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Stem Cell Therapies > Stem cell immunogenicity and immune regulation > Flashcards

Stem cell immunogenicity and immune regulation Flashcards

1
Q

List the criteria stem cell products for use in patients must conform to

A

home to the diseased or injured tissue
engraft (not simply fuse with existing cells)
show correct functionality
be contaminant free (residual stem cells, other differentiated cells or pathogens)
lack tumorigenicity
endure

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2
Q

What can be a problem with stem cell products even if they adhere to the usual criteria they should conform to?

A

Depending on donor compatibility or autoimmune involvement, immune rejection could be an issue

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3
Q

what is the central dogma of transplantation? (note the cytokines involved)

A

Transplantation will lead to inflammation.

Early acting chemokines (e.g. CXCL2, CXCL5,CCL2, and CCL3) cause inflammation in response to transplantation and potentiate further inflammation caused by in increase in inflammatory expression of genes including:
Cytokines: IL-1, IL-6, TNF-a
Enzymes: iNOS, HO-1

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4
Q

Define an immunogen

A

A substance that induces a specific immune response.

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5
Q

Define an antigen

A

A substance that reacts with the products of a specific immune response

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6
Q

define the word immunogenic

A

causing or producing immunity or an immune response

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7
Q

Define syngenic

A

genetically identical and hence immunologically compatible, so closely related transplantation does not provoke an immune response.

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8
Q

define allogeneic

A

relating to or denoting tissues or cells which are genetically dissimilar and hence immunologically incompatible, although from individuals of the same species

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9
Q

List immunogens in order of increasing immunogenicity

A 
Increase in immunogenicity as compounds get more complex:
Amino acids
Haptens
Lipids 
Steroids 
Carbohydrates
Proteins
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10
Q

How will the recipient immune system respond to stem cells or cells derived from them?

A

Innate immune response in allogeneic (unrelated) and autologous/syngeneic (genetic match) setting

Adaptive immune response in the allogeneic setting

Expression of MHC molecules (key transplant antigens) during stem cell differentiation which might be recognized as antigens by the adaptive immune response

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11
Q

Why study the immune response to transplanted stem cell derived tissues?

A

May inform future strategies to modulate the immune response to stem cell derived tissue and prevent rejection of (pluripotent) stem cell derived tissue in transplantation

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12
Q

Describe the likelihood of encountering immune attack depending on cells/tissues

A

Specialised cells, committed progenitors, and multipotent stem cells: autologous normal (low), autologus genetically modified (Moderate), allogeneic (high)

ESC and iPSC: autologous (moderate), allogeneic (high)

Decellularised tissue: both autologous and allogenic arelow

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13
Q

What are human MHC called?

A

HLA

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14
Q

A variation in how many AA in the amino acid sequence of a single protein between donor and recipient is sufficient to trigger immune destruction or rejection of the transplant?

A

one

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15
Q

What are the main antigens responsible for initiating immune rejection are called?

A

Alloantigens or transplantation antigens

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16
Q

What are the categories of alloantigens?

A

Major Histocompatibility Complex or MHC

Minor histocompatibility antigens or mHC

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17
Q

MHC encodes a series of highly ___ groups of genes

A

polymorphic

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18
Q

Encoded within the MHC locus are __ classes of __

A

two; cell surface glyoproteins

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19
Q

Describe the structure of the MHC complexes

A

Class 1: Composed of a membrane-embedded alpha chain (a1, a2, a3) with a beta-microglobulin molecule ( beta-micro underneath a1)

Class 2: Composed of membrane-embedded alpha (a1 and a2) and beta (b1 and b2) chain

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20
Q

Where are the different MHC classes expressed?

A

Class 1: surface of all somatic cells

Class 2: restricted to immune APC cells e.g. B cells, dendritic cells and macrophages

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21
Q

roles of each MHC class?

A

Class 1: present antigens to CD8 T cells and enabling ‘immunosurveillance’ of host cells by NK cells

Class 2: Present peptide antigens to CD4 T cells

Class 3: nonclassical MHC molecules

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22
Q

How does MHC 1 enable ‘immunosurveillance’ of host cells by NK cells?

