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CHAPTER 19 Immunology
C
C
Site of papain cleavage
Antigen-
Antigen-
site
331
• humoral immunity is attributable to immunoglobulin
produced by plasma cells derived from B-lymphocytes
• T-lymphocytes can help and suppress B-lymphocyte
activity.
HUMORAL IMMUNITY
e production of antibodies, which are small, soluble
globulin proteins (immunoglobulins, Ig).
• e production of antibodies is dependent on the differentiation of B-lymphocytes into plasma cells.
• Immunoglobulin molecules comprise light chains (κ or λ)
and heavy chains (γ, µ, α, δ, ε).
• Molecules can be enzymatically separated into fragment
antigen-binding (Fab) or fragment crystallizable (Fc).
Some leucocytes have receptors for Fc.
• One plasma cell produces antibody of one class reactive
with only one antigen.
• Antibodies by binding to antigens can cause:
• lysis of bacteria
• neutralization of toxins
• opsonization (i.e. surface coating of foreign material
by complement to promote engulfment by phagocytic
cells which have cell surface receptors for complement)
• antibody-dependent cell-mediated cytotoxicity.
Antibody Production
• Antibodies are produced by plasma cells in lymph
nodes, bone marrow and spleen.
e basic structure of any immunoglobulin is shown in
Fig. 19.1.
• ere are ve classes of immunoglobulin: IgG, IgM,
IgA, IgD and IgE, characterized by dierences in structure of their heavy chains. Structure and roles of immunoglobulins are shown in Table 19.1.
• e antigen-binding site of an IgG molecule is at the
N-terminal end of the Fab polypeptide chain.
• Huge numbers of combining sites exist to recognize the
vast number of antigenic epitopes.
• Diversity in antibodies is due to variability of the amino
acid sequences at the N-terminal regions.
• e amino acid sequences of the N-terminal regions
vary between dierent antibody molecules and are
known as variable regions (V).
• Most of the dierences reside in three hypervariable
hypervariable chains come together with their counterparts on the other pair of heavy and light chains to form
the antigen-binding site.
• In any individual, 106 dierent antibody molecules
could be made up by 103 dierent heavy chain variable
regions associated with 103 dierent light chain variable
regions.
Cell-Mediated Immunity
• Cells responsible are T-lymphocytes.
• T-cells are characterized by antigen-specic T-cell
receptors (TCR).
binding
N
site
N
Light chain
Heavy chain
Heavy chain
Fc fragment
S
S
S
S
S
S
S
S
Light chain
Fab fragment
N
N
binding
Fig. 19.1 Basic structure of an immunoglobulin molecule showing the four polypeptide chains, the variable
regions (shaded), and the fragments produced by enzyme (papain) cleavage.
332
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SECTION III Pathology
TABLE 19.1 Properties and Functions of Immunoglobulins
Ig
Class
IgG
IgA
IgM µ 900 000
IgE
IgD
Heavy
Chain
γ
α
ε
δ
Molecular
Weight
150 000 5–15 2 Yes Crosses placenta (only one to do so)
380 000
(dimer in
secretions)
(pentamer)
185 000
185 000 0–0.5 2 No Lymphocyte membrane receptor
Plasma
Level
(g/L)
1.5–5 4 No Principal immunoglobulin in secretions
0.5–2 10 Ye s Characteristic of primary immune
2–4 ×
−7
10
AntigenBinding
Sites
2 No Binds to mast cells and basophils
Complement
Activation Role
Characteristic of secondary immune
response
Neutralizes toxins
opsonization
of respiratory and GI tracts
Secreted locally in tears, saliva, sweat,
mucus
Dimers of Ig joined by a J chain
Major immune protection for mucosal
surfaces
response
Powerful agglutinator (of bacteria) and
opsonin
Anaphylactic hypersensitivity
Antiparasitic by degranulating mast cells
and attracting eosinophils
Involved in B-cell differentiation
• TCRs are membrane-bound and are made of two pairs
of polypeptide chains: TCR1 (γ and δ chains), TCR2
(α and β chains).
• Leucocytes are dierentiated by their cell surface molecules known as clusters of dierentiation (CD), which
are identied by monoclonal antibodies.
• CD3 is closely linked to the receptor and is responsible
for transduction of the signal into the interior of the
T-cel l.
• Two main sets of T-lymphocytes exist:
• helper T-cells (CD4+)
• cytotoxic T-cells (CD8+).
