SUMMARY – OVERVIEW
Transplantation has revolutionized the lives of patients suffering from organ failure. The design of modern
immunosuppression has employed a time-honored focus on controlling T cell-mediated responses. However,
current immunosuppressive therapies have suboptimal success rates and induce significant side effects,
including increased susceptibility to infections, metabolic toxicity, and cancer risk. Given the growing body of
evidence showing that innate immunity is also critical to alloresponse initiation and allograft survival, it is not
surprising that current immunosuppressive regimens do not achieve satisfactory long-term graft and patient
survival.
Recent work by this P01’s investigators has shown that trained immunity plays a vital role in allograft
survival. Trained immunity is a long-term increase in the functional responsiveness of innate immune
cells, which is maintained by epigenetic modifications and can be considered de facto innate immune
memory. On a systems level, we demonstrated that trained immunity is regulated and maintained by epigenetic
modifications in bone marrow hematopoietic progenitors, which consequently release trained innate
immune cells with augmented inflammatory and antimicrobial function. Our preclinical and clinical preliminary
data revealed a discrete causative connection between allograft transplantation, the induction of trained
immunity, systemic inflammatory response, and activated or amplified T cell-mediated alloimmunity.
Furthermore, we identified trained immunity as a compelling therapeutic target in mouse and non-human primate
heart allograft models. Based on these results, our central hypothesis is that trained immunity is a critical
mechanism that amplifies and sustains both innate and adaptive rejection responses and is therefore a
compelling clinical therapeutic target for achieving long-term allograft survival without requiring chronic
immunosuppression.
In this P01, we will address our central hypothesis by drawing on the expertise of authorities in the fields of
immunology and bioengineering. This multidisciplinary team of scientists and clinicians will work together to
i) understand trained immunity’s clinical relevance in kidney transplantation, ii) elucidate the mechanisms by
which trained immunity is induced and leads to organ rejection, and iii) develop bioengineering solutions for
diagnosing and therapeutically regulating trained immunity in transplantation.
We anticipate that, together, these highly interactive Projects will generate innovative new therapeutic strategies
to more effectively prevent rejection and potentially achieve immune tolerance. If successful, these studies could
impact the entire field of transplantation and provide insights that could also be highly relevant for bone marrow
transplantation and autoimmune disease.