A

MHC1 usually gives inhibitory signals to NK cells

MHC1 is not expressed in tumourogenic cells and virally infected –> no inhibition signal –> activation signal to NK cell nucleus to start killing the other cell

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23
Q

What genes code for the MHC classes in humans and mice?

A

Class1:
Human: HLA- A,B,C genes
Mice: H2-K D, L

Class 2:
Human: HLA- DP, DQ, DR genes
Mice:H2- A, -E (I-A, I-E)

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24
Q

Where are minor HC antigens (mHC) genes encoded?

A

in the genome outside the MHC locus

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25
Q

Are mHC responsible for acute immune rejection?

A

No, these don’t give rise to acute rejection but can cause chronic long term rejection

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26
Q

What can cause GVHD in bone marrow transplants where HLA are matched?

A

mismatches for mHC antigens

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27
Q

give an example of a minor antigen

A

Y chromosome antigen differences (trigger rejection of male graft by female patient)

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28
Q

What is another name for Y chromosome antigen?

A

H-Y antigen

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29
Q

how do mHC cause rejection?

A
  1. Peptides generated from mHC antigens by antigen processing are presented by the MHC molecules of the recipient and can trigger a T cell response.
  2. Signal 1: TcR recognition of specific Ag by it’s cognate MHC molecule on an APC
  3. Signal 2: costimulatory signal
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30
Q

what problems do mHC pose for TERM?

A

In addition to genetic differences between the stem cell donor and the recipient giving rise to an immune response, even if the stem cells are from an autologous source, it is possible that during the differentiation process new molecules not previously present in the individual might be expressed.
If this were the case, they would also have the potential to be recognised by the immune system in the same way as mHC antigens.

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31
Q

how many signals are required before a T cell is activated in response to an Antigen?

A

2

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32
Q

Describe costimulatory signals received in signal 2 of T cell activation/

A

CD80 or CD86 (aka B7.1/2) on the APC bind to and stimulate CD28 on the T cell to tell it to proliferate in response to a specific antigen

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33
Q

Define allorecognition

A

FOREIGN peptide Ag can be recognised and presented to our T cells

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34
Q

What % of our T cell pool will respond to allogeneic Ag with allorecognition?

A

5%

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35
Q

What are the 3 types of allorecognition and how do they work?

A
  1. In direct allorecognition, T cells are activated directly by allogeneic cells (APCs or any cell expressing allogeneic MHC). T cell receptor activation is triggered by recognition of the complex comprising determinants of the allogeneic MHC class I or MHC class II molecule loaded with peptide (the peptide origin is irrelevant).
  2. For indirect allorecognition to occur, allogeneic transplantation-relevant proteins must first be processed by autologous APCs. Subsequently, peptides derived from these allogeneic antigens are cross-presented by autologous MHC II on autologous APCs. T cell receptor activation is triggered by recognition of the complex comprising determinants of the autologous MHC II molecule loaded with an allogeneic peptide.
  3. In semidirect allorecognition, allogeneic MHC class I or MHC class II molecules are acquired and MHC-peptide complexes displayed by autologous APCs. The peptide origin is again irrelevant.
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36
Q

define immune tolerance

A

state of indifference, or non-reactivity, towards a substance that would normally be expected to excite an immunological response

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37
Q

what diseases/ situations would immune tolerance help with?

A
  1. Autoimmune diseases
  2. Bone marrow transplants
  3. Infectious diseases/vaccine development
  4. Solid organ transplants
  5. Allergic conditions
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38
Q

Describe T cell development in the thymus

A
  1. committed lymphoid progenitor from bone migrate to the thymus (cortex)
  2. DN1 –> DN4 (double negative : no CD4/8)
  3. Double positive (DP) interact with cortical epithelial cells that express high density of MHC 1 and 2 molecules associated with self peptides
  4. Their fate depends on signalling mediated by interaction of the TCR with the self-peptide MHC ligands
  5. These CD8/4 committed DP cells go to the medulla where positive/negative selection occurs and they go on to be CD4/8 SP otherwise they die
  6. SP cells are ready for export from medulla to peripheral lymphoid tissues
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39
Q

Describe positive and negative selection in T cell development

A

Too little signalling results in delayed apoptosis (death by neglect). Too much can promote acute apoptosis (Negative selection)

Intermediate TCR signalling initiates effective maturation (positive selection)

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40
Q

Describe the stages of DN thymocyte development and the markers they express

A

DN1: CD44+CD25-
DN2: CD44+CD25+
DN3: CD44-CD25+
DN4: CD44-CD25-

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41
Q

Do DN2-4 express TCR?

