35 Passive and non-specific immunotherapy
The most dramatic and successful form of immunotherapy is vaccination, as described in the previous chapter. However, there are some situations where a different approach may be necessary. For instance:
• Alternatively, the patient’s immune system may be inadequate and unable to respond either to the infection or to a vaccine, through immunodeficiency or some especially resistant property of the parasite.
Before the introduction of antibiotics, acute infectious diseases were often treated by the injection of preformed antibody on the principle that the patient was already ill and it was too late for ‘active’ vaccination. Indeed, the demonstration that immunity to tetanus and diphtheria could be transferred to mice with serum from vaccinated rabbits was a key experiment in the discovery of antibody in the 1890 s. Subsequently, the production of antiserum for the passive treatment of diphtheria, tetanus and pneumococcal pneumonia, and against the toxic effects of streptococci and staphylococci, became an important industry, and generations of horses that had retired from active duty were kept on as the source of ‘immune serum’. The introduction of antitetanus serum in the early months of the First World War reduced the incidence of tetanus dramatically by up to 30-fold (Fig. 35.1).
Figure 35.1 Passive immunization significantly reduced the incidence of tetanus in the early months of the First World War. The figure shows the incidence of tetanus per 1000 wounded soldiers in British hospitals during 1914–1916. There was a dramatic fall after the introduction of antitetanus serum in October 1914.
The advent of penicillin and other antibiotics has, of course, changed the picture considerably, and passive immunotherapy is now used for only a select group of diseases (Table 35.1). The serum may be specific or non-specific and of human or animal origin.
|Source of antibody
|Prophylaxis in immunodeficiencies
|Post-exposure (plus vaccine)
|Pooled human immunoglobulin
Although not so commonly used as 50 years ago, passive injections of specific antibody can still be a life-saving treatment.
The use of antiserum raised in horses or rabbits has largely been abandoned because of the complications resulting from the immune response to the antibody, which is of course a foreign protein. These include progressively more rapid elimination (and therefore reduced clinical effectiveness) and, more seriously, serum sickness due to immune complex deposition in, for example, the kidney and skin (see Ch. 17), and even anaphylaxis. These complications can be avoided by using human serum taken during convalescence or following vaccination – to prevent infection after exposure (e.g. rabies) or to minimize its severity (e.g. varicella in immunodeficient children).
With common infections, it can be assumed that most normal people have antibody to the pathogen in their serum. The clearest proof of this is that patients with hypogammaglobulinaemia can be kept free of recurrent infection by regular injections of IgG from pooled normal serum, and that immunodeficient children can be protected against measles in the same way (Box 35.1). Immunoglobulin is prepared from batches of plasma from 1000–6000 healthy donors after screening for hepatitis B and C and HIV. With improvements in methods of preparation, intravenous injection is now preferred to intramuscular injection in most cases. Dosages for this type of therapy range from 100 to 400 mg IgG/kg per month.
In healthy individuals the probability of contracting hepatitis A in an endemic area is enormously reduced by a single injection of as little as 5 mL of IgG. The immunity conferred by mothers on their newborn infants by placental transfer of IgG and subsequently by colostral IgA (though the latter is not absorbed, but remains in the intestine) is further evidence for the protective effect of relatively small amounts of antibody.
Theoretically, the most effective therapy is provided by one or more monoclonal antibodies specific for a known target antigen
In practice, a mixture of several monoclonal antibodies mimicking just the relevant clones in a polyclonal serum might be required in situations where individual antigens are expressed in low quantities on the microbe or where binding to more than one epitope is required for full effectiveness. We have previously described the derivation of mouse monoclonal antibodies, but a serious complication is that they are highly immunogenic in humans and give rise to human anti-mouse antibodies (HAMA) which accelerate clearance of the monoclonal from the blood and possibly cause hypersensitivity reactions; they also prevent the mouse antibody from reaching its target and, in some cases, block its binding to antigen. Logic points to removal of the xenogeneic (foreign) portions of the monoclonal antibody and their replacement by human Ig structures using recombinant DNA technology. One refined approach is to graft the six complementarity determining regions (CDR) of a high-affinity rodent monoclonal onto a completely human Ig framework without loss of specific reactivity (Fig. 35.2). This is not a trivial exercise, however, and the objective of fusing human B cells to make hybridomas is still appealing, taking into account not only the gross reduction in immunogenicity but also the fact that, within a species, antibodies can be made to subtle differences such as major histocompatibility complex (MHC) polymorphic molecules and tumour-associated antigens on other individuals, whereas xenogeneic responses are more directed to immunodominant structures common to most subjects. Notwithstanding the difficulties in finding good fusion partners, large numbers of human monoclonals have been established.