FACTORS ASSOCIATED WITH THE INDUCTION OF AN IMMUNE RESPONSE
In addition to the chemical nature of the immunogen, other factors strongly influence the development and potency of an immune response.
Different animal species and different strains of one given species may show different de-grees of responsiveness to a given antigen. In humans, different individuals can behave as “high responders” or “low responders” to any given antigen. The genetic control of the im-mune response is poorly understood, but it involves the repertoire of MHC molecules that bind antigen fragments and present them to the responding T-cell population. The affinity of the peptide for the MHC and of the peptide-MHC complex for the T-cell receptor will dictate, at least in part, the T-cell response. Other factors that promote or suppress the im-mune response must exist, but they are less well understood.
The method of antigen administration has a profound effect on the immune response. A given dose of antigen may elicit no detectable response when injected intravenously, but a strong immune response is observed if injected intradermally. The presence of dendritic cells in the dermis (where they are known as Langerhans cells) may be a critical factor de-termining the enhanced immune responses when antigens are injected intradermally. This route of administration results in slow removal from the site of injection and in uptake and processing of the antigen by dendritic cells. The dendritic cells may present antigen to mi-grating T cells or may themselves migrate to the lymph node follicles, where the initial stages of the immune response take place. Thus, intradermal administration promotes pro-longed antigenic stimulation and facilitates the involvement of one of the most specialized populations of antigen-presenting cells.
Adjuvants are agents that, when administered along with antigens, enhance the specific re-sponse. In contrast to carrier proteins, adjuvants are often nonimmunogenic and are never chemically coupled to the antigens. Several factors seem to contribute to the enhancement of immune responses by adjuvants, including delayed release of antigen, nonspecific in-flammatory effects, and the activation of monocytes and macrophages. Several microbial and inorganic compounds have been used effectively as adjuvants both clinically and as in-vestigational agents.
One of the most effective adjuvants is complete Freund’s adjuvant (CFA), a water-in-oil emulsion with killed mycobacteria in the oil phase. This is the adjuvant of choice for production of antisera in laboratory animals. Bacille Calmette-Guérin (BCG), an attenuated strain of Mycobacterium bovis used as a vaccine against tuberculosis, and muramyl dipep-tide (MDP), the active moiety of Mycobacterium tuberculosis and of BCG, also have ad-juvant properties. BCG has also been used as an immunotherapeutic agent to boost the im-mune system in patients with special types of cancer (e.g., superficial bladder cancer). Their use is limited, however, by side effects such as intense inflammatory reactions and discomfort. Recently, growth factors such as GM-CSF have been found to have adjuvant properties that may be clinically useful for the induction of cancer-specific immune re-sponses .
Aluminum hydroxide, an inert compound that absorbs the immunogen, stimulates phagocytosis, and delays removal from the inoculation side, is an adjuvant frequently used with human vaccines. Aluminum hydroxide is not as effective as many of the adjuvants listed above, but it is considerably less toxic.
Finally, there is considerable interest in the development of adjuvants that may tilt the immune response in favor of TH1 responses, a critical goal for vaccines targeting the in-duction of cell-mediated immune responses. One compound with such properties currently being investigated is the Leishmania protein known as Lel-F, a potent inducer of TH 1 re-sponses in mice.
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