A

No, they express pre-TCR, a non-rearranged pre-Talpha chain and a rearranged TCR beta-chain.

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42
Q

What happens to pre-TCR to make it TCR?

A

It acquires a newly rearranged TCRalpha-chain

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43
Q

When is negative selection common (T cell development)?

A

common in the medulla on encounter with strongly activating seld-lifands onhaematopoietic cells, particularly dendritic cells

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44
Q

Depending on what do thymocytes become either CD8 or 4 cells?

A

Those binding MHC1 with their TCR become CD8

Those with TCRs binding self-peptide MHC2 become CD4

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45
Q

What are the two types of immune tolerance?

A

Central and peripheral

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46
Q

How does central immune tolerance occur?

A

CENTRAL TOLERANCE operates during T cell development with thymic DC presenting selfantigens: major histocompatibilty complex to naive T cells.
Auto-reactive T-cell clones are eliminated by apoptosis in a process called clonal deletion and only T cells that recognize and accept self-antigens are allowed to survive, mature, and migrate into the circulation

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47
Q

What are the two peripheral immune tolerance mechanisms?

A

T cell anergy and induction/expansion of Tregs

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48
Q

Explain the process of T cell anergy

A

The requirement for two signals to activate T cells maintains tolerance in the periphery. In the absence of signal 2, a process called T-cell anergy results in cell cycle arrest, inhibiting expansion of potentially dangerous autoreactive effector T cells.

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49
Q

explain induction of Tregs

A

When immune cells secrete immunosuppressive cytokines such as TGF-beta and IL-10, naïve T cells can differentiate de novo into regulatory T cells (Treg) or natural Treg populations can be expanded to maintain peripheral tolerance.

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50
Q

Give an example of immune tolerance in allografts

A

Maternal-foetal tolerance

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51
Q

How does maternal-foetal tolerance work?

A

Expression of non-classical MHC 1 molecule HLA-G (on trophoblast) acts as an inhibitory receptor for NK cells and further protects foetus from being rejected

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52
Q

list the types of regulatory immune cells

A 
Regulatory T cell (Treg)
Tolerogenic dendritic cell (DC)
Myeloid-derived suppressor cell
Regulatory macrophage
Mesenchymal stromal cell
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53
Q

Name the markers found on Tregs

A

CD4,CD25,FOXP3

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54
Q

What do Tregs do once recruited to a graft?

A

suppress ischaemia–reperfusion injury

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55
Q

What do Tregs do in draining lymphoid fluid?

A

inhibit Tcell proliferation

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56
Q

What factors do Tregs secrete to suppress the immune response?

A

Adenosine, IL-10, TGFb, IL35, Granzyme

57
Q

What molecule do Tregs deplete and why is this important?

A

IL-2 (important growth factor for T cells)

58
Q

What factor makes naive T cells turn into Tregs and what cells secrete it?

A

IL-10

Bregs ,Tregs,tolerogenic DCs, TR1

59
Q

What are the functions of Tregs

A

Inhibit APC function
Cause apoptosis of effector T cells with cytokines (e.g. TGFb and IL-10) and IL-2 depletion
Activate IDO

60
Q

What is IDO and what does it do?

A

activation of the enzyme indoleamine 2,3­dioxygenase (IDO) results in both a local deprivation of the essential amino acid tryptophan and the production of inhibitory molecules known as kynurenines, leading to attenuated Tcell proliferation

61
Q

What is the difference between Tregs and TR1s?

