Antibody-mediated immunity is efficiently induced by parenteral administration of antigens included in ISCOMs. In mice, the immune response was found to be a classical one, with an initial immunoglobulin M (IgM) response followed by an IgG response. The IgG response is distributed in all subclasses but the IgG2a response is dominant. In general, the antibody response to an antigen in an ISCOM is about 10 times higher than that induced by the same dose of the killed virus particles in saline or in micellar form.
After local intranasal administration of the hemag glutinin or neuroaminidase envelope proteins of influenza virus in ISCOMs, a high serum antibody response of the same order of magnitude as that following parenteral immunization was observed. A secretory IgA response is also efficiently evoked after intranasal immunization both at local respiratory mucosa and distant, e.g. genital tract, mucosa. In general, antigens derived from virus envelopes or cell membranes incorporated into ISCOMs retains biological activity and conformation provided their isolation is carried out under mild conditions. Thus, the biological activities of influenza virus surface glycoproteins borne by ISCOMs are conserved, facilitating the penetration of mucus, which explains their efficiency in evoking mucosal immune responses.
ISCOMs efficiently stimulate antigen-presenting cells (APCs) to produce interleukin 1 (IL-1) and IL-12. Other cytokines such as II.-6, granulocyte-macrophage colony-stimulating factor (GM-CSF) and tumor necrosis factor a (TNFa) are also induced. The ISCOM induces strong T cell responses of the Th1 type characterized by delayed-type hypersensitivity (DTH) and enhanced production of interferon y (IFNy) and IL-2, while IL-5 is enhanced IL-4 is not generally enhanced and IL-10 is downregul-ated. In general, ISCOMs are excellent inducers of IL-2 and IFNy.
ISCOMs efficiently induce antigen-specific cytotoxic T lymphocytes (CTLs) following either parenteral or mucosal routes of administration. It appears that the protein antigens contained in ISCOM can be delivered not only to endosomes bur also to the cytosol of APCs, leading to cytosolic processing, transportation to the endoplasmic reticulum, presentation by major histocompatibility complex (MHC) class I molecules to T cells, and a subsequent CD8+ T cell response. For example, ISCOMs containing the gpl60 of HIV-1 have been shown to induce MHC class I restricted CD8+ CTLs. The induction of relevant cytokines such as IL-12, IL-2 and IFNy is an additional benefit.
Protective immunity has been induced against a variety of microorganisms including viruses, bacteria, mycoplasma and parasites. Of particular interest is that protective immunity was induced by ISCOM-borne antigens to a number of retroviruses, e.g. feline leukemia virus infection in cats, to SIV, HIV-1 and HIV-2 in primates, to a tumor-inducing herpesvirus (e.g. Epstein-Barr virus) in cotton top tamarin monkeys, and against lethal infection of mice with Trypanosoma cruzi causing Chagas' disease in humans. Table 1 lists examples of ISCOM-borne antigens having induced protective immunity.
See also: Adjuvants; Immunogen; Immunopotenti-
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