• Helper T-cells respond to antigenic stimulus by producing cytokines, which activate T-cells (cytotoxic CD8+
T-cells), B-cells and macrophages.
• Cytotoxic T-cells, once activated (CD25+ T-cells),
destroy allogenic or infected target cells.
• Both CD4+ and CD8+ T-cells can suppress immune
response through production of suppressive cytokines,
negative regulation of signal transduction and via idiotypic network.
Major Histocompatibility Complex
Antigens (MHC)
• MHC is a set of genes encoding cell surface glycoproteins.
• MHC antigens play a fundamental role in the immune
response by presenting antigenic peptides to T-cells.
• TCR of an individual T-cell will only recognize antigen
as part of a complex of the antigenic peptide and the
individual’s MHC complex.
• e process of dual recognition of peptide plus MHC
is known as MHC restriction, since the MHC molecule
restricts the ability of the T-cell to recognize antigen.
• MHC genes are carried on the short arm of chromosome 6 and code for three classes of molecules:
• class I are divided into three dierent groups: A, B, C;
they are present on virtually all nucleated cells and
signal to cytotoxic T-cells
• class II loci are known as DP, DQ and DR; they are
restricted to a few cell types (i.e. B-cells, activated
T-cells, macrophages) and signal to T-helper cells
• class III are genes for components of the comple-
ment system.
CHAPTER 19 Immunology
333
BOX 19.1 Some HLA-Associated
Diseases
HLA Antigens Disease
B 27 Ankylosing spondylitis
Reiter’s disease
DR 2 Goodpasture’s syndrome
DR 3 Addison’s disease
Hashimoto’s disease
Myasthenia gravis
DR 4 Insulin-dependent diabetes
• MHC restriction allows antigens in dierent intracellular compartments to be captured and presented to
CD4+ or CD8+ cells.
• Endogenous antigens (including viral antigens) are
presented by MHC class I-bearing cells exclusively to
CD8+ T-cells (cytotoxic T-cells).
• Exogenous antigens are presented by MHC class
II-bearing cells to CD4+ T-cells (helper T-cells).
• HLA (human leucocyte antigen) subtypes are important in determining matching in transplantation.
• HLA subtypes are statistically related to certain diseases,
e.g. B27 and ankylosing spondylitis (see Box 19.1).
THE STRUCTURE OF THE IMMUNE SYSTEM
• All lymphoid cells originate from a pluripotential stem
cell in the bone marrow.
• Lymphoid progenitor cells destined to become T-cells
migrate from the bone marrow to thymus.
• B-cell development occurs in the bone marrow.
• e thymus and bone marrow are primary lymphoid
organs.
• Lymph nodes, spleen and MALT are secondary lymphoid organs.
Lymph Nodes
• Lymph node architecture is well adapted to function
(Fig. 19.2).
• Aerent lymphatics penetrate the capsule, and lymph
enters into the marginal sinus.
• A branching network of sinuses passes through the cortex and medulla to eerent lymphatics.
• e sinus network provides a ltration system for antigens entering the node.
• Cortex contains primary follicles of B-lymphocytes surrounded by T-cells in the paracortex.
• Cortex also contains dendritic cells, which form a mesh
within the follicles, i.e. antigen presenting cells (APC).
• Primary follicles develop into secondary follicles on antigenic stimulation. Secondary follicles contain germinal
centres comprising B-cells and a few helper T-cells.
• B-cells in secondary follicles are antigen activated.
• Activated B-cells migrate from the follicle to the medulla,
where they develop into plasma cells in the medullary
cords and release antibodies into the eerent limb.
• Interdigitating dendritic cells (IDC) are found in the
paracortex. ey stimulate T-cells within the paracortex.
Spleen
• Responds to antigens in the blood.
• Lymphoid tissue is in the white pulp, arranged around
arterioles.
• T-cells surround the central arteriole.
• B-cells are eccentrically placed within the white pulp;
they may form germinal centres when stimulated.
Mucosa-Associated Lymphoid Tissue (MALT)
• Responds to antigens at mucosal surfaces.
• Important in transport of immunoglobulins to luminal
surfaces.
• Consists of three components in the gut:
• Peyer’s patches: dense aggregates of lymphoid tis-
sue in the terminal ileum. The flattened epithelium
over these aggregates contains M-cells, which are
capable of antigen binding and processing. They
pass antigenic material to adjacent T-helper cells
• lamina propria cells: T-helper cells
• intraepithelial cells: T-suppressor cells; may be impor-
tant in maintaining tolerance to food antigens.
