IMMUNE REACTIONS

prof. Martínková 2006

Innate immune response
Adaptive immune response
Innate immune response
occurs soon after infection:

- tissue macrophages recognise, by means of specific

DNA-encoded receptors specific pathogen-associated
molecular patterns (PAMPs) on the microorganisms

release of of cytokines (IL-1 and TNF-α) and

various chemokines
Innate immune response
(vascular events, cellular events)
V a s c u l a r events
- local postcapillary venular endothelial cells:

vascular vasodilation and exudation of fluid (due to IL-1,

TNF-α, PGs, Hi, PAF)-
mediators derived from plasma:
the fluid exsudate contains a variety of mediators –
the components of cascades:
- the complement system (C5a and C3a –stimulate mast cells)
- the coagulation system (thrombin, fibrin)
- the fibrinolytic systém (plasmin)
- the kinin system (bradykinin)
- Innate immune response
Cellular events
- expression of adhesion molecules on the cell surfaces
mast cells,
polymorphonuclear leucocytes,
monocytes/ macrophages,
vascular endothelial cells,
platelets,
natural killer cells (NKcells),
neurons

Mediators derived from cells: PGs, NO, histamine, cytokines…

Adaptive immune response
is more specific
The key cells are the lymphocytes:
. B cells – responsible for antibody production –the
humoral immune response
. T cells - important in the induction phase of the
immune response
- responsible for cell-mediated immune
reaction

T w o p h a s e s:
Induction phase
Effector phase
- Adaptive immune response-

Induction phase
naive T cells bearing either the CD4 or CD8 coreceptors
are presented with antigen

- CD8-bearing cells proliferate further and develop into

cytotoxic T cells, which can kill virally infected cells
- CD4-bearing Th cells are stimulated by cytokines
to develop into Th1 or Th2 cells
Th2 cells control mostly antibody-mediated responses
---they interact with B cells, which proliferate giving rise to
antibody-secreting plasma cells and memory cells
Th1 cells proliferate, developing into cells that release
macrophage-activating cytokines. These cells, along with
cytotoxic T cells control cell-mediated responses
-Adaptive immune response-

Effector phase
involves antibody- and cell-mediated responses
Antibodies provide:
- more effective ingestion of microorganisms
- neutralisation of some viruses and of some bacterial toxins
Cell-mediated reactions involve:
- CD8 cytotoxic T cells interacting with and killing virus-infected
cells
- cytokine-releasing CD4 T cells: the cytokines enable
macrophages to kill intracellular pathogens
- memory cells - primed to react rapidly to the antigen that gave
rise to that clone of cells next time an organism bearing that
antigen is encountered
Inappropriately deployed immune reactions

= hypersensitivity reactions

These underlie the autoimmune diseases,

i.e. diseases caused by immune reactions directed
at the host´s own tissues
Immunosuppressant drugs
- inhibit interleukin-2 production or action
ciclosporin, tacrolimus, sirolimus

- inhibit cytokine gene expression

corticosteroids

- inhibit purine and pyrimidine synthesis

azathioprine

- block the T cell surface molecules involved in signalling

polyclonal and monoclonal antibodies

- act by cytotoxic mechanisms

cyclophosphamide, chlorambucil
Usage in therapy:

- autoimmune disease (some forms of

haemolytic anaemia, glomerulonephritis…)
- prevention /or therapy of
transplant rejection (kidneys, bone
marrow, heart, liver, etc.)
- combination -
Hazard:
- decreased response to infections
- facilitation of emergence of malignant
cells
Ciclosporin
-a fungal polypeptide with potent
immunosuppresive activity

Pharmacokinetics
- i.v., oral absorption (rather poor-alternative
formulations)
- hepatic metabolism-metabolites excreted in the
bile
-accumulation in most tissues at conc. 3 to 4 times
that seen in the plasma
-TDM?
Unwanted reactions:

- nephrotoxicity
- hepatotoxicity
- hypertension
Tacrolimus
- a macrolide antibiotic
- i.v., orally
- metabolized by the liver (drug-drug interactions)
- TDM?

Unwanted reactions:
- neurotoxicity
- GIT upsets, metabolic disturbances (hyperglycaemia)
reversible by reducing the dosage
Glucocorticoids
- restrain the clonal proliferation of Th cells through
decreasing transcription of the gene for IL-2

- decrease the transcription of many other cytokine

genes in both the induction and effector phases of the
immune response
Azathioprine
is activated to 6-mercaptopurine (a pure analogue –
antimetabolite - that inhibits DNA synthesis)

by a cytotoxic action on dividing cells inhibits clonal

proliferation in the induction phase of the immune response

Unwanted reactions:
- depression of the bone marrow,
- nausea and vomiting
 PK/PD 6-MP in ALL of childhood

Pharmacokinetics Pharmacodynamics

6-methyl MP

first pass effect TPMT

HPRT
6-MP AUC TGN WBC relaps
(ERY)
XO 1.5-3.5 x 109/l

6-thiouric acid
Mycophenolate mofetil
A semisynthetic derivative of a fungal antibiotic

bioactivated to mycophenolic acid

Action (fairly selective):

- restrains proliferation of both T and B lymphocytes
- reduces the production of cytotoxic T cells
Kinetics:
Well absorbed from the GIT
Enterohepatic circulation-inactive glucuronides
Monoclonal antibodies (mAbs)
genetically engineered imunoglobulins that react
with specific molecular target. They may be part
mouse, part human (humanised or chimeric) or fully
human. In chimeric mAbs, the antigen-recognising portion
of a mouse antibody is joined to the framework of a human
IgG molecule:
Basiliximab - a chimeric mAb
Daclizumab - a humanised mAb
mAbs against the α-chain on the IL-2 receptor on Th cells
the blockade of T cell signal transduction events
- Used in acute rejection of kidney transplants
Unwanted reactions:
serious hypersensitivity reactions
Current therapies based on manipulation
of the immune response
Immunoglobulins

Normal human IgG derived from pooled human plasma can

be used:
- as a replacement therapy in antibody-deficiency states
- to protect susceptible subjects against infections with hepatitis A
virus, measles...
Monoclonal antibodies
-infliximab
A chimeric mAb against the cytokine TNF-α used for rheumatoid
arthritis and Crohn´s disease
-abciximab
A chimeric mAb against the clotting receptor GpIIb/IIIa on
platelets- used to prevent clotting in patients undergoing coronary
angioplasty
-gentuzumab
A humanised mAb against an antigen on leukemia cells, used to
treat relapsed acute myeloid leukemia
and others