Immune modulation Flashcards
how do corticosteroids work
inhibit phospholipase A2
- Blocks arachidonic acid and prostaglandin formation and so reduces inflammation
what is the effect of steroids on phagocutes
decreases expression of adhesion molecules on endothelium leading to a transient increase in neutrophil counts as they cant enter the issue - decreased phagocytosis, decreased proteolytic enzymes
what is the action of steroids on lymphocytes
lymphopenia - sequestration of lymphocytes in lymphoid tissue mainly affecting CD4 >cd8> b cells promotes apoptosis
what are the side effects of steroids
diabetes, central obesity, moon face, lipid abnormalities, osteoporosis, hirsuitism, adrenal suppresion , cataracts, peptic ulcers, pancreatitis, avascular necrosis, infection
how do antiproliferative immunosuppresants/cytotoxic agents work
kill faster dividing cells first
side effects of cyclophasphamide
Toxic to proliferating cells Bone marrow depression Hair loss Sterility (male>>female) Haemorrhagic cystitis Toxic metabolite acrolein excreted via urine Malignancy Bladder cancer Haematological malignancies Non-melanoma skin cancer Infection Pneumocystis jiroveci
side effects of azathioprine
Side effects
Bone marrow suppression
Cells with rapid turnover (leucocytes and platelets) are particularly sensitive
1:300 individuals are extremely susceptible to bone marrow suppression
Thiopurine methyltransferase (TPMT) polymorphisms
Unable to metabolise azathioprine
Check TPMT activity or gene variants before treatment if possible; always check full blood count after starting therapy
Hepatotoxicity
Idiosyncratic and uncommon
Infection
Serious infection less common than with cyclophosphamide
side effects of mycophenolate mofetil
effects
Bone marrow suppression Infection
Cells with rapid turnover (leucocytes and platelets) are
particularly sensitive
Infection
Particular risk of herpes virus reactivation
Progressive multifocal leukoencephalopathy (JC virus
what is the aim of plasmapheresis
removal of pathogenic antibody
Patient’s blood passed through cell separator
Own cellular constituents reinfused
Plasma treated to remove immunoglobulins and then reinfused (or replaced with albumin in ‘plasma exchange’)
what are the indications for plasmaphoresis
Severe antibody-mediated disease
Goodpasture syndrome
Anti-glomerular basement membrane antibodies
Severe acute myasthenia gravis
Anti-acetyl choline receptor antibodies
Antibody mediated transplant rejection/ABO incompatible
Antibodies directed at donor HLA/AB molecules
describe how IL2 is expressed
t cell receptor engagement - increased cytoplasmic calcium, binds to calmodulin, activates calcineurin, activates NFATc, upregulates IL2
when are calcineurin inhibitors used
Inhibit T cell proliferation/function
Used in:
Transplantation
SLE
Psoriatic arthritis
how do ciclosporin and tacrolimus work
inactivates calcineurin
how do jak inhibitors work and what are they effective in treating
Inhibit JAK-STAT signalling (associated with cytokine receptors)
Influences gene transcription
Inhibits production of inflammatory molecules
Effective in Rheumatoid arthritis, psoriatic arthritis, axial spondyloarthritis
how do PDE4 inhibitors work
modulates cytokine production effective in psoriasis
what is rituximab
anticd20 (b cells) antibody
basiliximab
anti cd25 (t cells), blocks IL2 indicued signallinh
anti thymocyte globulin indications
allograft rejection, needs daily IV infusions, modulates t cell activity
abatacept
reduces costimulation of t cells via cs28 used for rheumatoid
anti IL1 use
gout, familial mediterranean fever, stills
anti il6
rheumatoid
anti il17/23
axial spondyloarthritis, psoriasis,
ant il4/5/13
eczema, asthma
anti rank
osteoporosis
anti tnf alpha
rhematoid, psoriasis, IBD, ank spond,
immunosuppression side effects
Infusion reactions
Urticaria, hypotension, tachycardia, wheeze – IgE mediated
Headaches, fevers, myalgias – not classical type I hypersensitivity. acute infection, TB, HBV, HCV, HIV
jcv, malignancy, autoimmunity
john cunningham virus
John Cunningham Virus (JCV)
Common polyomavirus that can reactivate
- Infects and destroys oligodendrocytes
Progressive multifocal leukoencephalopathy
Associated with use of multiple immunosuppressive agents
APCs include
dendritic cell, macrophage, b lymphocyte
describe the adaptive immune response
Clonal expansion following exposure to antigen
T cells with appropriate specificity will proliferate and differentiate into effector cells (cytokine secreting, cytotoxic)
B cells with appropriate specificity will proliferate and
differentiate to T cell independent (IgM) (memory and) plasma cells
undergo germinal centre reaction and differentiate to T cell dependent IgG/A/E(M) memory and plasma cells
Plasma cells secrete high affinity specific antibodies
Immunological memory
Pre-formed pool of high affinity specific antibodies
Residual pool of specific T and B cells with enhanced capacity to respond if re-infection occurs
how does the influenza vaccine work
targets hemagglutinin and neutralizes - haemagluttinates
how does the mantoux test work
Inject 0.1 ml of 5 tuberculin units of liquid tuberculin intradermally.