A

TR1 doesn’t express FOXP3

62
Q

What do TR1 cells do?

A

suppress pro-inflammatory activities of both APCs and effector Tcells with IL-10

63
Q

How are TR1 cells produced?

A

In response to IL-10 naive T cells differentiate to TR1

64
Q

what can cause Treg IDO release?

A

binding of CTLA4 to the co-stimulatory

molecules CD80 and CD86 on APCs

65
Q

How are CD8+ Tregs formed?

A

in the presence of IL‑10, naive CD8+ Tcells can be converted into CD8+ TReg

66
Q

What markers do naive CD8 T cells not express?

A

CD28

67
Q

What are the functions of CD8+ Tregs?

A

inhibit APC function to promote immune regulation

68
Q

What factor induces DN T cells and where is it secreted from?

A

IFN-gamma

Tolerogenic DCs

69
Q

What markers are DN T cells positive for?

A

CD3 and ab TCR

70
Q

What are the functions of DN T cells?

A

DN Tcells can acquire alloantigens through trogocytosis. This enables them to present antigens to effector Tcells in a manner that promotes Tcell apoptosis.

They also downregulate the expression of co-stimulatory molecules by DCs, thereby inhibiting the ability of DCs to stimulate pro-inflammatory immune responses and, instead, inducing the apoptosis of DCs

71
Q

What innate immune cells accumulate at transplant sites?

A

MSCs and MDSCs

72
Q

What do MSCs do (immune)?

A

Secrete MMP to inhibit T cell activation
Secrete TGFb and PGE2 to convert DC to tolerogenic DC
express all 3 to convert induce Tregs

73
Q

How does the innate immune system cause Treg/TR1 induction?

A

IL-10,TGFb,PGE2 from MSCs
IL-10 from MDSC
IL-10 from regulatory macrophages

74
Q

What are the functions of MDSCs and how?

A

suppress the proliferation of Tcells, Bcells and natural killer (NK) cells through the below mechanisms:

They secrete TGFb to cause NK cell anergy

They secrete HO1 which inhibits DC maturation, causes cytoprotection, and increases IL-10 secretion

They produce ROS and NOS by inducible nitric oxide synthase (iNOS) and arginase 1 expression which like IL-10 stops T cell activation

75
Q

What are the 2 methods of getting Tregs?

A

In the process of peripheral tolerance some T cells form naturally-occuring CD4 CD25 Tregs but you can also get iTregs extrathymically.

76
Q

list the factors/cytokines that cause naive T cell differentiation and the cell type they lead to

A 
IFNgamma,IL-12: Th1
IL-4: Th2
IL-6,TGFb: Th17
TGFb, retinoic acid, IL-2: iTreg
IL-21: Tfh
77
Q

List the types of mature T cells and their main transcription factors

A

Th1: Tbet
Th2:GATA3
Th17: ROR(gamma)t
iReg: Foxp3

78
Q

List the factors which cause mature T cells to change phenotype and the phenotype they change to

A

iTreg can change to Th17 with IL-6, IL-21
Th17 can turn to Th2 with IL-14 or Th1 with IL-12
Th2 cell can turn to Th9 with TGFb or maybe Th1 (factor unclear)

79
Q

What is CD25?

A

alpha chain of IL-2 receptor

80
Q

list the Treg markers

A

Main: CD4+CD25+
Key transcription factors: FoxP3 and maybe Runx1
Other positive markers: CTLA4, LAG-3,GITR
Negative/low markers: CD127
+/-Galectin-3

81
Q

What factors can fail in peripheral tolerance?

A

CTLA4,AIRE,INS,PTPN22,HLA,CD25

82
Q

What environmental factors can affect immune tolerance?

A

Microbes, milk products, sun exposue, vitamin D

83
Q

As SC differentiated do they become more or less immunogenic?

A

More

84
Q

What are the problems with SC having or not having MHC molecules?

A

If they have MHC they will trigger direct or indirect pathway responses in transplant recipients (allogenic settings)

If they don’t they are open to attack from NK cells which recognise cells lacking MHC class 1 and target them for death

85
Q

in T cell activation what is signal 3?