The Immune Response (Summary)
• Presentation of antigen to lymphocytes is performed by
specialized antigen presenting cells (APCs), which can
be dendritic cells, macrophages or B cells.
• Antigen presentation can be direct (unprocessed antigen presentation by donor cells) or indirect (processed
antigen presentation by recipient helper T cells).
• Processed antigen is presented to T-cells alongside MHC
class II antigen on the APC surface because T-cells do not
recognize processed antigen alone.
• Each B-lymphocyte is committed to the production of an
antibody with a unique antigen-binding site, i.e. idiotype.
• Antibody production usually requires the intervention
of T-helper cells.
• T-helper cells are divided into two subgroups according
to the cytokines which they produce:
• 1-cells secrete TNF and IFN-γ, and mediate cel-
lular immunity
• 2-cells secrete IL-4, IL-5, IL-10 and IL-13, and
stimulate antibody production by B-cells.
334
thymus-dependent
Primary
Afferent
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SECTION III Pathology
lymphatics
Valve
Capsule
Secondary follicle
follicle
Trabeculum
Efferent
lymphatic
Fig. 19.2 The structure of a normal lymph node.
Subcapsular sinus
Paracortical
zone
Medullary cords
Medullary sinus
Artery and vein
• opsonization promoting phagocytosis
• removal of immune complexes
• mediation of vascular and cellular components of
acute inammation.
IMMUNE DEFICIENCY
• Immune deciency can be classied as:
• specic deciencies: defects in the immune system
itself, i.e. primary and secondary
• non-specic deciencies, e.g. neutrophil deciency,
complement deciencies.
• Specic deciencies are divided into:
• primary: due to an intrinsic defect in the immune
system (usually genetic)
• secondary: due to an underlying condition.
• e eciency of the secondary antibody response is due
to clonal expansion.
• T-lymphocytes can directly kill virus-infected cells or
release cytokines which contribute to inammation.
COMPLEMENT
• Complement is a complex series of proteins that act as
an enzymatic cascade. Activation occurs in a stepwise
cascade, each activated component having the ability
to activate several molecules of the next protein in the
cascade.
• Complement can be activated by antigen–antibody
complexes, i.e. the classical pathway, or by bacterial cell
surfaces, i.e. the alternative pathway (Fig. 19.3).
• In both pathways the outcome is the production of a
membrane attack complex.
• Functions of complement include:
• bacterial killing or target cell killing by membrane
lysis
Primary Immune Deficiency
• Rare.
• May aect dierent cell types:
CHAPTER 19 Immunology
Classical pathway
Alternative pathway
335
Antigen–antibody
complexes
C5a C4a C3a
Inflammation
Chemotactic for neutrophils
Increased vascular
permeability
Release of histamine from
mast cells
Fig. 19.3 Pathways of complement activation.
• several types of cell, i.e. reticular dysgenesis – failure
of stem cells, severe combined immunodeciency
(SCID) – T- and B-cells aected
• predominantly T-cells, e.g. di George syndrome,
Nezelof syndrome
• predominantly B-cells, e.g. agammaglobulinaemia.
Secondary Immune Deficiency
• Age: relative lack of immune response in infancy and
old age.
• Malnutrition: defect in antibody and, in severe cases,
T-cell function.
• Neoplastic disorders of immune system, e.g. Hodgkin’s
disease, B-cell lymphoma, myeloma, chronic lymphocytic leukaemia.
• Iatrogenic, e.g. drugs to prevent allogra rejection,
splenectomy.
• Infection: immunodeciency extreme with HIV, may
occur transiently with cytomegalovirus (CMV), rubella,
infectious mononucleosis and viral hepatitis.
Infections characteristic of the dierent types of immunodeciency are shown in Fig. 19.4.
HYPERSENSITIVITY REACTIONS
Hypersensitivity is an altered immunological response in
which a severe and harmful reaction occurs to extrinsic
antigens.
ere are four types of hypersensitivity reaction:
• type I: immediate hypersensitivity or ‘allergy’ due to
overproduction of IgE on mast cells and basophils (anaphylactic or immediate)
C3
C3 convertases
C3b
Opsonisation
Removal of immune
complexes
• type II: antibody to cell-bound antigen (cytotoxic)
• type III: immune complex reaction
• type IV: delayed hypersensitivity mediated by T-cells.
