P01AI181829
Project Grant
Overview
Grant Description
Innovative approaches to enhance regulatory immune cell function and renal transplant survival in nonhuman primates - Overall summary/abstract
In this P01, we will address the overall hypothesis that innovative regimens incorporating new agents and cutting-edge technologies that selectively enhance regulatory immune cell function, will extend kidney allograft survival and allow immunosuppressive drug withdrawal in Rhesus macaques.
The candidate regimens will be tested in combination with progressive tapering and withdrawal of conventional immunosuppression (IS).
Our hypothesis in Project 1 is that graft survival can be extended and is withdrawn in MHC-mismatched graft recipients using innovative strategies that selectively enhance inherent dendritic cell (DC) tolerogenicity.
These approaches are 1) to target DCs in situ, either with an exciting, novel myeloid cell checkpoint agonist, or with innovative, DC-directed nanobiologics and 2) to adoptively transfer autologous regulatory DCs (DCREGs) pulsed with donor-derived small extracellular vesicles (SEVs).
Our specific aims are:
Aim 1: To determine whether the novel myeloid cell checkpoint agonist (anti-LILRB3 MAB) that promotes DC tolerogenicity and allotolerance in mice, can extend graft survival/allow IS withdrawal;
Aim 2: To ascertain whether selective targeting of DCs in situ using novel, DC (DEC205)-directed nanobiologics can extend graft survival/allow IS withdrawal;
Aim 3: To assess whether infusion of autologous DCREGs pulsed with donor-derived immunoregulatory SEVs can extend graft survival/allow IS withdrawal.
Our hypothesis in Project 2 is that suppression of innate and adaptive immune mechanisms that would otherwise destabilize induction of tolerance, will be conducive to DCREG and TREG function and consequent prolongation of graft survival/IS withdrawal.
We will use new, Rhesus-specific MABs to modulate inflammation, attenuate donor-reactive TMEM and augment donor Ag alloreactive TREG (DARTREG); we will also test next generation donor Ag (BW6)-specific chimeric Ag receptor (CAR)TREGs.
Our specific aims are:
Aim 1: To mitigate post-TX inflammatory responses and eliminate IS-resistant, donor-reactive pathogenic TMEM through cytokine modulation using new, Rhesus-specific neutralizing anti-IL-6 or IL-7R and IL-15R blocking MABs;
Aim 2: To augment Ag-specific TREG through infusion of ex vivo-expanded, genetically-engineered BW6-specific CAR TREG;
Aim 3: To achieve durable, donor-alloreactive T cell regulation through CAR TREG infusion, combined with either cytokine modulation or in situ targeting of DC, depending on the results of Project 2 Aim 1, and Project 1 Aim 1 and 2 results.
Both projects will incorporate highly-interactive mechanistic studies and assess potential novel biomarkers.
The two projects will be supported by an administrative, biostatistics and bioinformatics core (Core A), a transplant pathology and tissue imaging core (Core B) and a nanotechnology core (Core C) and will utilize new agents from the NIAID NHP reagent resource.
Our program displays conceptual unity and strong component synergy and incorporates special/unique features of the investigative team and environment.
In this P01, we will address the overall hypothesis that innovative regimens incorporating new agents and cutting-edge technologies that selectively enhance regulatory immune cell function, will extend kidney allograft survival and allow immunosuppressive drug withdrawal in Rhesus macaques.
The candidate regimens will be tested in combination with progressive tapering and withdrawal of conventional immunosuppression (IS).
Our hypothesis in Project 1 is that graft survival can be extended and is withdrawn in MHC-mismatched graft recipients using innovative strategies that selectively enhance inherent dendritic cell (DC) tolerogenicity.
These approaches are 1) to target DCs in situ, either with an exciting, novel myeloid cell checkpoint agonist, or with innovative, DC-directed nanobiologics and 2) to adoptively transfer autologous regulatory DCs (DCREGs) pulsed with donor-derived small extracellular vesicles (SEVs).
