risk of developing rheumatoid arthritis

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13
Q

MHC Class I alloantigens stimulate…

A

strong antibody and CD8+ CTL responses

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14
Q

MHC Class II alloantigens stimulate…

A

CD4+ T cells to become effector T cells, and also stimulate Ab responses

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15
Q

What is the basis of rejection?

A

Different MHC, and different peptide epitope within the MHC

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16
Q

Direct pathway for mediating allograft rejection

A

Recipient T cell recognises donor MHC as foreign, and the donor epitope within it as foreign

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17
Q

Indirect pathway for mediating allograft rejection

A

Recipient T cell recognises allopeptide within its MHC

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18
Q

Different types of immunological rejection

A
  • Hyperacute rejection
  • Acute graft rejection
  • Chronic rejection
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19
Q

How should hyperacute rejection be prevented?

A

by cross-matching

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20
Q

How can blood type mismatch lead to hyperacute rejection?

A

Recipient has pre-existing Ab against graft. Ab induces complement & activation of clotting pathways. Graft turns into a massive blood clot within mins/hrs of transplantation

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21
Q

Why does acute graft rejection occur?

A

Due to direct recognition of allogeneic MHC

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22
Q

Why does chronic graft rejection occur?

A

Due to failure of immunosuppressants (takes many months to years)

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23
Q

What is the target of chronic rejection in renal and cardiac transplants?

A

Vasculature (thickening of arterial walls, which can lead to arterial occlusion & ischaemia)

24
Q

Chronic rejection is mediated by…

A

both T cells and antibodies (alloantigen important)

25
Q

GVHD happens particularly in…

A

allogeneic bone marrow transplants (lymphocytes within graft recognise the recipient as foreign)

26
Q

What is a major mediator of pathology in GVHD?

A

TNF

27
Q

How to prevent immunological rejection

A
  1. Blood types
  2. Cross matching
  3. HLA typing
  4. Immunosuppression (induction therapy, maintenance therapy, treatment of rejection episodes)
28
Q

What is induction immunosuppression therapy?

A

Delivery of intense immunosuppression at the time of transplantation to ensure that the immune system is stopped in its tracks when being provoked by the arrival of a foreign graft

29
Q

Examples of induction immunosuppression therapies

A
  • IL-2 receptor antagonists (e.g. Basiliximab) to block T cell proliferation (anti-CD25 mAbs)
  • Immediate-release tacrolimus
  • Mycophenolate mofetil
  • Anti-T cell antibodies e.g. rabbit anti-thymocyte globulin (rATG), OKT3 (withdrawn)
  • Anti-CD52 mAb: Alemtuzumab (Campath-1H) - long-term T cell depletion
30
Q

What is maintenance immunosuppression therapy?

A

If immunosuppression is removed, the donor graft will be immunologically rejected. A balance needs to be achieved between adequate dampening of the immune response to prevent graft rejection while limiting drug toxicity and also maintaining sufficient immune responsiveness for the patient to combat infection.

31
Q

Examples of maintenance immunosuppression therapies

A
  • Calcineurin inhibitors (tacrolimus, cyclosporine)
  • Purine metabolism inhibitors (azathioprine, mycophenolate mofetil)
  • mTOR inhibitors (Rapamycin) - often used with steroids
32
Q

How are rejection episodes treated?

A
  • Intravenous immunoglobulin
  • Plasmapheresis
  • Anti-CD20 mAb Rituximab
  • A variety of anti-T cell agents
33
Q

Classic anti-proliferative drugs used in immunosuppression

A
  • Azathioprine (inhibits purine synthesis)
  • Methotrexate (inhibits dihydrofolate reductase)
  • Mycophenolate (inhibits IMPDH i.e. purine synthesis)
  • Leflunomide (inhibits pyrimidine synthesis)
34
Q

Immunosuppressive drugs that will prevent the IL-2 growth signal from being enhanced?

A
  • Cyclosporine
  • Tacrolimus
  • Steroids
35
Q

How does calcineurin ultimately cause T cell proliferation?

A

Calcium binds calcineurin (phosphatase), which dephosphorylates NFAT transcription factors in T cells, which translocate into nucleus to activate genes involved in T cell activation. IL-2 is then produced by activated T cells to further drive T cell proliferation.

36
Q

A key signalling protein involved in the IL-2 receptor cascade

A

mTOR (mammalian target of rapamycin)

37
Q

What does Tacrolimus bind to?

A

FK506 binding protein (FKBP), to prevent dephosphorylation of NFAT

38
Q

How does Rapamycin work?

A

By binding to FKBP, which blocks mTOR kinase (instead of calcineurin). Inhibits lymphocyte responses to cytokines, ultimately preventing T cell proliferation (cell cycle arrest).

39
Q

What is Cyclophosphamide?

A
  • A type of chemotherapy
  • Immunosuppressant
  • DNA alkylating agent
  • Used for BMT
40
Q

Calcineurin inhibitors are very effective in transplantation. What are other less obvious effects of calcinuerin inhibitors?

A
  • Stimulation of TGF-β expression
  • Inhibition of IgE-stimulated mast cell degranulation
41
Q

New generation Rapamycin (Sirolimus)

A

Everolimus (improved bioavailability, shorter half-life)

42
Q

Cyclosporine commonly used with __ to prevent allograft rejections in renal, hepatic and cardiac transplants, and in RA and psoriasis

A

prednisone & other immunosuppressants

43
Q

Cyclosporine use is delayed post-transplantation due to…

A

neurotoxicity concerns

44
Q

What is tacrolimus approved for?

A
  • Prevention of solid-organ allograft rejection
  • Eczema (topical)
45
Q

Cyclosporine binds __ to form a complex that inhibits calcineurin

A

Cyclophilin

46
Q

Which is a more potent inhibitor of IL-2 synthesis: tacrolimus or CsA?

A

Tacrolimus (also less need for steroids compared to CsA)

47
Q

Common side effect of calcineurin inhibitors

A

Nephrotoxicity

48
Q

What is Rapamycin used for?

A
  • Prophylaxis of organ transplant rejection, in combination with a calcineurin inhibitor & glucocorticoids
  • Also used to sensitise cancer cells to other chemotherapies
49
Q

Glucocorticoids are used with other __ to prevent transplant rejection and GVHD by…

A

immunophilin inhibitors
by inhibiting production of pro-inflammatory cytokines and promoting production of anti-inflammatory cytokines

50
Q

Very high doses of which glucocorticoid used during acute organ rejection?

A

Methylprednisolone (IV)

51
Q

Glucocorticoids used before and after anti-thymocyte Abs to…

A

inhibit allergic reactions

52
Q

What is a major side effect of glucocorticoid administration due to high doses needed for immunosuppression?

A

Cushing’s syndrome (‘moon face’)

53
Q

Mycophenolate mofetil administered with __ for renal transplants

A

cyclosporine and prednisone

54
Q

Common first choice DMARD

A

Sulphasalazine (inhibits T cell proliferation & B cell activation)
- 5-ASA moeity inhibits COX & 5-LO
- Also inhibits NF-κβ

55
Q

Azathioprine (pro-drug) is metabolised to give __ , which inhibits __

A

6-mercaptopurine (anti-metabolite) - inhibits DNA synthesis

56
Q

How does methotrexate inhibit DNA synthesis?

A

It inhibits dihydrofolate reductase (higher affinity for DHFR than does FH2), depletes FH4 in cell and prevents production of thymine and, therefore, inhibits DNA synthesis.

57
Q

Two approaches to treating IBD

A
  • Induce remission
  • Maintain remission

BC4022 AM (8 decks)

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