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Lecture 3 Flashcards

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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

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A

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

21
Q

What are the clinical application of MSCs? (3)

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A
  • Immunomodulation
  • Tissue Repair
  • Haemopoiesis
22
Q

What are the 3 types of MSC immunomodulation?

Study These Flashcards
A

Graft v Host
Host v Graft
Autoimmune v Host

23
Q

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

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

What are the 4 phases of clinical trials?

Study These Flashcards
A

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

25
Phase I clinical trials
SAFETY | --> sml group ppl, first time intervention
26
Phase II clinical trials
SAFETY & EFFICACY | --> lrgr group ppl determine efficacy & evaluate safety
27
Phase III clinical trials
EFFICACY --> compare intervention to others Monitor adverse effects
28
Phase IV clinical trials
MONITORING EFFECTIVENESS | --> monitor effectiveness of approved intervention in general pop. collect info on adverse effects
29
What are the positive MSC markers? (3)
- CD105 - CD73 - CD90 +ve (>90%)
30
What are the negative MSC markers (5)
- CD34 - Cd11b - CD19 - CD45 - HLA-DR
31
What is the tri-lineage differentiation capacity of MSC?
- adipogenic - osteogenic - chondrogenic
32
Adipogenic features & staining
``` - stimulants o Dexamethasone o Insulin o Indomethacin o isobutyl methyl xanthine ``` - Stained with Oil Red O stain - neutral lipid globules
33
Osteogenic feature & staining
- stimulants o Dexamethasone o Asorbic acid 2 phosphate o B glycerophosphate - stained w Von Kossa Stain - caclium deposits
34
Chondrogenic features & staining
``` - 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
What is GVHD
Graft versus host disease
36
Define GVHD
Functional immune cells in donor graft recognise the recipient as foreign and mounts an immunological attach
37
Where does GVHD commonly occur?
- skin - liver - GI tract
38
Acute GVHD stats
- develops in 40% related and 70% unrelated grafts | - -> related to degree of HLA disparity donor and recipients
39
Chronic GVHD stats
- develops in 50-60% | - infection leading cause of non-relapse death
40
What are the phases of acute GVHD
Early Phase Second Phase Third Phase
41
Early phase acute GVHD
- 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
Second phase acute GVHD
- 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
Third phase acute GVHD
- 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
What is an example of host versus graft disease?
Solid organ transplant - chronic lung rejection & acute renal rejection
45
What are the clinical challenges of organ transplant? (4)
1. Explantation/Preservation damage 2. Ischaemia repurfusion damage 3. Acute rejection 4. Chronic rejection
46
What is Ischaemia Repurfusion Injury?
- 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
What is an example of Host v Host disease?
Autoimmune Disease - Crohn's disease
48
Crohn's disease
= 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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