Immunomodulation Flashcards
Key features of T memory cells
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)
Key features of memory B cells
o Longevity
o Pre-formed, high affinity IgG antibodies are present
o Rapid, robust response
What is the important target of influenza
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)
How can you detect influenza antibodies
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
Which cells are important in TB protection
T cells
Examples of live attenuated vaccines
. MMR, BCG, Yellow fever, Typhoid, Polio (Sabin), Vaccinia
Adv of live attenuated vaccines
- 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
Disadv of live attenuated vaccines
- Storage problems
- Possible reversion to virulence
- Spread to contacts (i.e. spread to immunocompromised/immunosuppressed
Adv of inactviated/component vaccines
• No mutation or reversion
Can be used in immunodeficient patients
• Easier storage
Lower cost
DIasadv of inactviated/component vaccines
- Often do not follow normal route of infection
- May have poor immunogenicity
- May need multiple injections
- May require conjugates or adjuvants
What is a conjugate vaccine and why is it useful
polysaccharide + protein carrier:
• Polysaccharide induces a T cell-independent B cell response (transient)
• Protein carrier promotes T cell-dependant B cell response (long-term)
What is an adjuvant
Increase the immune response without altering its specificity:
• Mimic the action of PAMPs on TLR and other PRRs
Aluminium Salts
Lipids
Dendritic cell vaccines
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
Indications of Haematopoietic stem cell transplantation
Life-threatening immunodeficiency (e.g. SCID, leucocyte adhesion defect)
Haematological malignancy
Antibody replacement indications
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
Specific immunoglobulin use
(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
Virus specific T cell therapy
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
Tumour infiltrating T cells
(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
Chimeric antigen receptor T cells therapy
(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
Ipilimumab MOA
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)
Pembrolixumab and Nivolumab MOA
o ABs against PD-1 prevent the inhibitory effect of binding PD1 and PD1-L activating the T cells to kill
MOA of steroids on the immune system
- 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
Cyclophosphamide MOA
Alkylates guanine base of DNA
Damages DNA and prevent cell replication
Affects B cells > T cells (used in antibody-mediated disorders)
When is cyclophosphamide used
Multisystem connective tissue disease
Vasculitis with severe end-organ involvement (e.g. GPA, SLE)
Cancer
Azathioprine MOA
– purine analogue
Blocks de novo purine synthesis (e.g. adenine and guanine)
Prevents replication of DNA
Affects T-cells > B-cells
When is azathioprine used
Transplantation
Auto-immune disease
Auto-inflammatory disease (e.g. Crohn’s, UC)
MYCOPHENOLATE MOFETIL MOA
anti-metabolite:
Blocks de novo guanosine nucleotide synthesis prevents replication of DNA
Prevent T cell > B cell proliferation
When in mycophenolate mofetil used
Transplantation (alternative to azathioprine)
Auto-immune disease (alternative to cyclophosphamide – i.e. sarcoidosis)
Vasculitis (alternative to cyclophosphamide)
What is plasmapheresis
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)
Indications of plasmapheresis
• 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)
MOA of calineurin inhibitors
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
MOA of JAK inhibitors and indications
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
MOA of PDE4 inhibitors and indications
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
Anti-thymocyte globulin MOA
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
Basiliximab moa and indication
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)
Abatacept MOA and indication
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
Rixuximab MOA and indications
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
Vedolizumab / Natalizumab MOA and indications
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
Toclizumab, Sarlimumab MOA and indications
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
Infliximab MOA and indications
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
Etanercept MOA and indications
TNFa antagonist
o Inhibits action of TNF-alpha and TNF-beta
Rheumatoid arthritis
Ankylosing spondylitis
Psoriasis and psoriatic arthritis
Ustekinumab MOA and indications
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
Guselkumab MOA and indication
anti-p19 (alpha) in IL-23
Psoriasis
SC every 8 weeks
Secukinumba MOA
anti-IL17a
Psoriasis and ankylosing spondylitis
Denosumab MOA and indication
anti-RANK-ligand
o RANKL from osteoblasts acts on RANK (receptor) on osteoclasts osteoclast differentiation resorb bone
Osteoporosis
