The reduced ability of the elderly to respond to new antigens is linked to a decreased number of peripheral naïve T cells. Naïve T cells are abundant in youth, but may become “used up” by exposures to microorganisms and viruses over the course of life. In addition, Th1-mediated cellular immunity, which is necessary for immune clearance of viral infections is diminished in the elderly resulting in an inverted Th1/Th2 immune imbalance, further contributing to immunosenescence. In addition, existing memory cells in the elderly become exhausted due to continuous re-exposure to foreign antigens, especially in the setting of sub-clinical infections common in the elderly.
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The Alloprime® mechanism increases the titer of non-exhausted Th1 memory cells in circulation, remodeling the senescent immune system by shifting the th1/Th2 balance and providing an immediate source of interferon-gamma (IFN- ϒ) upon activation. The release of IFN- ϒ by the allo-specific memory cells creates an “anti-viral state” and activates innate immunity resulting in rapid viral clearance. Applied to the broad population, the rapid clearance of virus can reduce virulence and person-to-person spread which in turn can prevent pandemic emergencies. Crucial for limiting the extent of viral spread in host tissues is a rapid innate immune response.
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The innate immune response lyses viral infected cells, releasing internal contents into the local microenvironment. This creates the conditions necessary for in-situ vaccination in order to bridge the development of viral-specific immune responses. Thus, the allogeneic priming and resulting immunomodulation of healthy adults’ immune systems can serve as a “Universal Vaccine”. As a Universal Vaccine, it is not necessary to know and educate the immune system in advance to specific viral antigens of the invading pathogens. The rapid innate, non-specific and cross-reactive immune responses can be effective against any viral infection.
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The interferon response represents an early host defense, one that occurs prior to the onset of the immune response to viral infection. Viral infection causes the release of Type I and Type III interferons which have potent anti-viral activity against both infected and non-infected cells. This broad anti-viral activity is known as the “anti-viral state”. However, many viruses evade immune attack by down-regulating release of type I/III interferons.
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AlloPrime® technology provides a unique solution to this problem of viral immunoavoidance by creating a large pool of memory Th1 cells that release Type II interferon (interferon-gamma). Interferon-gamma can stimulate the same anti-viral state as Type I/III interferons. In this manner, the release of interferon-gamma can by-pass viral suppression.
CREATING AN ANTI-VIRAL STATE
The Alloantigen priming results in the modulation of systemic Th1/Th2 balance and provides a pool of non-exhausted Th1 memory T-cells that can be non-specifically activated by the by-stander effect of cytokines, such as type I/III interferons released by innate immune cells upon initial viral encounter. This non-specific activation can cause the release of type II interferon (IFN-ϒ) from the allo-specific Th1 memory cells in circulation. The release of IFN-ϒ can further activate additional memory cells and innate immune cells, which in turn can amplify IFN production. The early release of IFN creates an anti-viral state as a result of activating interferon signaling genes (ISG). This combination of activity supports the formation of a robust acute innate immune response to accelerate the clearance of any viral infection. In addition to memory Th1 cells, the allo-specific CTL memory cells developed during allo-priming are capable of cross reacting to many viral antigens, providing additional effector cells in the early response to virus.