Promoting and Visualizing Immune Regulation in Transplantation

PROJECT SUMMARY
Two main issues currently plague the field of transplantation in humans: (i) poor control of chronic rejection
by current immunosuppressive drugs; and (ii) low success of tolerance induction. At the center of these issues
is innate immune memory stemming from both innate allorecognition and trained immunity, which generate a
state of chronic inflammation. Unfortunately, innate immune memory is not specifically targeted by current
immunosuppressive drugs. In addition, commonly used immunosuppressive regimens hinder the much-needed
immune regulation processes required for tolerance by impeding CD4+ Foxp3+ regulatory T cells (Treg)
homeostasis and suppressor function.
Thus, a key deficit in the field is a lack of available therapeutics that both target innate immune
memory and promote immune regulation.
In this regard, our data demonstrate that innate cells are central to Treg suppressor function within
allografts, highlighting the robust relationship between innate cells and Treg. Therefore, we hypothesize that
inhibition of innate immune memory promotes a long-lasting regulatory environment by enhancing
both myeloid regulatory cells (MRCs) and Treg suppressor functions, which protects allograft from
rejection. We will test this in the following AIMs:
This project will investigate whether inhibition of innate immune memory promotes MRC (AIM 1) and Treg
(AIM 2) regulatory functions in the setting of transplantation. We will use both genetic approaches and novel
nanotherapeutics to specifically inhibit innate allorecognition and trained immunity in transplanted mice, and the
promotion of MRCs and Treg, as well as their immune regulatory functions, will be assessed. These experiments
will enhance our knowledge on the role of innate immune memory in immune regulatory functions, which remains
largely unexplored.
Importantly, the visualization of MRC and Treg suppressor function using multi-photon intravital microscopy
and the use of novel nanotherapeutics targeting innate immune memory are central in testing these hypotheses.
These AIMs will be accomplished through the collaborative efforts of an interdisciplinary group of experts in the
fields of in nanotherapeutics, intravital microscopy, innate allorecognition trained immunity, and transplant
immunobiology. Therefore, this grant application is dually responsive to this RFA (Emerging Science and
Technology in Transplantation (U01)) as it will both use intravital imaging and targeted therapeutic delivery.
Overall, new knowledge generated from this grant will: 1) identify molecular targets to inhibit innate immune
memory and promote immune regulatory function; and 2) visualize – at the cellular level, in the living host, and
in real time – MRCs and Treg immune regulation in the setting of transplantation.

Grant Number: 5U01AI170074-05
NIH Institute/Center: NIH
Principal Investigator: Geoffrey Camirand