# Innovative approaches to enhance regulatory myeloid cell function and renal transplant survival in nonhuman primates

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $804,385

## Abstract

R01 Summary
Therapeutic regulation of innate immunity remains underexplored. Our overall hypothesis, based on key
preliminary data, is that NHP kidney allograft survival can be extended and immunosuppression (IS) withdrawn
by innovative strategies and cutting-edge technologies that potentiate dendritic cell (DC) tolerogenicity. These
strategies will enable 1) selective inhibitory targeting of DCs in situ, or 2) adoptive transfer of autologous
regulatory DC (DCregs) pulsed with donor small extracellular vesicles (sEVs). The regimens we propose will (i)
provide new mechanistic insight into the induction and maintenance/stability of donor-specific unresponsivess
and (ii) potentially identify novel predictive biomarkers. In due course, our findings may provide opportunities to
interact with/participate in NIAID-funded clinical trials, such as those currently assessing DCreg therapy in organ
transplantation at the University of Pittsburgh. Recent data show that activation of the inhibitory leukocyte
immunoglobulin-like receptor B (LILRB) family member LILRB3 (ILT5; CD85a) that is highly expressed on DCs,
confers profound immunoinhibitory functions on myeloid cells that induce T cell tolerance to alloAgs in
humanized mice. We will test our hypothesis that an agonistic LILRB3 mAb can extend graft survival/allow IS
withdrawal. An alternative novel approach to selective targeting DCs in situ is use of Ab-directed, DC-targeting
nanobiologics. We hypothesize that nanoparticles (NP) functionalized with mAb against the endocytic receptor
DEC205 (CD205) and loaded with the mTOR inhibitor rapamycin (mTORi-NP) will promote Treg generation,
extend graft survival and allow IS withdrawal. We discovered that acquisition of donor MHC Ag (via sEVs) and
upregulation of co-inhibitory/anti-inflammatory molecules by recipient DCs subverts anti-donor T cell responses
in rodent liver transplant tolerance. In patients, we have shown that infusion of DCreg results in acquisition (via
sEVs) of donor MHC, co-expressed with enhanced levels of co-inhibitory molecules on host DCs. We therefore
hypothesize that infusion of autologous DCregs pulsed with donor sEVs (sEV-DCs) will extend graft
survival/allow IS withdrawal. Our Specific Aims are:
Aim 1: To determine whether agonistic LILRB3 mAb combined with baseline IS can extend kidney graft
survival/allow IS withdrawal (n=12 transplants)
Aim 2: To ascertain whether selective targeting of DCs in situ using novel DC (DEC205)-directed
nanoparticles (mTORi-NPs) can extend graft survival/allow IS withdrawal (n=6 transplants)
Aim 3: To assess whether post-transplant infusion of autologous DCregs pulsed with donor sEVs (sEV-
DCregs) can extend graft survival/allow IS withdrawal (n=12 transplants)

## Key facts

- **NIH application ID:** 10937187
- **Project number:** 1R01AI184406-01
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Angus W Thomson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $804,385
- **Award type:** 1
- **Project period:** 2024-06-07 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10937187

## Citation

> US National Institutes of Health, RePORTER application 10937187, Innovative approaches to enhance regulatory myeloid cell function and renal transplant survival in nonhuman primates (1R01AI184406-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10937187. Licensed CC0.

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