Type I
• Overproduction of IgE on mast cells and basophils.
• Release of vasoactive substances, e.g. histamine, chemo-
• Anaphylactic shock, e.g. bee and wasp venom, antibiot-
• Atopic diseases (individuals producing an excessive
Type II
• Circulating antibodies (IgG or IgM) react with antigen
• Death of cells occurs via:
• Examples of Type II hypersensitivity include:
Type III
• Deposition or formation of immune complexes in the
Bacterial cell
surfaces
C5–9
Cell lysis
‘Membrane attack
complex’
kines, leading to vasodilatation.
ics (penicillin), peanuts.
reaction to antigens are termed atopic), e.g. asthma,
hayfever, allergic rhinitis.
on cell surface.
• lysis of cell membrane due to complement activation
• phagocytosis of cell to which antibody is bound
• promotion of killer cell cytotoxicity.
• transfusion reactions
• rhesus incompatibility
• autoimmune haemolytic disease
• idiopathic thrombocytopaenic purpura
• myasthenia gravis
• Goodpasture’s syndrome.
tissues.
336
Specific immunity
organisms
Cryptosporidium
Non-specific
Gram-negative
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SECTION III Pathology
Immunity
Defence
Usual
isolated
Antibody
Pyogenic bacteria
Staphylococci
Strep. pneumoniae
H. influenzae
Some viruses
Enteroviruses
Cellular immunity
Virus
CMV
Herpes zoster
Papilloma
Fungi
Candida
Aspergillus
Pneumocystis
Bacteria
Mycobacteria
Listeria
Protozoa
Pyogenic bacteria
Fig. 19.4 Infections characteristic of types of immunodeficiency.
• Free antigen and antibody (IgG or IgM) combine in
the presence of complement and precipitate as immune
• Example: TSH receptor antibody results in prolonged
hypersecretion of thyroid hormone in Graves’ disease.
complexes, causing tissue destruction.
• Tissue destruction results from:
• release of lysosomal enzymes by neutrophils
• vasoactive amines released by platelet aggregates
• platelet aggregates occlude circulation.
• Examples include:
• endogenous antigens, e.g. serum sickness, druginduced haemolytic anaemia (quinine)
• microbial antigens, e.g. post-streptococcal glomerulonephritis
• autologous antigens, e.g. rheumatoid arthritis, systemic lupus erythematosus, polyarteritis nodosa.
AUTOIMMUNITY
• Autoimmunity is an immune response against a selfantigen, i.e. loss of tolerance to ‘self ’.
• Autoimmune disease results in tissue damage or disturbed function resulting from an autoimmune response.
• Autoimmune responses can occur without resulting
disease.
• Autoimmune disease may attack a single organ, i.e.
organ-specic; or involve autoantigens widely distributed throughout the body, i.e. non-organ-specic.
Complement
Neisseria
immunity
Phagocytes
Bacteria
Staphylococci
Fungi
Candida
Aspergillus
Type IV
• Cell-mediated hypersensitivity involving specically
primed T-lymphocytes.
• Release of lymphokines.
Possible Mechanisms of Autoimmunity
• Genetic factors.
• Antigenic abnormality.
• Dysregulation of the immune response.
• Reaction takes 2–3 days to develop.
• Examples include:
• microbial agents, e.g. tuberculosis, viruses and fungi
• tuberculin test
Genetic Factors
• Association of disease with specic alleles of MHC class
II (HLA-D region) (see Box 19.1).
• rejection of tissue and organ gras
• contact dermatitis.
Type ‘V’ (Not Part of the Original Gell & Coombs
Classification)
• Some IgG antibodies stimulate cells against which they
are directed.
Antigenic Abnormality
• Surface antigens modied by drugs, e.g. haemolytic
anaemia due to antibodies against e-antigen of rhesus
system with methyldopa.
• Cell antigens modied by inammation or disease processes when new antigens are formed, e.g. Epstein–Barr
virus.
CHAPTER 19 Immunology
337
BOX 19.2 Examples of Autoimmune
Disease
Examples of
Autoimmune Disease
Organ-specific
Hashimoto’s thyroiditis Thyroglobulin, thyroid
Graves’ disease TSH receptor
Pernicious anaemia Parietal cells, intrinsic
Goodpasture’s syndrome Glomerular and lung
Myasthenia gravis Acetylcholine receptor
Non-organ-specific
Systemic lupus
erythematosus (SLE)
Rheumatoid arthritis IgG (rheumatoid factor)
Scleroderma (CREST
variant)
Autoantibodies Present
Against
peroxidase
factor
basement membrane
Nuclear antigens, DNA,
smooth muscle
Centromere
• Microbial antigens crossreacting with host tissues, e.g.
