Immunosuppression
Suppression
of immune responses, a regular part of the management of organ transplantation, can also be of value
in cases of severe hyper- sensitivity and autoimmunity. Most of the methods
currently available are more or less non-specific, and their use is limited by
dangerous side-effects (right).
The problem is to interfere with
specific T and/or B cells (top centre, darker colour) or their effects, without
causing damage to other vital functions. T cells can be depleted by
antilymphocyte antisera (ALS) and by removing or damaging recirculating cells
(which are mostly T); however, this will remove not only undesirable
lymphocytes, but also others upon whose normal response to infection life may
depend (B, T, lighter colour). Lymphocytes almost always divide
in the course of responding to antigen (centre), so drugs that inhibit cell
division are effective immunosuppressants (the same drugs tend to be useful
in treating cancer for the same reason);
here the danger is that other dividing
tissues, such as bone marrow and intestinal epithelium, will also be inhibited.
A third point of attack is the non-specific effector mechanisms involved
in the ‘inflammatory’ pathways (bottom) which so often cause the actual damage,
but here again useful and harmful elements are knocked out indiscriminately.
What is clearly needed is an attack
focused on antigen-specific lymphocytes, i.e. an attack via their receptors
(top left). This might take the form of masking the antigens by which they are
stimulated, masking or removing the receptors themselves, or using them to
deliver a ‘suicidal’ dose of antigen to the cell. Whether any of these
experimental approaches will be effective enough to replace the present clumsy
but well-tried methods of immunosuppression time will tell.
ALS (antilymphocyte serum) is made by immunizing
horses or rabbits with human lymphocytes and absorbing out unwanted
specificities. It depletes especially T cells, probably largely by opsonizing
them for phagocytosis. It has found a limited use in organ transplantation.
Monoclonal antibodies to B cells, particularly to CD20 on the B-cell surface,
were originally introduced to treat B-cell lymphomas (see Fig. 42), but have
also proved useful in treatment of rheumatoid arthritis. Antibodies to particular
T-cell subsets or surface molecules, such as CD4, may have a more useful
future.
Extracorporeal irradiation of blood, and thoracic duct drainage are
drastic measures to deplete recirculating T cells, occasionally used in
transplant rejection crises.
6MP (6-mercaptopurine)
and its precursor azathioprine (Imuran) block purine metabolism, which
is needed for DNA synthesis; despite side effects on bone marrow polymorph and
platelet production, they were for many years standard therapy in organ
transplantation and widely used in autoimmune diseases, e.g. rheumatoid
arthritis and SLE. A more recent analogue is mycophenolate mofetil.
Cyclophosphamide and chlorambucil are ‘alkylating’
agents, which cross-link DNA strands and prevent them replicating properly. Cyclo-
phosphamide tends to affect B cells more than T cells, and there is some
evidence that it also acts on Ig receptor renewal. It is effective in
autoimmune diseases where antibody is a major factor (rheumatoid arthritis,
SLE), but the common side-effect of sterility limits its use to older patients.
Methotrexate,
fluorodeoxyuridine and cytosine
arabinoside are other examples of
drugs inhibiting DNA synthesis by
interfering with various pathways, which have been considered as
possible immunosuppressives.
Asparaginase, a bacterial enzyme, starves dividing
lymphocytes (and tumour cells) of asparagine, bone marrow, etc. being spared.
Cyclosporin and FK506 are important
immunosuppressive agents obtained from fungi and bacteria, respectively. They
bind to intracellular molecules called immunophilins, and in doing so block
activation of the T-cell-specific transcription factor NF-AT, and hence the production
of cytokines such as IL-2. Both have proved remarkably effective in bone marrow
transplantation and have become the drugs of choice for most transplants,
although long-term use is associated with a risk of kidney damage. Cyclosporin
has the added advantage of killing a number of microorganisms that might
otherwise infect the immunosuppressed host.
Plasma exchange (plasmapheresis), in which blood is removed and
the cells separated from the plasma, and returned in dextran or some other
plasma substitute, has been successful in acute crises of myasthenia gravis and
Goodpasture’s syndrome by reducing (usually only transiently) the level of
circulating antibody or complexes. It is also life-saving in severe haemolytic
disease of the newborn.
Corticosteroids (e.g. cortisone, prednisone) are, together with
cyclosporin, the mainstay of organ transplant immunosuppression, and are also
valuable in almost all hypersensitivity and autoimmune diseases. They can act on T cells, but their
main effect is probably on polymorph
and macrophage activity. Sodium retention (→ hypertension) and calcium loss (→
osteoporosis) are the major undesirable side effects.
Aspirin, indometacin, disodium
cromoglicate (DSCG) and a
variety of other anti-inflammatory drugs are useful in autoimmune diseases with
an inflammatory component (for other ways to control type I hypersensitivity
see Fig. 35).
Antibodies to inflammatory cytokines, especially TNF and
IL-1 have proved powerful weapons in the treatment of chronic inflammatory
diseases such as rheumatoid arthritis, Crohn’s disease, psoriasis and gout. An
alternative to antibodies is to use soluble forms of the cytokine receptors to
‘mop up’ free cytokine in the blood.
Specific immunosuppression
Antibody against target antigens, which is
especially effective in preventing rejection of tumours, probably works by
blocking class II determinants, which may also be how blood transfusion
improves kidney graft survival (see Fig. 39). Anti-Rh (D) antibodies will
prevent sensitization of Rh-negative mothers by removing the Rh-positive cells
(see Fig. 36).
Antibody against the CD4 molecule on T cells, when
administered at the same time as antigen, seems to induce a state of
long-lasting antigen-specific tolerance, at least in animal models. A similar approach
is being tried for prevention of transplant rejection in humans.
Antigen administered over a prolonged period in
very low doses can induce antigen-specific tolerance.
This approach, known as desensitization, has long been used for the suppression
of allergies. However, because of the rare but dangerous risk of inducing
anaphylaxis, it is seldom used in the UK. Antigen administered via the oral
(and perhaps also nasal) route induces strong antigen-specific suppression in
animals. A similar approach is being used in the treatment of autoimmune
diseases; in one such trial patients with multiple sclerosis, in which
autoimmune T cells attack the CNS, were fed extracts of animal myelin. Although
some small therapeutic effects were observed, further testing has been
disappointing.
Clonal elimination, or ‘classic tolerance’ (see Fig. 22), can be
induced in vitro by coupling cytotoxic drugs or radioisotopes to
antigen, which is then concentrated on the surface of those cells specifically
binding it; some success has also been obtained in vivo with this
‘retiarian therapy’ (named after Roman warriors who caught their victims with a
net and then killed them with a spear). It is quite possible that the
suppression caused by antiproliferative drugs (e.g. cyclophosphamide,
ciclosporin) in the presence of antigen, contains an element of specific clonal
elimination.
