Immunomodulation by Iscoms, Immune Stimulating Complexes

doi:10.1006/meth.1999.0833

Methods

Volume 19, Issue 1, September 1999, Pages 94-102

https://doi.org/10.1006/meth.1999.0833 Get rights and content

Abstract

The iscom is a uniform stable complex consisting of cholesterol, phospholipid, adjuvant-active saponin, and antigen. The iscom matrix is a particulate complex with identical composition, shape, and morphology, but lacking the incorporated antigen. The assembly of the complex is based on hydrophobic interactions, but antigens that are not hydrophobic can be conjugated with a hydrophobic tail or hidden hydrophobic regions can be exposed, e.g., by acid treatment, to facilitate the incorporation into iscoms. The functional aspects of iscoms are described emphasizing immunomodulation in mouse models. Iscoms prominently enhance the antigen targeting, uptake, and activity of antigen presenting cells including dendritic and B cells and macrophages resulting in the production of proinflammatory cytokines, above all interleukin (IL)-1, IL-6, and IL-12. The expression of costimulatory molecules major histocompatibility complex (MHC) class II, B7.1 and B7.2, is also enhanced. The latter partly explains why the iscom is an efficient adjuvant for elderly mice. Iscoms enhance the Th1 type of response with increased production of IL-2 and interferon γ. However, with some antigens and particularly in monkeys immunized with HIV iscoms, the production of IL-4 was enhanced. IL-4, IL-2, and interferon γ (IFNγ) together with the β chemokines MIP-1α and MIP-1β correlated with protection against challenge infection with a chimeric virus (simian immunodeficiency virus–human immunodeficiency virus). Iscoms were also shown to induce a potent immune response in the newborn and to be an efficient delivery system for mucosal administration. Technical information is given about formulation of iscoms and about handling of antigens to optimize their incorporation into iscoms.

References (90)

G.F.A. Kersten et al.
Biochim. Biophys. Acta
(1991)
M. Özel et al.
Quarternary structure of the immunostimulating complex (ISCOM)
J. Ultrastruct. Mol. Struct. Res.
(1989)
K. Lövgren et al.
Biotechnol. Appl. Biochem.
(1988)
K. Lövgren Bengtsson
M. Browning et al.
Vaccine
(1992)
G. Reid
Vaccine
(1992)
A.McI. Mowat et al.
Immunology
(1991)
K. Scheepers et al.
Med. Microbiol. Immunol.
(1994)
A.D. Wilson et al.
Vaccine
(1999)
B. Morein et al.
J. Immunol. Methods
(1990)

S. Pyle et al.

Vaccine

(1989)

R.F. Dourmashkin et al.

Nature

(1962)

J.A. Lucy et al.

J. Mol. Biol.

(1964)

B. Morein et al.

Nature

(1984)

R. Bomford et al.

Vaccine

(1992)

B. Rönnberg et al.

Vaccine

(1995)

K. Lövgren Bengtsson et al.

Vaccine

(1996)

J. Cox et al.

Vaccine

(1997)

G.E. Jones et al.

Vaccine

(1995)

D.R. Snodgrass et al.

Vaccine

(1995)

Lövgren, K, and, Sundquist, B. 1994, in, IBC Conference on Novel Vaccine Strategies, Washington, February...

G.A.W. Rook et al.

Immunol. Today

(1998)

B. Morein et al.

Clin. Immunother.

(1995)

B. Morein et al.

D. Hansen et al.

Parasite Immunol.

(1996)

D.S. Hansen et al.

Scand. J. Immunol.

(1998)

M.C. Villacrés et al.

Cell. Immunol.

(1998)

Villacrés-Eriksson, M. 1993, Induction of Immune Response by Iscoms, dissertation, Swedish University of Agricultural...

S. Behboudi et al.

Clin. Exp. Immunol.

(1996)

S. Behboudi et al.

Cytokine

(1997)

M. Villacrés-Eriksson et al.

Cytokine

(1997)

D.L. Watson et al.

Microbiol. Immunol.

(1992)

M. Bergström-Mollaoglu et al.

Scand. J. Immunol.

(1992)

Sambhara, S., Woods, S., Arpino, R., Kurich, A., Tamane, A., Lövgren Bengtsson, K., Morein, B., Underdown, B., Klein,...

S. Sambhara et al.

Vaccine

(1998)

T.F. Gajewski et al.

J. Immunol.

(1995)

J.C. Renauld et al.

J. Immunol.

(1989)

M. Villacrés-Eriksson

Clin. Exp. Immunol.

(1995)

Villacrés-Eriksson, M., Behboudi, S., Lövgren Bengtsson, K., and Morein, B.1997inVaccine Design: The Role of Cytokine...

B. Morein et al.

Immunol. Cell Biol.

(1998)

R.S. Van Binnendijk et al.

J. Exp. Med.

(1992)

A. Lanzavecchia

Nature

(1985)

R.W. Chesnut et al.

J. Immunol.

(1982)

R. Shimonkiewitz et al.

J. Exp. Med.

(1983)

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Regular ArticleImmunomodulation by Iscoms, Immune Stimulating Complexes

Abstract

Biochim. Biophys. Acta

Quarternary structure of the immunostimulating complex (ISCOM)

J. Ultrastruct. Mol. Struct. Res.

Biotechnol. Appl. Biochem.

Vaccine

Vaccine

Immunology

Med. Microbiol. Immunol.

Vaccine

J. Immunol. Methods

Vaccine

Nature

J. Mol. Biol.

Nature

Vaccine

Vaccine

Vaccine

Vaccine

Vaccine

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Immunol. Today

Clin. Immunother.

Parasite Immunol.

Scand. J. Immunol.

Cell. Immunol.

Clin. Exp. Immunol.

Cytokine

Cytokine

Microbiol. Immunol.

Scand. J. Immunol.

Vaccine

J. Immunol.

J. Immunol.

Clin. Exp. Immunol.

Immunol. Cell Biol.

J. Exp. Med.

Nature

J. Immunol.

J. Exp. Med.

Regular Article
Immunomodulation by Iscoms, Immune Stimulating Complexes