Two new papers in the advance online section of the Journal of Experimental Medicine report that blocking immunosuppressive signals can give therapeutic immunization a boost. The studies follow on from work covered on the blog previously in which the IL-10/IL-10 receptor and PD-1/PD-L1 signaling pathways were identified as key contributors to viral persistence in the mouse model of chronic infection with lymphocytic choriomeningitis virus (LCMV).
In the first paper, David Brooks and colleagues from Mike Oldstone’s laboratory at Scripps show that combining DNA vaccination with an antibody blocking the IL-10 receptor leads to improved LCMV-specific CD4 and CD8 T cell function and accelerated clearance of the virus from chronically infected mice. In the second paper, Sang-Jun Ha and a team from Rafi Ahmed’s lab at Emory University report that immunization with a vaccinia vector encoding a single CD8 T cell epitope from LCMV also accelerates viral clearance when combined with an antibody blocking PD-L1 (the ligand for the molecule PD-1). The vaccine had no effect when given alone. In addition, these researchers demonstrate an effect of the vaccine plus PD-L1 blockade in mice transiently depleted of CD4 T cells, suggesting that the approach might have an impact in settings of CD4 T cell deficiency.
Both groups conclude by citing each other’s work and noting that, taken together, the results indicate that immunosuppressive signaling in chronic infection may explain the disappointing results of most therapeutic vaccination studies conducted to date. The authors also argue that their data point toward new strategies for boosting the impact of therapeutic immunization. In the hopeful closing words of Brooks et al: “a similar dual immunotherapeutic adjuvant/vaccination strategy that alleviates immunosuppressive signals while boosting immunity may stimulate effective, long-term, immune-mediated control of persistent viral infections in humans, and may also be an adjuvant for primary vaccination.”
The Journal of Experimental Medicine
Published online 10 March 2008
doi:10.1084/jem.20071948
BRIEF DEFINITIVE REPORT
David G. Brooks1, Andrew M. Lee1, Heidi Elsaesser1, Dorian B. McGavern1, and Michael B.A. Oldstone1,2
1 Viral-Immunobiology Laboratory, Department of Molecular and Integrative Neuroscience, and 2 Department of Infectology, The Scripps Research Institute, La Jolla, CA 92037
Therapeutic vaccination is a potentially powerful strategy to establish immune control and eradicate persistent viral infections. Large and multifunctional antiviral T cell responses are associated with control of viral persistence; however, for reasons that were mostly unclear, current therapeutic vaccination approaches to restore T cell immunity and control viral infection have been ineffective. Herein, we confirmed that neutralization of the immunosuppressive factor interleukin (IL)-10 stimulated T cell responses and improved control of established persistent lymphocytic choriomeningitis virus (LCMV) infection. Importantly, blockade of IL-10 also allowed an otherwise ineffective therapeutic DNA vaccine to further stimulate antiviral immunity, thereby increasing T cell responses and enhancing clearance of persistent LCMV replication. We therefore propose that a reason that current therapeutic vaccination strategies fail to resurrect/sustain T cell responses is because they do not alleviate the immunosuppressive environment. Consequently, blocking key suppressive factors could render ineffective vaccines more efficient at improving T cell immunity, and thereby allow immune-mediated control of persistent viral infection.
The Journal of Experimental Medicine
Published online 10 March 2008
doi:10.1084/jem.20071949
ARTICLE
Sang-Jun Ha1, Scott N. Mueller1, E. John Wherry1, Daniel L. Barber1, Rachael D. Aubert1, Arlene H. Sharpe2, Gordon J. Freeman3, and Rafi Ahmed1
1 Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322
2 Department of Pathology, Harvard Medical School and Brigham and Women’s Hospital, 3 Department of Medical Oncology, Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston, MA 02115
Therapeutic vaccination is a potentially promising strategy to enhance T cell immunity and viral control in chronically infected individuals. However, therapeutic vaccination approaches have fallen short of expectations, and effective boosting of antiviral T cell responses has not always been observed. One of the principal reasons for the limited success of therapeutic vaccination is that virus-specific T cells become functionally exhausted during chronic infections. We now provide a novel strategy for enhancing the efficacy of therapeutic vaccines. In this study, we show that blocking programmed death (PD)-1/PD-L1 inhibitory signals on exhausted CD8+ T cells, in combination with therapeutic vaccination, synergistically enhances functional CD8+ T cell responses and improves viral control in mice chronically infected with lymphocytic choriomeningitis virus. This combinatorial therapeutic vaccination was effective even in the absence of CD4+ T cell help. Thus, our study defines a potent new approach to augment the efficacy of therapeutic vaccination by blocking negative signals. Such an approach may have broad applications in developing treatment strategies for chronic infections in general, and perhaps also for tumors.
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