A

cytokines for lineage differentiation

86
Q

What does CTLA4 do?

A

It is a receptor on the surface of T cells which bind to B7.1/2 and stop T cell proliferation

87
Q

Describe how T cell activation occurs in response to iPSCs

A

direct recognition (unlikely due to lack of iPSC-derived APC)

indirect recognition –> immunological synapse formation –> costimulation with CD40 or B7.1/2 (CD80/86) on the APC and CD40L or CD28 on T cells

CD8 T cells can directly recognize peptides displayed by class I MHC molecules on any cell type, including iPSC, without the need for presentation by APC but they need Th1 cells to activate them completely

Memory CD8 T cells can become activated to kill a cell by the recognition of antigen alone but they are improved by cytokines/costimulation

88
Q

when might memory CD8 cells be problematic

A

repeated iPSC infusion

89
Q

describe the effect of negative costimulatory molecules

A

CTLA4 on T cells with B7.1/2, which binds with a higher affinity than to CD28, generally acts to downregulate T-cell activation but may also trigger immune regulation or tolerance.

90
Q

What do CD8 T cells secrete to kill cells?

A

granzyme and perforin

91
Q

What happens to MHC class 1 as cells differentiate?

A

MHC class 1 increases

92
Q

What happens to MHC 1/2 expression in differentiated ESC tissue following IFN-gamma stimulation?

A

MHC1 increases a lot but not as much MHC2

93
Q

How do we model allogenic transplant rejection?

A

BM3 T cells (all target H-2Kb) injected into H2k mouse (has different H-2K) and immunostain for transgenic TCR to see cell fate

94
Q

What happens when you inject ESC-derived H2 missmatched IPCC into Rag-/- BM3 rats vs normal rats?

A

since Rag is important for rearranging and making TCR, without it the rats show no rejection of the IPCC unlike the WT

95
Q

iPSC mHC could arise during differentiation. What is the consensus on this so far?

A

syngeneic iPSC are not immunogenic. There was one in 2010 that said there was rejection but other groups showed that this was negligible

Clinically relevant Primate studies also show that autologous iPSC are not immunogenic. Good news, further step toward confirming safety of autologous human iPSC therapies (must be examined, particularly for gene corrected cells)
However, some cellular therapies may require allogeneic cells– still prudent to investigate immunogenicity of PSCs and ways to circumvent their rejection

96
Q

What have primate studies shown about iPSCs?

A

That they have questionable immunogenicity

97
Q

What happens when you knockin PDL-1 and CTLA4-Ig into a h-ESC and inject them into mice mouse ?

A

h-ESC are no longer rejected

98
Q

describe the nude mouse phenotype and how it is used

A

Athymic (no thymus!)- no T cells
Intact humoral immunity (i.e. B cells, Ab) Normal NK cell activity

Used to engraft solid human tumours*
Human haematopoietic cells do not engraft - cannot make them humanised
Human ES cells engraft (develop teratomas)
Rabbit hair xenograft accepting

99
Q

what is the molecular basis of the athymic nude mouse?

A

Forkhead box N1(Foxn1nu)

100
Q

Describe CB17-scid mouse phenotype and how they ar used?

A 
No T cells or B cells 
 Some (moderate) NK cell activity 
 Radiosensitive 
Leaky
Severe combined immunodeficiency (scid) mutation
101
Q

How is the CB17-scid mouse different from the nude one in terms of engraftment of transplants?

A

In CB17-scid:
Human haematopoietic cells engraft at low levels
Human ES cells engraft (develop teratomas)

102
Q

What is the molecular basis of the CB17-scid mouse?

A

Protein kinase, DNA activated, catalytic polypeptide [Prkdcscid]

103
Q

list the different types of genetically optimised humanized mouse models

A

Eliminate adaptive immunity: scid, Rag1null, or Rag2null
Utilize permissive strain background: Non-obese diabetic (NOD)
Eliminate NK cells: IL2rgammanull
Transgenic expression of human cytokines, HLA molecules, etc.
Reduce activity of other innate immune components

104
Q

what are humanised mice exactly?

