Abstract
BCG has been administered globally for more than 75 years, yet tuberculosis (TB) continues to kill more than 2 million people annually. Further, BCG protects childhood TB but is quite inefficient in adults. This indicates that BCG fails to induce long-term protection. Hence there is a need to explore alternative vaccination strategies that can stimulate enduring T cell memory response. Dendritic cell based vaccination has attained extensive popularity following their success in various malignancies. In our previous study, we have established a novel and unique vaccination strategy against Mycobacterium tuberculosis (M. tb) and Salmonella typhimurium by utilizing infected macrophages (IM). In short-term experiments (30 days), substantial degree of protection was observed. However, remarkable difference was not observed in long-term studies (240 days) due to failure of the vaccine to generate long-lasting memory T cells. Hence, in the present study we employed T cell memory augmenting cytokines IL-1+IL-6+TNF-α and IL-7+IL-15 for the induction of the enhancement of long-term protection by the vaccine. We co-administered the M. tb infected macrophages vaccine with IL-1+IL-6+TNF-α (IM-1.6.α) and IL-7+IL-15 (IM-7.15). The mice were then rested for a reasonably large period (240 days) to study the bona fide T cell memory response before exposing them to aerosolized M. tb. IM-1.6.α but not IM-7.15 significantly improved memory T cell response against M. tb, as evidenced by recall responses of memory T cells, expansion of both central as well as effector memory CD4 and CD8 T cell pools, elicitation of mainly Th1 memory response, reduction in the mycobacterial load and alleviated lung pathology. Importantly, the protection induced by IM-1.6.α was significantly better than BCG. Thus, this study demonstrates that not only antigen-pulsed DCs can be successfully employed as vaccines against cancer and infectious diseases but also macrophages infected with M. tb can be utilized with great efficacy especially in protection against TB.
Highlights
In 1992, nearly 100 million children received BCG [1]
In the present study, we investigated how enduring T cell memory can be elicited by M. tb infected syngeneic macrophages
It is reported that combination of either IL1+IL-6+TNF-a or IL-7+IL-15 can induce long-term T cell memory response [14,16,19]
Summary
In 1992, nearly 100 million children received BCG [1]. Despite the reality that more people have been immunized with BCG than any other vaccine, TB continues to kill some 2 million people annually and 2 billion people worldwide are infected with M. tb [2]. There may exist a possibility that growing bacilli express discrete molecules inside the macrophage [5], that may act as protective antigens necessary for the generation of effector and memory T cells responsible for protective immunity Whether such protective antigens of M. tb that can be exploited as vaccines, still remains to be identified. Noteworthy observations obtained on vaccination with the infected macrophages was that it augmented T cell proliferation, IFN-c production and reduction in mycobacterial load, the parameters that are crucial for protection against M. tb This vaccination strategy worked successfully for TB and against S. typhimurium [5].
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