OVERALL – SUMMARY/ABSTRACT With an ever increasing aging population and prolonged life spans, there has been a significant increase in the number of older transplant recipients. At the same time, older patients represent the fastest growing cohort waiting for a transplant. Those older patients are treated in the same way as young recipients, yet their alloimmune responses differ substantially. There is thus a significant unmet need to provide treatments for older transplant recipients that are based on a solid understanding of age-specific changes in alloimmunity. However, that cannot be done until cellular and humoral mechanisms regulating alloimmunity in aging are fully elucidated. The unmet need to conduct studies such as those proposed in this PPG is further stressed by: A) our extensive data indicating that immunoregulation controlling allo-specific responses is distinct in aging, B) that established transplant immunosuppression has been designed for a youthful immune system with an exclusion of older recipients from the vast majority of clinical studies, and C) that current immunosuppression strategies are not fully effective in older individuals and predisposes them to undesired effects. Indeed, our collected data indicate that the current aged- related immunosuppressive paradigm is overly simplistic and does not recognize important heightened inflammatory features of aging alloimmunity. Our overall hypothesis is that cellular senescence in fibroblastic reticular cells (FRCs) of lymph nodes induces a maladaptive T and B cell response leading to a dysregulated alloimmunity in aging. Clinically, this dysregulated immunity results in age-specific effects of established immunosuppressants. Co-stimulatory agents, although prime candidates for use as immunosuppression in older recipients due to the absence of nephrotoxic effects, work effectively only in young but not old recipients.. To this end, our major goals are to fully examine the cellular and molecular mechanisms that drive transplant immunity in aging. This PPG sets forth a platform that merges three highly synergistic teams (Drs. Abdi, Tullius, and Sage) with complementary skills and expertise in LN stroma, T and B cell immunity. Project 1 will test the hypothesis that aged FRCs contribute significantly to the divergent immune responses observed in aged vs. young mice. Aim 1 will study the mechanisms by which senescence in FRCs regulates alloimmunity in the LN. Aim 2 will examine the importance of lymphotoxin pathways for transplant immunity in the stroma of aged LN. Aim 3 will study novel approaches to rejuvenate the aging LN stroma thereby restoring immune tolerance following co-stimulatory blockade. Project 2 will test the hypothesis that increased age-specific changes in innate and T cell immunity rewire allorecognition, T cell metabolism, and immunosuppressive targets. As our corollary hypothesis we submit that cellular senescence augments alloimmunity and that the depletion of se...