A

Mice (e.g. scid mice) which engraft humanised haematopoietic SCs and generate a functional immune system

105
Q

are some tissues more immunogenic than others? Give examples

A

yes. iPSC derived -RPE and stromal muscle cells were injected into humanized mice and SMCs were rejected unlike the RPE.

106
Q

list factors that can impact immunogenicity

A

Method of reprogramming (integrations vs. no integrations)
Type of (differentiated) cells used– some cells more immunogenic than others? Length of differentiation protocol??
Minor H differences between recipient and donor (cell line)?
Site of implantation may play a role in outcome…?
In tissue engineering: use of biomaterials/scaffolds

107
Q

list the different ways of obtaining stem cells

A

nuclear fusion
cell fusion
cell explantation (just get germ cells)
nuclear reprogramming

108
Q

What are the advantages and disadvantages of nuclear fusion?

A 
advantages:
HLA typed oocyte banks
Autologous somatic cell source
No age limit
Evidence that functional cells can be generated from a patient with established disease

disadvantages:
Requirement for human oocytes
Immunogenicity-missmatched mitochondrial antigens from the oocyte donor

109
Q

What are the disadvantages of cell fusion?

A

Immunogenicity through male germ cell imprinting

Potential risk of tumours due to frequent tetraploidy

110
Q

What are the disadvantages of cell explantation?

A

limited therapeutic application

111
Q

What are the advantages and disadvantages of nuclear reprogramming?

A 
Advantage:
Autologous cell source 
No age limit
Reliable technique
Relatively efficient
Viral and non-viral transfer can be used

Disadvantages:
potential risk for tumors due o the use of oncogenes
Immunogenicity of the transcription factors used for reprogramming

112
Q

Is there a role for Cell cycle status in immunogenicity of stem cells?

A

Non-proliferating stem cells are able to evade host immune surveillance

113
Q

how do non-proliferating cells evade host immune suveillance?

A

Non-dividing cells do not express Nlrc5 which usually upregulates factors which increase MHC1 expresion –> they block APC machinery expression –> gives a way to evade detection by the Jedi T cells

114
Q

what factors does Nlrc5 increase the transcription of?

A

MHC1
beta2-m
Tap 1,2
Tapb

115
Q

What are the implications of the paper which showed how non-dividing cells evade the immune system?

A

Are there any evolutionary advantages of stem cell quiescence?

Method for cancer stem cells to evade detection?

Particular to just these stem cell types?? (skin and gut cells)

116
Q

What are the characteristics of immune privilage?

A

Physical barrier to immune system

Secretions of anti-inflammatory compounds e.g. TGFβ

Expression of molecules like FasL which induce T cell apoptosis (or HLA-G in placenta)

117
Q

Immune-privileged tissues survive for ____ times in normal transplant sites

A

extended

118
Q

list immune privilaged sites

A 
Eye: cornea,anterior chamber, citreous cavity, and subretinal space
brain: ventricles and striatum
Pregnant uterus
Ovary
Testis
Adrenal cortex
Hair follicles
hamster cheek pouch
certain tumours
119
Q

list immune privielged tissues

A 
eye: cornea, lens, pigment epithelium, and retina
Brain and spinal cord
placenta
ocary
testis
liver
hamster cheek pouch
certain tumours
120
Q

describe the immune privilage of the eye

A

In different sites in the eye there are molecules which can be released to supress or apoptose cells

Physical barriers prevent cells from entering (tight junctions)

Expression of suppressive cytokines (RPE) e.g. TGFb

The ability of APCs to induce regulatory T cells

Secretions of different anti-inflammatory molecules to make immune cells have more of a suppressive capacity

121
Q

what is haematopoietic chimerism

A

You have both host and donor immune system coexisting as one

After giving a bone marrow transplant you wait and add your transplant graft and it is more likely to be accepted

122
Q

should we use haematopoietic chimerism in SC transplants?

A

Not really because it’s quite a heavy duty thing to ablate the whole immune system

123
Q

What happens to immunity with age?

