99th Dahlem conference on infection, inflammation and chronic inflammatory disorders: viruses, autoimmunity and immunoregulation.

Based on studies in animal models, viral infections, in particular by enteroviruses, can accelerate or halt type 1 diabetes (T1D) development. Among factors that determine the outcome are the degree of viral replication in the target organ (viral titres), the tropism of the virus for beta cells, and the precise time-point of infection in relation to the diabetogenic process. Mechanisms underlying these phenomena have been assessed in mouse studies and should now be verified for human T1D. For enhancement of diabetes development, up-regulation of interferon pathways, expression of class-I major histocompatibility complexes and Toll-like receptor-dependent immunity appear important. In contrast, prevention of T1D involves pathways that the immune system usually invokes to shut down anti-viral responses to limit immunopathology, and which can 'clean out' autoreactive memory effector T cells as a bystander phenomenon: up-regulation of inhibitory molecules and invigoration of regulatory T cell (T(reg)) function. Importantly, these immunoregulatory processes also appear to foster and sustain persistent viral infections. Induction of immunoregulatory mechanisms, and in particular the phenotype and function of T(regs), is of interest therapeutically and will be discussed.

IL-10 and the resolution of infections.

Chronic viral infections pose serious health concerns, as secondary complications such as immunodeficiencies and cancers are common. Treating such infections with conventional vaccine approaches has proved to be difficult. Studies in animals and humans suggest that vaccine failure is probably due to exhaustion of antiviral T cell responses, which occurs in a number of chronic infections. Attempts to elucidate the causes of impairment of antiviral immunity have pointed to a role for the immunomodulatory cytokine IL-10 in the ability of viruses to establish persistence. Induction of IL-10 production by the host during chronic infection appears to be one of the viral means to alter the class of the antiviral immune response and induce generalized immune suppression. Recent work by us and others suggests that it is possible to resuscitate antiviral immunity by interfering with the IL-10 signalling pathway. Targeting IL-10 thus constitutes a promising alternative to conventional vaccine strategies which have not proved to be successful in treating chronic infections. In addition, sterile cure may be achieved with minimal side-effects by combining agents that alter the IL-10 signalling pathway with other compounds, such as antiviral drugs or interferon, but also agents neutralizing other crucial elements of T cell exhaustion, such as PD-1.