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Pii: s1471-4906(01)01985-8

Research Update
TRENDS in Immunology Vol.22 No.8 August 2001 the sphingosine kinase pathway. Proc. Natl. Acad. 4 Kwak, B. et al. (2000) Statins as a newly recognized type of immunomodulator. Nat. Med. specificity and produce side-effects.
5 Proudfoot, A.E. et al. (2000) The strategy of blocking the chemokine system to combat disease.
6 Reedquist, K.A. et al. (2000) The small GTPase, Rap1, mediates CD31-induced integrin adhesion.
7 Aurrand-Lions, M.A. et al. (2000) Cloning of adhesion molecular family? Curr. Top. Microbiol. 8 Risau, W. et al. (1998) Differentiation of blood–brain barrier endothelial cells. Pathol. Biol. properties of the BBB are frequently lost, leukocytes will point to novel therapeutic specific loss of immunostaining for the TJ molecule claudin-1 from inflamed cerebral Beat A. Imhof*
claudin-5 and other TJ molecules, such as occludin and ZO-1, was conserved. In an in vitro model of the BBB, this selective loss Britta Engelhardt
of claudin-1 correlates directly with the the text represents only a small selection Max-Planck-Institut fur Physiologische und opening of endothelial TJs (Fig. 1). These Klinische Forschung, W.G. Kerckhoff-Institut, References
1 Butcher, E.C. et al. (1999) Lymphocyte trafficking and regional immunity. Adv. Immunol. 72, 209–253 Mathew A. Vadas
2 Johnson-Leger, C. et al. (2000) The parting of the endothelium: miracle, or simply a junctional affair? J. Cell Sci. 113, 921–933 3 Xia, P. et al. (1998) Tumor necrosis factor α Medical and Veterinary Science, University of induces adhesion-molecule expression through Adelaide, Adelaide, SA 5000, Australia.
IL-10 and its homologs: important immune mediators
and emerging immunotherapeutic agents