A

it decreases

124
Q

list the changes seen in different parts of the body due to age-related immune changes

A

Skin: decreased TNF by macrophages, decreased neutrophil recruitment

Liver: increased NKT cell cytokine production

Adipose tissue: NLRP3-dependant inflammation, dysregulation of cytokines, decreased dicer-mediated microRNAprocessing

Brain: activation of TLR and inflammasome pathways, microglial activation

Lungs: increased neutrophil inflammation, decreased NK NK function, increased PGF2 levels, decreased NLRP3 function

Vasculature: increased cytokines (IL-6) production by VSMCs

125
Q

list diseases that result due to ageing-related immune changes

A

Skin: decreased DTH response, impaired wound healing

Liver: liver inflammation in response to viral infection or PAMPs

Adipose tissue: metabolic syndrome, insulin resistance

Brain: neurodegeneration

Lungs: increased inflammation (burn model), infections with respiratory pathogens, increased chronic lung disease?

Vasculature: atherosclerosis

126
Q

describe the effects of age on innate immunity

A 
Macrophages: 
reduced MHCII, CD68,CD14
Reudced IFNgamma, LPS responses
reduced TLR1,4
reduced function

Neutrophils:
increased TLR recruitment of lipid rafts
decreased TREM1 recruitment
decreased function

DC:
change in mDC/pDC ballance
reduced DC precursors, TLR7,8,9 signalling, and costimulation

NK cells:
decreased cytotoxicity and decreased production of proinflammaory cytokines

127
Q

desccribe the effects of ageing on the adaptive immune system

A

B cells: reduction function, blunted vaccine response

HSCs: altered subset development, reduced lymphoid precursors

Thymus: thymic involution, decreased naive T cells

CD4 T cells: reduced function and IL-2 production + dampened costimulation

CD8 T cells: narrowing of repertoire, more memory cells

Tregs: retain some supressive activity but have altered repertoire

128
Q

What is a method of combatting age-related immune problems?

A

Replace thymus with PSC differentiation into thymic lineages

129
Q

what are the two ways in which thymic epithelial cells can be replenished?

A

by active stem cells (note that without self-renewal, the stem cell compartment becomes progressively depleted)

or by avtive committed progenitors (in this case, the stem cell pool is much less affected)

130
Q

list the interventions which can be used to reduce IPSC rejection

A

Encapsulation (with capsules with pores so cells get nutrients and get rid of products of waste)

standard immunosuppression

functionalisation (e.g. adding FasL, adding drugs/cytokines to material)

giving tolerogenic immune cells from stem cells or donor

131
Q

In 2013 pig islets were encapsulated in alginate to prevent rejection. What are the benefits of these and what are some encapsulation biomaterials?

A

Advantage: using pig cells removes problem of not having enough source cells

biomaterials: alginate,gelatin, peptide-polymer, peptide only

132
Q

___ protects MHC class-I mismatched embryoid bodies from transplant rejection

A

Dikkopf3 (Dkk3)

133
Q

how do MSCs help transplantation?

A

reduce ischemia reperfusion injury, rejection, use of immunosuppressive meidcations, and allograft pathologies (GVHD)

134
Q

___ are the most potent antigen presenting cells, specially adapted to ___

A

DCs; activate naïve T cells

135
Q

DCs have roles in both __ and __

A

priming immune responses ; induction of immunological tolerance

136
Q

esDCs can induce expansion of ___ cells in vitro

A

regulatory T cells (Tregs)

137
Q

what kind of esDCs induce Treg expansion in vitro?

A

Immature, LPS-matured esDCs and both rapamycin and retinoic acid (RA)-pre-treated immature and mature esDCs

138
Q

what happens to the markers expressed by ESCs as they are differentiated to DCs?

A

As cells mature they become better at presenting antigen (at the beginning its about picking up antigens and after its about costimulatory molecules)

CD11c, MHC2, CD80/86 and CD40 increase

139
Q

are mouse esDCs good at presenting antigens?

A

No, they were good at making normal T cells turn into Tregs. But they were not so good at presenting antigens

Stem Cell Therapies (1 decks)

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