β-haemolytic streptococcus and antigen in cardiac muscle, resulting in rheumatic fever.
• Exposure of previously secluded antigens, e.g. sympathetic ophthalmitis with penetrating eye injuries, sympathetic orchidopathia and testicular damage (torsion,
mumps).
Immune Dysregulation
• Abnormal presence/activity of autoreactive T-cells.
• Failure of regulatory cells.
• CD4+ cell activity increased.
Examples of self-antigens and autoimmune disease are
shown in Box 19.2.
ORGAN TRANSPLANTATION
Types of Graft
• Autogra: tissue is transferred from one area of the
body to another in the same individual, e.g. skin gra.
• Isogra: tissue is transferred between genetically identical individuals, e.g. monozygotic twins.
• Allogra: tissue is transferred between genetically dissimilar individuals of the same species, e.g. deceased
donor renal transplant.
• Xenogra: tissue is transferred between dierent
species.
Major Histocompatibility Complex (MHC)
• Located on short arm of chromosome 6.
• Group of antigens governing rejection are part of the
human leucocyte antigen (HLA) system.
HLA Class I: Coded at A, B, C Loci
• To date, 1381 alleles for HLA-A, 1927 for HLA-B and
960 for HLA-C have been identied.
• HLA-A and HLA-B induce formation of complementxing cytotoxic antibodies, and act as cell surface recognition markers for cytotoxic T-cells.
• In kidney gras, class I antigens are present on vascular
endothelium, interstitial cells, mesangial cells and tubular epithelium.
Class II
• HLA-D locus: DR (927 alleles), DP (170 alleles) and DQ
(162 alleles).
• Class II antigens are expressed on the surface of B-cells,
macrophages, activated T-cells and antigen-presenting
cells.
• Class II molecule recognition activates CD4+ T-helper
cells, which begin the process of clonal expansion, and
also support cytotoxic T-cell clonal expansion by stimulating the CD4+ lymphocyte generation of regulatory
cytokines.
• Matching of class II antigens is the most important factor in predicting the outcome of transplantation.
Immunological Pathology of Graft Rejection
e alloimmune response or rejection process has two
phases (Fig. 19.5):
• aerent (sensitization) phase
• eerent (eector) phase.
Afferent Phase
• Allorecognition may occur in the gra itself, or in the
lymphoid tissue of the recipient.
• Donor MHC molecules found on donor gra tissue are
recognized by recipient CD4+ T-cells, i.e. allorecognition (direct pathway).
• Recipient helper T-cells recognize donor MHC molecules that have been processed by APCs of recipient
origin (indirect pathway).
• Following antigen presentation, binding of the costimulation molecules present on the APC and T-cell
receptor activates the intracellular signalling pathways, leading to IL-2 gene transcription, translation
and release. IL-2 binds to CD25, resulting in T-cell
proliferation.
338
Efferent
(effector
phase)
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SECTION III Pathology
Afferent
(sensitisation)
phase
Donor
antigens
Donor dendritic cell
(antigen presenting)
Th
Tc
Lymph nodeKidney
CD8+
Th1
CD4+
Th2
Plasma cell
Cytokines
Macrophages
Tc
Fig. 19.5 Immunopathology of graft rejection.
Efferent Phase
• CD4+ T-cells (helper cells) enter the gra and recruit
cells responsible for the tissue damage of rejection.
• Cells recruited include B-lymphocytes, macrophages,
natural killer cells, CD8+ T-cells (cytotoxic T-cells).
• Activated cytotoxic cells damage the gra cells by proteolytic action (granzyme B and perforin).
• Cytokines important in gra rejection are IL-2 and
gamma interferon.
Clinical Rejection
ere are four types of clinical rejection:
• hyperacute
• accelerated acute
• acute
• chronic.
Hyperacute
• Rare.
• Occurs within minutes to hours.
• Occurs during operation and in the case of the kidney it is seen to be accid, cyanotic, and eventually
thromboses.
• Occurs with ABO incompatibility or preformed cytotoxic antibodies as a result of failed transplant, pregnancy or blood transfusion.
