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.
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.
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.
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.
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.