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Pathology Year 5 > Immunomodulation > Flashcards

Immunomodulation Flashcards

1
Q

Key features of T memory cells

A

o Longevity (persist without antigen via low level proliferation in response to cytokines)
o Different cell surface proteins (chemotaxis / adhesion) to access non-lymphoid tissues (where microbes enter)
o Rapid, robust response to subsequent antigen exposure (lower threshold of activation than naïve cells)

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2
Q

Key features of memory B cells

A

o Longevity
o Pre-formed, high affinity IgG antibodies are present
o Rapid, robust response

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3
Q

What is the important target of influenza

A

o Although CD8 T cells control the viral load, the antibody is responsible for providing a protective response

Haemagglutinin (HA) is the membrane fusion glycoprotein of influenza virus (i.e. a target for ABs)

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4
Q

How can you detect influenza antibodies

A

Haemagglutinin inhibition assay:
 If normal red cells in a dish  clump at the bottom forming a red spot
 If add influenza virus to RBCs, the HA will make cells stick together  diffuse coloration across the well
 If add serum of someone who has a lot of ABs against HA with the virus and red cells, it will inhibit the HA from causing the above effect  cells clumping at the bottom as if the virus was not present

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5
Q

Which cells are important in TB protection

A

T cells

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6
Q

Examples of live attenuated vaccines

A

. MMR, BCG, Yellow fever, Typhoid, Polio (Sabin), Vaccinia

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7
Q

Adv of live attenuated vaccines

A
  • Establishes infections (ideally mild symptoms)
  • Raises broad immune response to multiple antigens (offer protection against different strains)
  • Activates all phases of immune system (T cells, B cells – local IgA, humoral IgG, etc.)
  • Often confer life-long immunity after one dose
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8
Q

Disadv of live attenuated vaccines

A
  • Storage problems
  • Possible reversion to virulence
  • Spread to contacts (i.e. spread to immunocompromised/immunosuppressed
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9
Q

Adv of inactviated/component vaccines

A

• No mutation or reversion
Can be used in immunodeficient patients
• Easier storage
Lower cost

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10
Q

DIasadv of inactviated/component vaccines

A
  • Often do not follow normal route of infection
  • May have poor immunogenicity
  • May need multiple injections
  • May require conjugates or adjuvants
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11
Q

What is a conjugate vaccine and why is it useful

A

polysaccharide + protein carrier:
• Polysaccharide induces a T cell-independent B cell response (transient)
• Protein carrier promotes T cell-dependant B cell response (long-term)

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12
Q

What is an adjuvant

A

Increase the immune response without altering its specificity:
• Mimic the action of PAMPs on TLR and other PRRs

Aluminium Salts
Lipids

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13
Q

Dendritic cell vaccines

A

 Take a patient’s dendritic cells and load them with a tumour antigen and reintroduce them to the patient to try and boost the immune response against the tumour antigens
 Requires antigens specific to the tumour and distinct from normal cells

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14
Q

Indications of Haematopoietic stem cell transplantation

A

 Life-threatening immunodeficiency (e.g. SCID, leucocyte adhesion defect)
 Haematological malignancy

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15
Q

Antibody replacement indications

A

 Primary antibody deficiency
• Bruton’s X-linked hypogammaglobulinemia
• X-linked hyper-IgM syndrome
• Common variable immunodeficiency

 Secondary antibody deficiency
• Haematological malignancies (CLL, MM)
• After bone marrow transplantation

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16
Q

Specific immunoglobulin use

A

(e.g. HBV Ig, tetanus Ig, rabies Ig, VZV Ig)
o Passive immunisation – human Ig used for post-exposure prophylaxis (PEP)
o Derived from plasma donors with high titres of IgG antibodies to specific pathogens

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17
Q

Virus specific T cell therapy

A

 I.E. in EBV in those immunosuppressed to prevent development of B cell lymphoproliferative disease

