After the recent flurry of papers on blocking PD-1 as a strategy for treating chronic viral infection, now two new studies report that using an antibody to block the receptor for the cytokine IL-10 (IL-10R) can effectively treat chronic LCMV infection in mice (the same system employed in the original PD-1 paper back in January). Although unfortunately there is no way of knowing yet if this can apply to humans, the novel (and at least potentially promising) finding with both these approaches is that they didn’t just have an effect on a marker of the immune response, they actually reduced or cleared the LCMV viral load and resolved symptoms. However, as with blocking PD-1, the safety of the anti-IL-10R approach will need to be carefully evaluated due to the potential risk of causing not just an antiviral immune response but an autoimmune response.
Commentary from the Journal of Experimental Medicine:
http://www.jem.org/cgi/content/full/jem.20311iti1v1
Published online 9 October 2006. doi:10.1084/jem.20311iti1
Curtailing chronic infection
Certain crafty viruses can cause the host's immune system to suppress itself, and thereby establish persistent chronic infection. But Ejrnaes et al. and Brooks et al. (Nat. Med., In press) have now found that suppressing the suppressor, which they show is the cytokine IL-10, can fight persistent infection.
IL-10 is known to exert a suppressive effect on cells of the immune system, including T cells and antigen-presenting cells, and elevated levels of IL-10 have been observed during persistent infection with hepatitis C virus, human immunodeficiency virus, and Epstein-Barr virus.
Now, both teams have observed that mice lacking IL-10 are resistant to persistent infection with lymphocytic choriomeningitis virus (LCMV). They also show that normal mice infected with LCMV have increased IL-10 production and decreased numbers of virus-killing CD8+ T cells. Ejrnaes et al. show that treating LCMV-infected mice with antibody that blocks the IL-10 receptor restored these antiviral CD8+ T cells and resulted in low or undetectable viral load, less weight loss and healthier coats. Importantly, the same reversal of symptoms and eradication of virus was achieved if treatment was administered later in infection.
Blocking the action of IL-10 might, therefore, be a potential therapy for human cases of persistent viral infection. Prolonged treatment with a potent stimulator of the immune system, however, might lead to undesirable autoimmune conditions, explains Matthias von Herrath, who led the study published here. His team is thus looking into the use of shorter and lower dose IL-10 treatments in combination with vaccines against virus-specific antigens.
Ruth Williams
Study abstracts:
http://www.jem.org/cgi/content/abstract/jem.20061462v1
Published online 9 October 2006. doi:10.1084/jem.20061462
The Journal of Experimental Medicine
ARTICLE
Resolution of a chronic viral infection after interleukin-10 receptor blockade
Mette Ejrnaes1, Christophe M. Filippi1, Marianne M. Martinic1, Eleanor M. Ling1, Lisa M. Togher1, Shane Crotty2, and Matthias G. von Herrath1
1 Immune Regulation Lab – DI3 and 2 Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037
A defining characteristic of persistent viral infections is the loss and functional inactivation of antiviral effector T cells, which prevents viral clearance. Interleukin-10 (IL-10) suppresses cellular immune responses by modulating the function of T cells and antigen-presenting cells. In this paper, we report that IL-10 production is drastically increased in mice persistently infected with lymphocytic choriomeningitis virus. In vivo blockade of the IL-10 receptor (IL-10R) with a neutralizing antibody resulted in rapid resolution of the persistent infection. IL-10 secretion was diminished and interferon {gamma} production by antiviral CD8+ T cells was enhanced. In persistently infected mice, CD8{alpha}+ dendritic cell (DC) numbers declined early after infection, whereas CD8{alpha}– DC numbers were not affected. CD8{alpha}– DCs supported IL-10 production and subsequent dampening of antiviral T cell responses. Therapeutic IL-10R blockade broke the cycle of IL-10–mediated immune suppression, preventing IL-10 priming by CD8{alpha}– DCs and enhancing antiviral responses and thereby resolving infection without causing immunopathology.
http://www.nature.com/nm/journal/vaop/ncurrent/abs/nm1492.html
Nature Medicine Advance Online Publication
Published online: 15 October 2006; | doi:10.1038/nm1492
Interleukin-10 determines viral clearance or persistence in vivo
David G Brooks1, Matthew J Trifilo1, Kurt H Edelmann1, Luc Teyton2, Dorian B McGavern1, 3 & Michael B A Oldstone1, 4
1 Viral Immunobiology Laboratory, Molecular and Integrative Neuroscience Department, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
2 Department of Immunology, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
3 The Harold L. Dorris Neurological Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
4 Department of Infectology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
Persistent viral infections are a major health concern. One obstacle inhibiting the clearance of persistent infections is functional inactivation of antiviral T cells. Although such immunosuppression occurs rapidly after infection, the mechanisms that induce the loss of T-cell activity and promote viral persistence are unknown. Herein we document that persistent viral infection in mice results in a significant upregulation of interleukin (IL)-10 by antigen-presenting cells, leading to impaired T-cell responses. Genetic removal of Il10 resulted in the maintenance of robust effector T-cell responses, the rapid elimination of virus and the development of antiviral memory T-cell responses. Therapeutic administration of an antibody that blocks the IL-10 receptor restored T-cell function and eliminated viral infection. Thus, we identify a single molecule that directly induces immunosuppression leading to viral persistence and demonstrate that a therapy to neutralize IL-10 results in T-cell recovery and the prevention of viral persistence.
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