• Preformed cytotoxic antibody reacts with MHC class I
antigen in donor organ.
y
t
i
n
y
t
u
i
n
m
u
m
i
m
l
a
m
i
r
o
m
u
H
Renal
cells
e
t
y
c
o
h
p
m
y
d
l
-
e
t
T
a
i
c
i
d
x
e
o
t
m
-
o
l
t
l
y
e
C
C
• Activation of complement: influx of polymorphs,
platelet aggregation, obstruction of blood vessels,
ischaemia.
• IgG and C3 bound to endothelial cells.
• No successful therapy.
• Gra loss occurs.
Accelerated Acute
• Occurs within 2–4 days.
• Previous sensitization to donor antigens oen due to
previous transplant.
Acute Rejection
• Cell-mediated or antibody-mediated
• Common.
• Treatable.
• Occurs between 1 week and 3 months post-transplant,
but is commonest around 7–10 days.
• Patient may have several episodes of acute rejection in
rst 3 months post-transplant.
• Early diagnosis is essential, as prompt treatment curtails
organ damage.
• Histology of cell-mediated rejection shows inltration
of tubules and interstitium by cytotoxic T-cells, which
destroy the gra in the absence of treatment.
• In antibody-mediated rejection, there are detectable
donor-specic antibodies (DSA) in recipient blood,
and histology of the kidney shows intimal arteritis and
CHAPTER 19 Immunology
339
thrombosis of blood vessels with deposition of C4d in
the peritubular capillaries.
Chronic Rejection
• Characterized by slow loss of organ function over a
period of months or years. In kidneys, there is associated hypertension and proteinuria.
• Histological ndings include thickening of the glomerular basement membrane, hyalinization of glomeruli,
intimal hyperplasia, tubular atrophy and interstitial
brosis.
• Both immunological and non-immunological factors
are implicated in the process.
• Chronic allogra injury (CAI) is the latest nomenclature because the aetiology is poorly understood.
• Chronic rejection is untreatable; however, modulation
of risk factors prolongs allogra survival.
Transplant Tolerance
• Induction of tolerance (unresponsiveness) to donor
antigen and elimination of the requirement of maintenance immunosuppression remains the ultimate goal.
• Still remains in experimental stage.
• Regulatory T-cells (Tregs) suppress the responses of
activated T-cells in tolerance.
• Co-stimulation blockade for the induction of tolerance
using belatacept is under investigation.
IMMUNOSUPPRESSION
Prevention of rejection requires:
• good matching between donor and recipient HLA
• suppression of the immune system of the recipient.
antimetabolite (mycophenolate mofetil or azathioprine) and prednisolone.
• Maintenance therapy:
• drugs used as prophylaxis against acute rejection are
usually continued as maintenance therapy
• the dose is gradually reduced over a period of time
• in some cases, one of the drugs may be eliminated with time, e.g. steroids, to prevent long-term
complications
• sirolimus is used to substitute CNIs if intolerance or
nephrotoxicity develops.
• Anti-rejection therapy:
• cell-mediated acute rejection is treated with three
intravenous pulses of steroids (methylprednisolone);
steroid-resistant cell-mediated rejection is treated
wi th ATG
• antibody-mediated acute rejection is treated with
plasmapheresis to remove anti-HLA antibodies,
intravenous immunoglobulin to neutralize the circulating antibodies, and rituximab (anti CD-52
monoclonal antibody) to suppress further production of antibodies by B cells.
Immunosuppressive Drugs
Corticosteroids
• Mainstay of immunosuppression since the 1950s.
• Interfere with antigen presentation.
• Inhibit T-cell activation by blocking IL-1, IL-2, IL-6 and
IFN-γ.
• Exert anti-inammatory eects as well as immunosuppressive eects.
• Inhibit neutrophil phagocytic activity.
Immunosuppressive Drugs
ese have the following indications:
• Induction therapy:
• given prior to transplantation and in the early postoperative period in order to avoid or delay acute
rejection episodes
• examples include anti-IL-2R monoclonal antibodies
(basiliximab and daclizumab), anti-thymocyte globulin (ATG). Orthoclone anti-CD3 monoclonal antibody (OKT3) is seldom used these days because of the
severe side-eects from cytokine release syndrome
• combination of immunosuppressive agents are commenced immediately following transplantation
• combinations are used to allow reduction in dose of
each agent in attempt to reduce toxicity
• examples of acute rejection prophylaxis combination therapy include: calcineurin inhibitor (tacrolimus or ciclosporin) in combination with an
Antiproliferative Drugs
ese include azathioprine, mycophenolate mofetil (MMF)
and mycophenolate sodium (MPS).
