TYPE-I HYPERSENSITIVITY
This results from the combination of antigen with high-
affinity IgE (reaginic) antibody on the surface of tissue mast
cells and/or blood basophils, releasing potently vasoactive
and pro-inflammatory mediators. These mediators include
histamine, leukotrienes C 4 , D 4 and E 4 , eosinophil chemotac-
tic factor (ECF), serotonin, tachykinins and prostaglandins.
This can cause anaphylaxis, bronchospasm, hay fever or
urticaria.
TYPE-II HYPERSENSITIVITY
These reactions occur when antibody combines with antigenic
components on a cell or tissue surface. This leads to cell lysis or
tissue damage as a result of antibody-directed cell-mediated
cytoxicity (ADCC) by macrophages and natural killer (NK)
cells through Fc receptors or by activation of complement. This
reaction may form the basis of a drug reaction (e.g. penicillin-
orquinidine-induced haemolytic anaemia or thrombocyto-
penia). This is because although most drugs are low molecular
weight, they can bind to a protein to form an immunologically
active entity (‘hapten’). Another example of this type of reac-
tion is haemolytic disease of the newborn, when antibodies
produced by a rhesus-negative mother against the rhesus fac-
tor on the red cells of the fetus cross the placental barrier and
cause haemolysis. Such reactions may be mediated by IgM or
IgG antibodies.
TYPE-III HYPERSENSITIVITY (ARTHUS REACTION –
IMMUNE COMPLEX MEDIATED)
This is the result of the deposition of soluble antigen–antibody
complexes in small blood vessels (e.g. in the renal glomeruli)
or other tissues. Immune complex deposition activates com-
plement and initiates a sequence which results in chemotaxis
of polymorphs, tissue injury and vasculitis. This reaction is
slower in onset than the immediate type I reaction. Serum
sickness is an example of this type of response.
TYPE-IV (DELAYED OR CELL-MEDIATED
HYPERSENSITIVITY)
This is mediated by sensitized CD41 circulating T lymphocytes
reacting with antigen. Circulating antibodies are not involved.
Activation of primed CD41 T cells causes their proliferation
and the release of cytokines which produce local inflammation,
attracting and activating NK cells, macrophages and granulo-
cytes. This type of reaction takes place after one to two days
and is exemplified by contact dermatitis, the Mantoux reaction
and organ transplant rejection.
IMMUNOSUPPRESSIVE AGENTS
For therapeutic purposes, immunosuppression should ideally
be specific and not impair immune responses indiscriminately.
The sites of action of immunosuppressive agents are shown
in Figure 50.1. Immunosuppressive agents are inevitably a
two-edged sword and before considering individual agents it
is worth considering some of their general adverse effects.
GENERAL ADVERSE EFFECTS OF
IMMUNOSUPPRESSIONIncreased susceptibility to infectionBacterial infections are
common and require prompt treatment with appropriate
antibiotics. Tuberculosis may also occur and sometimes
takes unusual forms. Viral infections may be more severe
than usual and include the common herpes infection, but
occasionally also such rarities as progressive multifocal
leukoencephalopathy. Fungal infections are also common,
includingCandida albicans(which may be local or systemic).
Protozoal infections (e.g. Pneumocystis carinii) also occur
with increased frequency.SterilityAzoospermia in men is common, especially with
alkylating agents (Chapter 48). In women, hormone failure
leading to amenorrhoea is common.TeratogenicityThis is less common than might be anticipated.
However, it is prudent to avoid conception while on these
drugs. Men should wait 12 weeks (the time required to clear
abnormal sperm) after stopping treatment.CarcinogenicityImmunosuppression is associated with an
increased incidence of malignant disease. Large-cell diffuse
lymphoma can present early in treatment, but with
prolonged treatment other types of malignancy may arise.
The incidence in transplant patients is about 1%.GLUCOCORTICOSTEROIDS
For more information, see Chapter 40.Uses
Glucocorticosteroids are used in each of the four kinds of
hypersensitivity disease:- Glucocorticosteroids are used in the treatment of allergic
rhinitis, atopic dermatitis, acute severe asthma, chronic
asthma and anaphylaxis. In allergic rhinitis and atopic
dermatitis (type-I reactions), the principal benefit
probably arises from their non-specific anti-inflammatory
effects, including vasoconstriction and decreased vascular
permeability.
2.Glucocorticosteroids are often effective in type-II
autoimmune diseases. They are the drugs of choice for
pemphigus vulgaris and autoimmune haemolytic
anaemia, and are often effective in idiopathic
thrombocytopenic purpura (ITP).
3.Immune complex disease (type-III hypersensitivity) may
also be treated with glucocorticosteroids, although they
often produce symptomatic relief without altering the
underlying disease process.
4.Glucocorticosteroids are potent inhibitors of the cell-
mediated hypersensitivity (type IV) reactions. Clinically
they are used to prevent acute graft rejection and improve
severe contact dermatitis.
400 CLINICAL IMMUNOPHARMACOLOGY