The use of a vasoactive intestinal peptide (VIP) antagonist to enhance the cellular immune response.
- Has antiviral activity and increases the immune response following a vaccine or viral infection.
- Can be used in tandem with antivirals for more effective and efficient treatment.
- Upregulation of the cellular immune response has anti-cancer activity by targeting tumor cells for apoptotic cell death.
Mortality from viral infections including viral hepatitis, HIV, and influenza is a major concern in the United States and worldwide. Although current therapies exist for these diseases, the mortality rates remain high indicating a need for additional therapeutics. Moreover, emerging viral infections and the potential threat of bioterrorism indicates a need to develop broader, multi-use anti-infectives as opposed to specific therapeutics developed for the treatment of a single type of viral infection. Current treatments aimed to stimulate the cellular immune response include interleukin-2 (IL-2) and thalomide, which increases circulating levels of IL-2. While IL-2 treatment has been shown to increase natural killer cells (NKs) activity effectively, it has no effect on cytotoxic T lymphocytes (CTLs), which kill cancer and otherwise infected cells. IL-2 treatment can sometimes be fatal due to capillary leak syndrome. Thalomide has been linked to severe birth defects and fetal death and it can remain in the body long after stopping treatment, making it a less than ideal treatment for many patients. In addition to antiviral activity, up-regulation of the cellular immune response may also increase the anti-cancer activity of NKs and CTLs and elicit a more robust vaccine response
Researchers at Emory have shown that up-regulation of the cellular immune response via VIP antagonism results in more efficient viral clearance and increased survival in animal models. The cellular immune response, specifically CTLs and NKs, recognize abnormal antigens expressed on the surface of infected cells and then target those cells for cell death. VIP was identified as a negative regulator of the cellular immune response and down-regulation of VIP results in increased activity of CTLs and NKs. VIP induces regulatory dendritic cells in vitro to inhibit cellular immune responses. Mice infected with mouse cytomegalovirus (CMV) and treated with a VIP receptor antagonist, VIPhyb, exhibited reduced viral load, reduced inflammation and increased survival when compared to untreated controls. VIPhyb treated mice and VIP knockout mice had elevated expression of CTL and NK co-stimulatory cytokines and reduced expression of molecules that inhibit CTL activation compared to controls which correlates to increased numbers of activated T cells. In addition, dendritic cell maturation was accelerated in VIPhyb treated mice. Because the cellular immune response is also involved in anti-cancer activity and response to vaccines, increasing the activity of the cellular immune response via VIP antagonism may likely have beneficial effects for additional indications.
Blocking VIP signaling in a lymphoma mouse model enhanced T cell activation, stimulatory cytokines, and survival without increasing rates of graft-vs.-host disease. In addition, treatment with a VIP antagonist was shown to increase survival in a mouse model of CMV infection.
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