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Lecture 3 Flashcards

1
Q

Features of mesenchymal stem cells

A
  • adult stem cells
  • multipotent
  • isolated from many tissues
  • adherent, fibroblastoid-like cells
  • plasticity-differentiate in vitro
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2
Q

What are the functions of mesenchymal stem cells?

A
  • aid in tissue repair
  • Immunosuppressive and immunoregulatory activity
  • hypo-immunogenic
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3
Q

Immunosuppressive & immunoregulatory activity of MSC

A
  • respond to inflammation by homing to affected tissues

- control inflammatory and immunological reactions locally at site

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4
Q

Hypo-immunogenic properties of MSCs

A
  • Low/moderate expression class I HLA antigens
  • Negative for class 2 HLA antigens & CD40, CD80, CD86
  • Escape recognition by allo-reactive T cells and NK cells
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5
Q

What is the universal donor type cell?

A

Mesenchymal Stem Cells

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6
Q

Features of Bone Marrow Mesenchymal Stem Cells (BM MSC)

A
  • Rare (0.01-0.001% TNC)
  • Isolated and expanded ex-vivo –> phenotype and function maintained
  • fate determined by engraftment env.
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7
Q

What are the functions of BM MSCs?

A
  • constitute connective tissue scaffolding
  • support haemopoiesis
    o Secrete cytokines, chemokines, GFs
    o Promotes cell interactions driving prolif,
    expansion and diff. of haemopoietic cells
  • Able to differentiate into different cell types
  • Immunosuppressive & Immunoregulatory activity
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8
Q

What are the cellular targets of MSC - Innate Immunity

A
  • NK cells
  • Neutrophil
  • Macrophage
  • Dendritic Cell
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9
Q

Effects of MSC on NK cell targeting

A

Inhibits cells activation and proliferation

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10
Q

Effects of MSC on Neutrophil cell targeting

A

Inhibits neutrophil apoptosis

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11
Q

Effects of MSC on Macrophage cell targeting

A

Inhibits pro-inflammatory cytokine secretion

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12
Q

Effects of MSC on dendritic cell targeting

A

Inhibits differentiation from monocyte, expression of co-stim molecules, pro-inflam cytokine secretion

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13
Q

What are the cellular targets of MSC - Adaptive Immunity

A
  • Effector T cells
  • Cytotoxic T cells
  • Regulatory T cells
  • B cells
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14
Q

Effects of MSC on effector T cell targeting

A
  • inhibit T cell proliferation, pro-inflam cytokine secretion
  • promotes anti-inflam cytokine secretion
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15
Q

Effects of MSC on cytotoxic T cell targeting

A
  • inhibits CTL activation

- inhibits IFNy

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16
Q

Effects of MSC on Regulatory T cell targeting

A
  • supports generation of Tregs
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17
Q

Effects of MSC on B cell targeting

A
  • inhibits B-cell proliferation and Ig production
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18
Q

What is the immunomodulatory activity of MSC

A
  • MSC sense inflammation and adopt pro- or anti-inflammatory phenotype
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19
Q

Anti-inflammatory MSC

A

MSC (high lvls cytokines IFNy-TNFa) –> MSC2 (TRL3 ligation) –> CD4+, CD25+ FOXP3 + Treg cell

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20
Q

Pro-inflammatory MSC

A

MSC (low lvls cytokines IFNy/TNFa) –> MSC1 (TLR4 ligation) –> Activated T cell

21
Q

What are the clinical application of MSCs? (3)

A
  • Immunomodulation
  • Tissue Repair
  • Haemopoiesis
22
Q

What are the 3 types of MSC immunomodulation?

A

Graft v Host
Host v Graft
Autoimmune v Host

23
Q

What are the current MSC clinical trials (and their %) (4)

A
  • BM-MSC (70%)
  • Allogenic MSC (53%)
  • Placenta MSC (17%)
  • Adipose MSC (9%)
24
Q

What are the 4 phases of clinical trials?

