Antibody Mediated Rejection and Post-transplantation Anti-Viral Immunity in Aging

The proportion of aged patients undergoing solid organ transplantation is steadily increasing. Despite this, therapeutics to treat rejection are designed based on a youthful immune system. The aged immune system likely has unique mechanisms controlling transplant rejection which increase susceptibility to opportunistic infections. T follicular helper (Tfh) cells play a critical role in mediating B cell responses, including antibody mediated rejection (AbMR). Newer data suggest Tfh cells are a heterogeneous composition of uniquely functioning cell subsets. Therefore, it may be possible to uncouple transplant rejection from anti-viral immunity. However, a fundamental understanding of Tfh differentiation stages and how these function to promote alloimmunity and rejection in the context of aging is lacking. The objective of the proposed studies is to elucidate how the aged immune system controls alloimmunity in the context of kidney and heart transplantation. We hypothesize that the inflamm-aging environment causes Tfh rewiring which promotes B cell alloimmunity. We also hypothesize that targeting specific Tfh stages may uncouple allo- and anti-viral immunity. To test these hypotheses, we will: 1) determine how aging alters Tfh-mediated B cell alloimmunity after solid organ transplantation, 2) assess how the inflamm-aging environment causes Tfh rewiring to induce a senescence-like state, and 3) determine if nanoparticle therapy to age-associated Tfh rewiring can alleviate transplant immunity while maintaining anti-viral immunity. We will pursue these aims using innovative strategies to identify and perturb Tfh cell stages in vivo during kidney transplantation in aged mice. We will combine these innovative tools with transcriptomics, metabolomics and high-dimensional analyses of B cell responses at the single cell level. The expected outcome of these studies is to determine mechanisms controlling allo- and anti-viral immunity in aging. These studies are significant because they will provide strategies to prevent rejection in aging while limiting susceptibility to infection.