The tuberculin used in the Mantoux skin test is also known as purified protein derivative, or PPD.
The patient’s arm is examined 48 to 72 hours after the tuberculin is injected.
The reaction is an area of induration (swelling that can be felt) around the site of the injection.
what are the types of vaccines (5)
- Live vaccines
- Inactivated/Component vaccines
Conjugates+ Adjuvants increase immunogenicity - RNA vaccines
- Adenoviral vector vaccines
- Dendritic cell vaccines
give examples of live attenuated vaccines
MMR
BCG
Yellow fever
Typhoid (oral)
Polio (Sabin oral)
Influenza (Fluenz tetra for children 2-17 years)
what are the advantages of live vaccines
Establishes infection – ideally mild symptoms
Raises broad immune response to multiple antigens – more likely to protect against different strains
Activates all phases of immune system. T cells, B cells – with local IgA, humoral IgG
May confer lifelong immunity, sometimes just after one dose
what are the problems of live vaccines
Possible reversion to virulence (recombination, mutation).
Vaccine associated paralytic poliomyelitis (VAPP, ca. 1: 750,000 recipients)
Spread to contacts
Spread to immunosuppressed/immunodeficient patients
Storage problems
what are some inactivated vaccines
Inactivated Vaccines
Influenza (inactivated quadrivalent), Cholera, Bubonic plague, Polio (Salk), Hepatitis A, Pertussis, Rabies.
Component/subunit vaccines Hepatitis B (HbS antigen), HPV (capsid), Influenza (recombinant quadrivalent - less commonly used)
Toxoids (inactivated toxins)
Diphtheria, Tetanus.
what are conjugate vaccines and name some
polysaccharide plus protein carrier to promote b cell response Haemophilus Influenzae B
Meningococcus
Pneumococcus (Prevenar)
how do adjuvants work
mimic PAMPS Aluminium salts (humans)
Lipids – monophosphoryl lipid A (humans HPV)
Oils -Freund’s adjuvant (animals)
Dendritic cell vaccines
Acquired defects in DC maturation and function associated with some malignancy suggests a rationale for using ex vivo–generated DC pulsed with tumour antigens as vaccines
Focus on tumour associated antigens or mutational antigens
how does dendritic cell vaccine work for prostatic cancer
Personalised immunotherapy for prostatic cancer
Remove white cells from patient’s blood (leukaphoresis)
APCs are harvested and incubated with recombinant protein PAP-GMCSF
Prostatic acid phosphatase-granulocyte macrophage colony stimulating factor
APCs infused back to patient
Stimulates patient’s immune response
what are the indications for antibody replacement therapy
Primary antibody deficiency
X linked agammaglobulinaemia
X linked hyper IgM syndrome
Common variable immune deficiency
Secondary antibody deficiency Haematological malignancies Chronic lymphocytic leukaemia Multiple myeloma After bone marrow transplantation
when are specific Igs used
Hepatitis B immunoglobulin – needle stick/bite/sexual contact – from HepBSag+ve individual
Rabies immunoglobulin – to bite site following potential rabies exposure
Varicella Zoster immunoglobulin – women <20 weeks pregnancy or immunosuppressed where aciclovir or valaciclovir is contraindicated
Tetanus immunoglobulin – no specific preparation available in UK – use IVIG for suspected tetanus
what are the types of adoptive cell transfer of t cells
Virus specific T cells
Tumour infiltrating T cells (TIL – T cell therapy)
T cell receptor T cells (TCR - T cell therapy)
Chimeric antigen receptor T cells (CAR – T cell therapy
what is CAR -T therapy
T cells with chimeric receptors targeting CD19
Patient’s own T cells
Genetically engineered to express receptor
Expanded in vitro
Used for acute lymphoblastic leukaemia in children
Used for some forms of non-Hodgkin lymphoma
what is ipilimumab antibody against CTLA 4 and pembrolizumab/nivolumab antibody against PD1 used for?
Action
Antibody binds to CTLA4
Blocks immune checkpoint
Allows T cell activation
Indications
- Advanced melanoma
Complications
- Autoimmunity