Our specific aims are:
Aim 1: To determine whether the novel myeloid cell checkpoint agonist (anti-LILRB3 MAB) that promotes DC tolerogenicity and allotolerance in mice, can extend graft survival/allow IS withdrawal;
Aim 2: To ascertain whether selective targeting of DCs in situ using novel, DC (DEC205)-directed nanobiologics can extend graft survival/allow IS withdrawal;
Aim 3: To assess whether infusion of autologous DCREGs pulsed with donor-derived immunoregulatory SEVs can extend graft survival/allow IS withdrawal.
Our hypothesis in Project 2 is that suppression of innate and adaptive immune mechanisms that would otherwise destabilize induction of tolerance, will be conducive to DCREG and TREG function and consequent prolongation of graft survival/IS withdrawal.
We will use new, Rhesus-specific MABs to modulate inflammation, attenuate donor-reactive TMEM and augment donor Ag alloreactive TREG (DARTREG); we will also test next generation donor Ag (BW6)-specific chimeric Ag receptor (CAR)TREGs.
Our specific aims are:
Aim 1: To mitigate post-TX inflammatory responses and eliminate IS-resistant, donor-reactive pathogenic TMEM through cytokine modulation using new, Rhesus-specific neutralizing anti-IL-6 or IL-7R and IL-15R blocking MABs;
Aim 2: To augment Ag-specific TREG through infusion of ex vivo-expanded, genetically-engineered BW6-specific CAR TREG;
Aim 3: To achieve durable, donor-alloreactive T cell regulation through CAR TREG infusion, combined with either cytokine modulation or in situ targeting of DC, depending on the results of Project 2 Aim 1, and Project 1 Aim 1 and 2 results.
Both projects will incorporate highly-interactive mechanistic studies and assess potential novel biomarkers.
The two projects will be supported by an administrative, biostatistics and bioinformatics core (Core A), a transplant pathology and tissue imaging core (Core B) and a nanotechnology core (Core C) and will utilize new agents from the NIAID NHP reagent resource.
Our program displays conceptual unity and strong component synergy and incorporates special/unique features of the investigative team and environment.
Funding Goals
NOT APPLICABLE
Grant Program (CFDA)
Awarding / Funding Agency
Place of Performance
Pittsburgh,
Pennsylvania
152221808
United States
Geographic Scope
Single Zip Code
Related Opportunity
Analysis Notes
Amendment Since initial award the total obligations have increased 146% from $1,455,073 to $3,575,266.
University Of Pittsburgh - Of The Commonwealth System Of Higher Education was awarded
Enhancing Regulatory Immune Cells for Transplant Success in Primates
Project Grant P01AI181829
worth $3,575,266
from the National Institute of Allergy and Infectious Diseases in July 2025 with work to be completed primarily in Pittsburgh Pennsylvania United States.
The grant
has a duration of 4 years 10 months and
was awarded through assistance program 93.855 Allergy and Infectious Diseases Research.
The Project Grant was awarded through grant opportunity NIAID Investigator Initiated Program Project Applications (P01 Clinical Trial Not Allowed).
Status
(Ongoing)
Last Modified 6/22/26
Period of Performance
7/3/25
Start Date
5/31/30
End Date
Funding Split
$3.6M
Federal Obligation
$0.0
Non-Federal Obligation
$3.6M
Total Obligated
Activity Timeline
Subgrant Awards
Disclosed subgrants for P01AI181829
Transaction History
Modifications to P01AI181829
Additional Detail
Award ID FAIN
P01AI181829
SAI Number
P01AI181829-4021417068
Award ID URI
SAI UNAVAILABLE
Awardee Classifications
Other
Awarding Office
75NM00 NIH National Institute of Allergy and Infectious Diseases
Funding Office
75NM00 NIH National Institute of Allergy and Infectious Diseases
Awardee UEI
MKAGLD59JRL1
Awardee CAGE
1DQV3
Performance District
PA-12
Senators
Robert Casey
John Fetterman
John Fetterman
Modified: 6/22/26