# Regulatory dendritic cell therapy, promotion of tolerance and underlying mechanisms in NHP renal transplantation

> **NIH NIH U19** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2021 · $620,325

## Abstract

Uniquely, using a short-term minimal immunosuppressive (IS) drug regimen comprising costimulation blockade
(CoSB; CTLA4Ig/belatacept) + tapered rapamycin, we have shown that maturation-resistant, donor-derived
DCreg, infused 1w before transplant, can safely prolong renal allograft survival in rhesus macaques,
accompanied by selective attenuation of donor-reactive memory T cell (Tmem) responses, a mechanism that
may help overcome a critical barrier to transplant tolerance induction in NHP and humans.
We will now ascertain whether a novel, modified, CNI-free IS regimen that is (i) more permissive to extended
graft survival and (ii) that we hypothesize will enhance the immunomodulatory function of DCreg, can achieve
donor-specific tolerance. There is recent evidence that lymphocyte depletion followed by CoSB (belatacept)
and rapamycin maintenance (the 2-drug regimen we used to demonstrate DCreg efficacy in monkeys) can
control CoSB-resistant rejection in transplant patients, with reduction in CoSB (belatacept)-resistant Tmem.
However, operational tolerance was not achieved. Notably, combination of donor DCreg infusion (a week
before transplant) with perioperative lymphodepletion, promotes permanent, donor-specific allograft survival in
rodents. This indicates that lymphodepletion after DCreg infusion does not interfere with their therapeutic
effect. Moreover, DCreg infusion post-transplant following lymphodepletion, can also promote indefinite graft
survival. We therefore hypothesize that maturation-resistant rhesus DCreg, administered to ATG-
lymphodepleted, CoSB and rapamycin-treated renal graft recipients, will induce immunological changes and
selective attenuation of donor-reactive Tmem conducive to donor-specific tolerance. We further hypothesize
that novel biomarker analyses of host alloreactive Tmem responses (in particular, their expression of Eomes)
will correlate with and be predictive of safe withdrawal of IS. Our Specific Aims are:
Aim 1: To determine the influence of donor-derived DCreg infusion before transplant on renal allograft
survival in NHP given combined lymphodepletion (ATG), belatacept and rapamycin (ABR).
Aim 2: To determine the influence of donor-derived DCreg infusion before transplant on renal allograft
survival in NHP given combined ATG, non-depleting αCD40 mAb and rapamycin (AAR).
Aim 3: To compare the influence of donor-versus recipient-derived DCreg infusion post-transplant on
renal allograft survival in NHP given combined ATG, CoSB and rapamycin (ABR or AAR).
Each Aim will be accompanied by comprehensive, rationally-designed mechanistic studies that will elucidate
the trafficking, fate and immune regulatory function of the adoptively-transferred DCreg and underlying
mechanisms.

## Key facts

- **NIH application ID:** 10217985
- **Project number:** 5U19AI131453-05
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Angus W Thomson
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $620,325
- **Award type:** 5
- **Project period:** 2017-08-17 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10217985

## Citation

> US National Institutes of Health, RePORTER application 10217985, Regulatory dendritic cell therapy, promotion of tolerance and underlying mechanisms in NHP renal transplantation (5U19AI131453-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10217985. Licensed CC0.

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