This F30 application describes a comprehensive plan for my research project. I expect this plan to provide a
solid foundation for my goal of becoming an independently funded physician-scientist specializing in the fields
of immunology and transplant biology.
My research will examine how hyperlipidemia affects Th17 development, pathogenicity, and plasticity. I will first
examine the fate and functional significance of Th17-lineage cells in hyperlipidemic and non-hyperlipidemic
grafts. I will use immunocytochemistry of tissue sections, single-cell RT-PCR, and flow cytometry, as well as in
vivo ablation of the Th17-lineage to investigate this question. Secondly, I will investigate the mechanisms by
which hyperlipidemia promotes a tissue-destructive Th17 response, specifically, the role of CD55 in tissue-
destructive Th17 development and function.
Advances in immunosuppression and after-transplant care have resulted in excellent one-year survival rates
for heart transplant patients, but long-term survival remains a challenge and median survival times have not
significantly improved. The Iacomini lab has shown that hyperlipidemia, a common co-morbidity in the human
transplant population, results in accelerated IL-17 dependent graft rejection in heterotopic mouse heart grafts.
We have also recently demonstrated the presence of lymphocytes that do not express IL-17 despite being
positive for a Th17-lineage fate mapping marker in non-hyperlipidemic heart grafts. Aim 1 will use
immunocytochemistry to investigate the fate of Th17-lineage cells in non-hyperlipidemic heart grafts, and
determine whether Th17-lineage cells are undergoing lineage plasticity in non-hyperlipidemic grafts but are
maintained as bona fide IL-17 producing cells in hyperlipidemic grafts. Aim 1 will also ablate the Th17-lineage
in hyperlipidemic and non-hyperlipidemic graft recipients, and investigate the functional role of the Th17
lineage in graft rejection. This would be the first clinically relevant demonstration that Th17-lineage cells play
an important role in rejection. Aim 2 will focus on how hyperlipidemia promotes tissue-destructive Th17 cell
development through increased expression of CD55. CD55 is a complement regulatory protein that is known to
enhance Th17 cell development. We will determine whether CD55 affects the development of de novo Th17
cells as well as the function of already generated Th17 cells, and determine the functional consequences of
Th17-lineage specific loss of CD55 in heart graft rejection. The knowledge generated in this proposal is
clinically relevant and may lead to better therapies for heart transplant rejection.