A

Phase I: safety
Phase II: Efficacy & Safety
Phase III: Efficacy
Phase IV: Monitoring Effectiveness

25
Q

Phase I clinical trials

A

SAFETY

–> sml group ppl, first time intervention

26
Q

Phase II clinical trials

A

SAFETY & EFFICACY

–> lrgr group ppl determine efficacy & evaluate safety

27
Q

Phase III clinical trials

A

EFFICACY
–> compare intervention to others
Monitor adverse effects

28
Q

Phase IV clinical trials

A

MONITORING EFFECTIVENESS

–> monitor effectiveness of approved intervention in general pop. collect info on adverse effects

29
Q

What are the positive MSC markers? (3)

A
  • CD105
  • CD73
  • CD90 +ve (>90%)
30
Q

What are the negative MSC markers (5)

A
  • CD34
  • Cd11b
  • CD19
  • CD45
  • HLA-DR
31
Q

What is the tri-lineage differentiation capacity of MSC?

A
  • adipogenic
  • osteogenic
  • chondrogenic
32
Q

Adipogenic features & staining

A 
- stimulants 
o Dexamethasone
o Insulin
o Indomethacin 
o isobutyl methyl xanthine
  • Stained with Oil Red O stain
  • neutral lipid globules
33
Q

Osteogenic feature & staining

A
  • stimulants
    o Dexamethasone
    o Asorbic acid 2 phosphate
    o B glycerophosphate
  • stained w Von Kossa Stain
  • caclium deposits
34
Q

Chondrogenic features & staining

A 
- stimulants 
o TGF-B
o Dexamethasone
o Ascorbic Acid phosphate
o Sodium pyruvate
o L proline 
o ITS X
  • Stained w Alcian Blue Stain
  • Sulphated PG
35
Q

What is GVHD

A

Graft versus host disease

36
Q

Define GVHD

A

Functional immune cells in donor graft recognise the recipient as foreign and mounts an immunological attach

37
Q

Where does GVHD commonly occur?

A
  • skin
  • liver
  • GI tract
38
Q

Acute GVHD stats

A
  • develops in 40% related and 70% unrelated grafts

- -> related to degree of HLA disparity donor and recipients

39
Q

Chronic GVHD stats

A
  • develops in 50-60%

- infection leading cause of non-relapse death

40
Q

What are the phases of acute GVHD

A

Early Phase
Second Phase
Third Phase

41
Q

Early phase acute GVHD

A
  • host tissue injury –> mucosa, liver
  • Activated cells from damaged tissue produce cytokine storm
    o TNFa, IL-1, IL-6, GM-CSF, IFNy
    o Leakage of lipopolysaccharide from mucosa
  • cytokines cause up-regulation of host MHC antigens
42
Q

Second phase acute GVHD

A
  • Activation and expansion of infused donor immune cells
  • antigen presentation & activation of infused T cells polarised to Th1 immune pthwy
  • Activated donor T cells expand, produce IL2, IL1a, differentiate into effector cells
43
Q

Third phase acute GVHD

A
  • Activated T cells release IL2, GM-CSF, TNFa, IFNy (Th1 resp.)
  • Recruit monocytes, NK cells
  • Ultimately tissue damage produced by cytotoxic T cell lymphocytes (CTL)
44
Q

What is an example of host versus graft disease?

A

Solid organ transplant

  • chronic lung rejection & acute renal rejection
45
Q

What are the clinical challenges of organ transplant? (4)

A
  1. Explantation/Preservation damage
  2. Ischaemia repurfusion damage
  3. Acute rejection
  4. Chronic rejection
46
Q

What is Ischaemia Repurfusion Injury?

A
  • tissue injury following re-establishment of circulation, in particular where donor organ cold-ischaemia prolonged

Risks:

  • delayed graft function
  • graft dysfunction
  • increased immunogenicity of graft
47
Q

What is an example of Host v Host disease?

A

Autoimmune Disease - Crohn’s disease

48
Q

Crohn’s disease

A

= chronic, uncontrolled inflammation of intestinal mucosa

  • segmental and granulomatous changes
  • etiology unknown
  • chronic relapsing & remitting course
  • current treatment - antibiotics, corticosteroids, immunosup. drugs

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