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.
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.
Regulatory T cells Several research groups are also exploring the possibility of expanding the TREG population, and hence inhibiting the specific immune response. However, one needs to proceed with caution. A recent trial on six volunteers at a London hospital ended in disaster, as an antibody that was supposed to stimulate expansion of TREG cells in fact set off a ‘cytokine storm’ akin to a toxic shock reaction, resulting in severe damage to several of the volunteers.