CD137CD137 Ligand in the Antiviral Immune Response and in Viral Vaccination

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Immunotherapy has potential for chronic and latent viral infections. Therapeutic vaccination and adoptive T-cell transfer are the strategies that are being explored for HIV and chronic viral hepatitis. Mice lacking CD137 or CD137 ligand show defects in CD8 T cell responses against viruses (DeBenedette et al.,

1999; Kwon et al, 2002; Tan et al, 1999), with no defects in antibody or CD4 T cell responses to vesicular stomatitis virus (VSV), LCMV, or influenza virus (Kwon et al., 2002; Tan et al., 1999). Studies in CD137 ligand-/- mice suggest that the role of this molecule is mainly focused in the long term CTL response and in the induction and maintenance of memory in the CD8+ T cell compartment (Bukczynski et al., 2004). These features make the CD137/CD137 ligand pair a very interesting target for manipulation in antiviral immunotherapy. However, very few reports have explored this possibility.

A pioneering study (Halstead et al., 2002) demonstrated increased CTL responses against experimental influenza. In vivo CD137 stimulation with an agonistic monoclonal antibody enhanced the primary CD8+ T cell response to influenza type A viral infection in mice. Stimulation of CD137 increased the absolute number of CD8+ T cells to influenza epitopes in the lungs of infected animals, preferentially expanding CD8+ T cells that recognized nondominant epitopes and greatly enhancing direct ex vivo cytotoxicity. The studies confirmed that the CD137 costimulatory pathway could operate independently from CD28 (Halstead et al., 2002). The effects enhancing memory to a broadened series of epitopes suggested potential to enhance the effect for vaccines relying on CTLs for prophylaxis or therapy.

The induction of protective or therapeutic cellular immunity against hepatitis C virus (HCV) is a difficult goal. Immunization with a recombinant aden-ovirus encoding HCV-NS3 (RAdNS3) could partially protect mice from challenge with a vaccinia virus encoding HCV antigens. It was found that treatment with anti-CD137 mAb after the administration of a suboptimal dose of RAdNS3 enhanced cytotoxic and T helper cell responses against HCV NS3 (Arribillaga et al., 2005). Importantly, the ability of RAdNS3 to induce protective immunity against challenge with a recombinant vaccinia virus expressing HCV proteins was markedly augmented. Thus, combination of immunostimulatory anti-CD137 mAb with recombinant adenoviruses expressing HCV proteins might be useful in strategies of immunization against HCV However in this case the epitope broadening seen with influenza viruses was not seen with subdominant peptides of the NS3 antigen, indicating that this might be not a general feature (Arribillaga et al., 2005).

In another study, agonistic anti-CD137 mAb were shown to potentiate threefold the T-cell immunity raisedby vaccination with poxviruses (Munks et al., 2004). These authors studied the murine CD8 T cell response to a DNA prime, poxvirus boost vaccine, similar to those used for human and simian immunodeficiency viruses vaccines. CD137 stimulation increased the number of functional memory CD8 T cells by two- to four-fold. Interestingly the enhancement was observed both at the peak of the response and in the memory phase. In this report the combination with anti-OX40 mAb was also tested. OX40 stimulation increased the number of antigen-specific CD4 T cells approximately three-fold. Stimulating both CD137 and OX40 enhanced the CD8 T-cell response more than CD137 alone (Munks et al., 2004).

These studies agree to suggest a potential in vaccination against viral diseases in which protection is achieved by memory T cells and deserves attention for translation into clinical benefit. On the contrary, anti-CD137 mAb should not enhance the vaccines relying on the induction of neutralizing antibodies.

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