Hans-Dieter Volk, Khusru Asadullah, Grant Gallagher, Robert Sabat and Gerald Grütz The 3rd International Workshop on IL-10
Phase II clinical trials using recombinant and Related Molecules was held at Charité
inflammatory cytokine initially, but recent Berlin, Germany from 4–7 April 2001.
safety and efficacy of this therapy for all of complex characteristics. In addition, novel positive response to treatment with IL-10 was observed for psoriasis (K. Asadullah, T helper 2 (Th2)-cell clones and inhibits the synthesis of interferon γ (IFN-γ) by Th1-cell clones1. Today, this ‘cytokine The role of IL-10 in disease and its use as a
therapeutic agent
IL-10 therapy after the clearance of active demonstrated for various cell populations, psoriasis by conventional therapy is very including certain T-cell subsets [e.g. Th2 1471-4906/01/$ – see front matter 2001 Elsevier Science Ltd. All rights reserved. PII: S1471-4906(01)01985-8 Research Update
TRENDS in Immunology Vol.22 No.8 August 2001 (‘immunoparalysis’) contributing to the high rate of late mortality seen in patients influence the capacity for the secretion of have been published on ‘high’- and ‘low’- are associated with the incidence andseverity of various immune diseases, Newcastle, UK; A. Vergopoulos, Berlin,Germany; and J. May, Tuebingen, Fig. 1. The genomic localization of the genes encoding interleukin-10 (IL-10), interferon γ (IFN-γ) and the novel IL-10
homologs on human chromosomes 1 and 12. Abbreviations: AK155, Andrea Knappe 155 gene; MDA-7, melanoma polymorphisms to facilitate thecomparison of the data (G. Gallagher, disorders seems to be complex. On the one IL-10 and regulatory T cells
tumor necrosis factor (TNF) and/or IFN-γ].
as effective and safe in the treatment of allergen (C. Akdis, Davos, Switzerland).
On the other hand, a lack of effectiveness of IL-10 or transforming growth factor β (TGF-β) is thought to be important for the the different types of allergies and atopic adenoviral vectors and the difficulties in important role in the pathogenesis of post- A. O’Garra (Palo Alto, CA, USA) described counter-regulation is realized at the level Research Update
TRENDS in Immunology Vol.22 No.8 August 2001 Table 1. The properties of IL-10-related moleculesa
Cellular source
Biological effects
No effects on cytokine synthesis by PBMCs ND Overexpression in mice causes retardation of growth and development, skin abnormalities Application in adult mice induces an acute phase response and basophilia in proximal (hepatoma cell lines), inhibition of IL-4 renal tubules; it acts as an autocrine factor for Melanoma cells, skin fibroblasts Antitumor effects (induction of apoptosis or differentiation), aAbbreviations: AK, Andrea Knappe; GM-CSF, granulocyte–macrophage colony-stimulating factor; IL, interleukin; LPS, lipopolysaccharide; MDA, melanoma differentiationassociated gene; ND, not determined; PBMC, peripheral blood mononuclear cell; PHA, phytohemagglutinin; Th, T helper; STAT3, signal transducer and activator of regulatory T cells in coculture. So far, it in vitro-generated regulatory T cells efficiently. The addition of IL-15 (instead Berlin, Germany). T. Mijatovic (Brussels, IL-10 signaling and molecular mechanisms
of inhibitory function
action of IL-10; their possible inhibition 3′ untranslated region (UTR) of the TNF there have been conflicting reports about well as the 5′UTR, seem to be necessary the molecular basis of this inhibition. The nuclear translocation of the transcription factor NF-κB heterodimer is considered to depend very much on the model used wasdiscussed by B. Foxwell (London, UK).
Key outcomes of the meeting
There are obvious differences betweencell lines and primary cells. Both • IL-10 has been shown to be effective and safe in several clinical trials (e.g. for the treatment of rheumatoid arthritis) although it was less effective than therapy with • In the treatment of psoriasis, IL-10 reversed acute disease effectively and prevented the relapse of disease activity. This might represent a novel approach for therapy with • It is possible to expand IL-10-driven regulatory T-cell populations in vitro using IL-15, without the loss of their suppressor function.
• IL-10 upregulates the expression of >300 genes, suggesting the complexity of its signaling.
• Several IL-10 homologs have been described. None of these appear to share the immunoregulatory and anti-inflammatory properties of IL-10. However, they have interesting biological activities including: antitumor effects, the induction of expression of acute-phase proteins and the stimulation of keratinocytes to showed only the 3′UTR-mediatedinhibition, regardless of the timing of Research Update
TRENDS in Immunology Vol.22 No.8 August 2001 IL-10-related molecules
(SFB 421). Additional support was provided mostly as a result of in silico work. At the which is strongly influenced by signaling would like to apologize to all speakers whose groups (R. de Waal Malevyt; G. Gallagher; the effects of IL-10 (M. Cassatella, Verona, abstracts of this meeting are published in Genes and Immunity (2001) 2, 161-179.
1 Fiorentino, D.F. et al. (1989) Two types of mouse T helper cell. IV. Th2 clones secrete a factor that inhibits cytokine production by Th1 clones.
and H. Fickenscher, Erlangen, Germany).
2 Gallagher, G. et al. (2000) Cloning, expression and dispensable for the activating function of initial characterisation of interleukin-19 (IL-19), IL-10 in B cells (B. Weaver, St Louis, MO, chromosomes one and 12, close to the gene a novel homologue of human interleukin-10 loci encoding IL-10 and IFN-γ, respectively (IL-10). Genes Immun. 1, 442–450 (Fig. 1). Three of these homologs [IL-19, Hans-Dieter Volk*
Gerald Grütz
which is dependent on the presence of this Institute of Medical Immunology, Charité, Humboldt University Berlin, D-10098 Berlin, identify the downstream signaling events.
immunosuppressive function of IL-10.
Robert Sabat
Khusru Asadullah
mRNA analysis to address this question.
important properties of these homologs.
Experimental Dermatology, Muellerstr. 178, London, UK), but there is a long way to go Acknowledgements
to prove the function of those genes whose This meeting was organized by the authors, Grant Gallagher
Keeping up with the Trends
Articles of interest to immunologists in other Trends journals: Arroyo, J. et al. (2001) Yellow fever vector live-virus vaccines: West Nile virus vaccine development. Arold, S.T. and Baur, A.S. (2001) Dynamic Nef and Nef dynamics: how structure could explain the complex activities of Zeh, H.J., III et al. (2001) Vaccines for colorectal cancer. Khanna, R. et al. (2001) Immunotherapeutic strategies for EBV-associated malignancies. Imler, J-L. and Hoffmann, J.A. (2001) Toll receptors in innate immunity.



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