• Azathioprine:
• interferes with nucleic acid
• aects cells that are actively replicating, i.e. T-cells
undergoing clonal expansion
• non-specic and aects all proliferating cells.
• MMF and MPS:
• inhibit enzyme in pathway of purine synthesis
through inhibition of inosine monophosphate dehydrogenase (IMPDH)
• more eective than azathioprine in prevention of
acute rejection
• more selective than azathioprine
• block proliferation of T- and B-cells, inhibit antibody formation, inhibit generation of cytotoxic
T-cel ls
340
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SECTION III Pathology
• prevent smooth muscle cell proliferation, which
might have additional benefit for chronic rejection.
Calcineurin Inhibitors (CNI)
ese include ciclosporin and tacrolimus.
• Both drugs are fungal products.
• CNIs inhibit T-cell activation through inhibition of IL-2
gene transcription, thereby inhibiting generation of
cytotoxic T-lymphocytes.
• Both drugs are nephrotoxic at high dose so blood concentrations require measurement.
Other Drugs
Sirolimus (Rapamycin) and Everolimus
• Macrolide antibiotic.
• Engages a protein-designated mammalian target of
rapamycin (mTOR) and its inhibition reduces cytokinedependent cellular proliferation at G1 to S phase of cell
division cycle, thereby blocking T-cell activation.
• Non-nephrotoxic.
• Impairs wound healing.
Antilymphocyte Globulin (ALG) and Antithymocyte
Globulin (ATG)
Both prepared by immunizing animals with lymphocytes,
which increases the risk of anaphylaxis.
• ymocytes are used to prepare ATG.
• Used to treat steroid-resistant rejection episodes.
• May be used prophylactically in highly sensitized patients.
Drugs Under Evaluation
• Belatacept: costimulation blockade.
• Alemtuzumab: anti-CD52 monoclonal antibody.
• Bortezomib: proteosome inhibitor.
• Eculizumab: anti-C5 monoclonal antibody.
• Sotrastaurin: protein kinase C inhibitor.
Side Effects of Immunosuppression
Apart from side eects specic to the dierent drugs, the
general side eects of immunosuppression include infection and neoplasia.
Infection
• Patients are prone to infection, particularly with opportunistic organisms.
• Opportunistic infections include:
• bacterial, e.g. TB and urinary tract infection
• viral, e.g. cytomegalovirus, herpes simplex, herpes
zoster and BK virus infections
• fungal, e.g. Candida, Aspergillus, Pneumocystis jirovecii
• protozoal, e.g. toxoplasmosis.
Neoplasia
• Skin tumours, e.g. squamous cell carcinoma.
• Post-transplant lymphoproliferative disease (PTLD),
e.g. B-cell lymphoma.
• Kaposi’s sarcoma.
• Other cancers have up to a 100-fold increase compared
with age-matched controls.
Monoclonal Antibodies
ese include anti-CD3 monoclonal antibody and anti-IL2R monoclonal antibody.
• Anti-CD3 (OKT3):
• directed against CD3 complex of T-cell receptor
• also blocks the function of killer T-cells
• can be used to treat steroid-resistant rejection.
• Anti-IL-2R (basiliximab and daclizumab):
• targeted against IL-2 receptors
• designed to prevent, but not treat, acute rejection
episodes.
Graft-Vs-Host Disease
• Occurs when immunocompetent lymphocytes are
introduced into an immunocompromised host in sufcient numbers.
• Complication of bone marrow transplantation when
immunocompetent cells recognize the host as foreign
and start an immunological attack.
• Clinical manifestations include fever, weight loss, rash,
hepatosplenomegaly, diarrhoea.
• Mortality severe: 70% of those with severe disease die.
OSCE SCENARIOS
OSCE Scenario 19.1
A 17-year-old female presents to your trauma service with
an infected dog bite to her right arm, with associated lymphangitis. Whilst on the ward awaiting theatre for washout
and debridement, she is started on intravenous antibiotics.
Shortly aer, the sta nurse in the patient’s bay calls for
help, and you nd that the patient is ushed, anxious and
you can hear a slight wheeze when she is breathing.
1. What is the most likely diagnosis?
2. What type of immune reaction is this?
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