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Targeting altered immune-crosstalk in tissues to enhance immunity

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This talk will take place online via Zoom & Kings Hedges Room

Akbar has identified new mechanisms for immune decline in human ageing and has demonstrated unequivocally that targeting these age-associated alterations can enhance human immunity in vivo. The importance of these new discoveries is underscored by infections by novel viruses, that affect the older population disproportionately and these new findings offer the possibility to enhance anti-viral and anti-cancer immunity in old subjects. He showed that antigen-specific responses in old humans animals can be boosted by the inhibition of inflammation with small molecule inhibitors in vivo. Akbar’s career in Immunology spans 40 years from his PhD to the present. In addition is group identified of a new multi-protein inhibitory complex that that actively maintains the reduced T cell activity in old human as well as murine T cells and the inhibition of signalling via this complex enhances T cells function.

The development of a novel experimental system for investigating human immunity during ageing in vivo. Most studies on human immunity are performed on leukocyte populations from peripheral blood, which do not reflect tissue-specific immune events. Akbar developed a unique experimental model to study immune responses in the skin of human volunteers in vivo that involves the intradermal injection of viral antigens, followed by the harvest of leukocytes from the challenge site by the induction and harvest of suction blisters or by taking skin biopsies. An accelerated rate of telomere erosion was identified in T cells in the skin versus the blood after a single episode of antigen challenge, associated with inhibition of telomerase activity by inflammatory cytokines, including Type 1 IFN in situ. The cutaneous experimental system developed by Akbar has been adopted by pharmaceutical companies including GSK and has been the cornerstone of international collaborations with the University of Arizona, the Rockefeller University in New York and the National University of Singapore. Discovery of a multi-protein, inhibitory complex in aged T cells. The Akbar Group showed that inhibition of sestrins in highly differentiated T cells from old humans significantly enhanced anti-virus-specific activity in vitro. Furthermore, response to vaccination against influenza was significantly increased in aged sestrin knockout mice compared to old controls, and both T cell and antibody responses were enhanced. Although inhibition of individual MAP kinases in old mice had no effect on the influenza vaccine response, inhibition of all 3 MAP kinases simultaneously re-capitulated the enhanced responsiveness that was observed tin the sestrin deficient animals. This indicates a pathway for intervention to enhance immunity during ageing in humans.

Interaction with the pharmaceutical industry. The Akbar group showed that inhibition of inflammation by treatment of old volunteers with a clinical grade anti-inflammatory p38 MAPkinase inhibitor (GSK; Losmapimod significantly enhanced the response to antigen challenge immunity in the skin of these healthy old sunjects. This has considerable therapeutic implications e.g. enhancement of vaccine and anti-tumour responses in the elderly. This was funded by a MRC Grand Challenge in Experimental Medicine Grant (Akbar PI). Akbar is also involved in the development of the widely used anti-rejection drug for solid organ transplants Basiliximab (Simulect) by Novartis. He produced key data on which the patent was based. This drug has been used in the treatment of >300,000 patients worldwide and has generated >£25 million in royalty income to UCL .

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