 (1) Blood is taken from the patient or from a matched individual
 (2) Peripheral blood lymphocytes isolated  stimulated with EBV peptides
 (3) Expansion of EBV-specific T cells  infused back into the patient
• This is done without any stimulation of B-cells, hence no B cell lymphoproliferative disease

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18
Q

Tumour infiltrating T cells

A

 (1) Remove tumour from patient
 (2) Stimulate T cells within tumour with cytokines (e.g. IL-2) so they develop a response against tumour
 (3) Select and expand the tumour infiltrating lymphocytes and reinfuse back into the patient

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19
Q

Chimeric antigen receptor T cells therapy

A

 (1) T cells taken from patient and viral / non-viral vectors used to insert gene fragments into T cells
 (2) Gene fragments encode receptors:

• TCR therapy  insert a gene that encodes a specific TCR (e.g. against a tumour cell antigen)
o Recognises MHC presented peptides

• CAR therapy  receptors are chimeric (it contains both B and T cell components)
o Recognises cell surface CD markers

20
Q

Ipilimumab MOA

A

o Ipilimumab will bind to CTLA4 meaning that all of the interactions of CD80 and CD86 (from APC) occur through CD28 thereby boosting the T cell response (you get more active T cells)

21
Q

Pembrolixumab and Nivolumab MOA

A

o ABs against PD-1 prevent the inhibitory effect of binding PD1 and PD1-L  activating the T cells to kill

22
Q

MOA of steroids on the immune system

A
  • Effects on Prostaglandins – inhibit phospholipase A2: prostaglandins and leukotrienes; these are proinflammatory)  reduce inflammation
  • Effects on Phagocytes:- Decrease chemotaxis
•	Effects on Lymphocyte Function:
o	Lymphopaenia (sequestration of lymphocytes in lymphoid tissue; affects: CD4 > CD8 > B cells)
o	Blocks cytokine gene expression 
o	Decreased antibody production 
o	Promotes apoptosis
23
Q

Cyclophosphamide MOA

A

 Alkylates guanine base of DNA
 Damages DNA and prevent cell replication
 Affects B cells > T cells (used in antibody-mediated disorders)

24
Q

When is cyclophosphamide used

A

 Multisystem connective tissue disease
 Vasculitis with severe end-organ involvement (e.g. GPA, SLE)
 Cancer

25
Q

Azathioprine MOA

A

– purine analogue
 Blocks de novo purine synthesis (e.g. adenine and guanine)
 Prevents replication of DNA
 Affects T-cells > B-cells

26
Q

When is azathioprine used

A

 Transplantation
 Auto-immune disease
 Auto-inflammatory disease (e.g. Crohn’s, UC)

27
Q

MYCOPHENOLATE MOFETIL MOA

A

anti-metabolite:
 Blocks de novo guanosine nucleotide synthesis  prevents replication of DNA
 Prevent T cell > B cell proliferation

28
Q

When in mycophenolate mofetil used

A

 Transplantation (alternative to azathioprine)
 Auto-immune disease (alternative to cyclophosphamide – i.e. sarcoidosis)
 Vasculitis (alternative to cyclophosphamide)

29
Q

What is plasmapheresis

A

o The patient’s blood is passed through a separator and their own cellular constituents are reinfused
o Plasma treated to remove Ig and is then reinfused (or replaced with albumin in plasma exchange)

30
Q

Indications of plasmapheresis

A

• Indications = severe antibody-mediated disease:
o Goodpasture’s syndrome (anti-GBM)
o Severe acute myasthenia gravis (anti-ACh-R)
o Severe transplant rejection (antibodies against donor HLA)

31
Q

MOA of calineurin inhibitors

A

o Inhibitors of calcineurin (e.g. ciclosporin, tacrolimus) prevent T cell signalling  blocks IL2 production
o Blocked IL-2 reduces activation of naive T-cells after successful APC interaction
o This results in reduced clonal expansion and proliferation

32
Q

MOA of JAK inhibitors and indications

A

o Interferes with JAK-STAT signalling (important in transducing the signals from cytokine binding)
o Influences gene transcription
o Inhibits the production of inflammatory molecules

o Indication = rheumatoid or psoriatic arthritis

33
Q

MOA of PDE4 inhibitors and indications

A

o PDE4 inhibitors increases cAMP  activate PKA (Protein Kinase A)  prevent activation of transcription factors
o This leads to a decrease in cytokine production
o Indication = psoriasis or psoriatic arthritis

psoriasis or psoriatic arthritis

34
Q

Anti-thymocyte globulin MOA

A

 Thymocyte (lymphocytes from thymus) from humans injected into rabbits  rabbits produced ABs against the thymocytes of varying specificities (e.g. antibodies to CD2, CD3, CD4, CD8, etc.)
 Serum injected into patients  very effective at targeting T cells, however it is very non-specific

35
Q

Basiliximab moa and indication

A

o Process  targets parts of IL2 receptor (potential alpha, beta and gamma components):
 Gamma chain shared amongst many IL-receptors, so not a good target
 Alpha chain (aka CD25) more specific for the IL2 receptor

= prophylaxis of allograft rejection (used before and after transplant surgery)

36
Q

Abatacept MOA and indication

A

o Abatacept = receptor made from a fusion of CTLA4 and IgG Fc component
CTLA4-Ig binds APCs’ CD80 and CD86  upregulated CTLA4-mediated reduced T cell activation

37
Q

Rixuximab MOA and indications

A

o Anti CD20- CD20 is expressed on mature B cells but NOT plasma cells  depletion of mature B cells

o Indications (given as 2 IV doses every 6-12 months in RhA):
 Lymphoma
 Rheumatoid arthritis
 SLE

38
Q

Vedolizumab / Natalizumab MOA and indications

A

 Alpha 4 is expressed with either beta-1 or beta-7 integrin
 This complex binds to MadCAM1 to mediate leukocyte epithelial rolling and arrest to enter tissues
 Blocking this complex then inhibits leucocyte migration to tissues

IBD, remitting/relapsing MS

39
Q

Toclizumab, Sarlimumab MOA and indications

A

anti-IL-6 receptor AB
o Reduces activation of macrophages, T cells, B cells and neutrophils
 Inhibits fusion of lymphoid and myeloid cells

 Castleman’s disease (IL-6 producing tumour)
 Rheumatoid arthritis

40
Q

Infliximab MOA and indications

A

anti-TNFa
o TNF-alpha is responsible for the inflammatory response in inflammatory arthritis

 Rheumatoid arthritis Ankylosing spondylitis
 Psoriasis and psoriatic arthritis Inflammatory bowel disease
 Familial Mediterranean fever

41
Q

Etanercept MOA and indications

A

TNFa antagonist
o Inhibits action of TNF-alpha and TNF-beta

 Rheumatoid arthritis
 Ankylosing spondylitis
 Psoriasis and psoriatic arthritis

42
Q

Ustekinumab MOA and indications

A

anti-p40 of IL-12 and IL-23
o These cytokines mainly act on T cells and NK cells thereby modulating their activity

 Psoriasis and psoriatic arthritis (action of IL23  production of IL17 by T cells important in psoriasis)
 Crohn’s disease

43
Q

Guselkumab MOA and indication

A

anti-p19 (alpha) in IL-23

Psoriasis
SC every 8 weeks

44
Q

Secukinumba MOA

A

anti-IL17a

Psoriasis and ankylosing spondylitis

45
Q

Denosumab MOA and indication

A

anti-RANK-ligand
o RANKL from osteoblasts acts on RANK (receptor) on osteoclasts  osteoclast differentiation  resorb bone

Osteoporosis

Pathology Year 5 (42 decks)

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