# Using Polyclonal Tregs to Develop a Compressed BMT Regiment for Deceased Donor Islets and Kidneys

> **NIH NIH U19** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2020 · $758,403

## Abstract

Project Summary: 
Project 1 aims to use polyclonal recipient Tregs in a compressed conditioning protocol to achieve mixed 
chimerism and tolerance to deceased-donor kidneys and/or islets. Islet transplantation for the cure of Type 1 
diabetes (T1D) is currently limited by low 5-year survival rates. Poor islet survival is likely the result of islet loss 
due to alloimmune responses, recurrent autoimmunity, and toxicity from immunosuppressive drugs. Thus, this 
therapy can only ethically be offered to patients with life-threatening complications of T1D. Inducing tolerance 
to islets through the development of mixed chimerism has the potential to eliminate both alloimmune and 
autoimmune islet loss, as well as the need for immunosuppressive medications. There are several barriers to 
inducing mixed chimerism and tolerance to kidneys and/or islets using deceased donors that we aim to 
overcome. Our current tolerance induction regimen, developed in cynomolgus monkeys and translated to 
humans, involves a 6-day conditioning of the immune system prior to organ transplant and is therefore only 
applicable to living donation. Previous attempts to compress immune conditioning to 24 hours, to allow the use 
of deceased donors, failed to induce chimerism or tolerance. Additionally, durable chimerism may be required 
for reversal of autoimmunity in T1D patients and might then be necessary for optimal islet survival post- 
transplant. Since the kidney has been shown to contribute to tolerance in the case of transient chimerism, it is 
even more important to achieve durable chimerism in recipients of islet transplants without co-transplantation 
of a donor kidney if tolerance is to develop. We now have data showing that expanded polyclonal recipient 
Tregs can achieve markedly prolonged chimerism and more robust tolerance than has previously been 
possible in the cynomolgus model. We hypothesize that the addition of polyclonal recipient Tregs, that can be 
prepared in advance, to a compressed conditioning regimen, will permit the development of mixed chimerism 
and tolerance to kidneys and/or islets. Our approach targets patients with end-stage renal disease alone (Aim 
1), patients with T1D and renal failure (Aim 2A), and finally T1D without renal failure (Aim 2B). Therefore, 
additional measures will be added in Aim 2 if durable chimerism is not achieved in Aim 1. Finally, accurate 
characterization of the mechanism(s) of tolerance following transient or durable chimerism in nonhuman 
primates is lacking, in large part due to the absence of precise tools to characterize deletional and regulatory 
mechanisms. In Aim 3, we will use standard immunologic assays combined with the high-throughput TCR 
CDR3 tracking system developed in Core B (based on the human TCR platform developed in this laboratory 
and modified for cynomolgus monkeys) to accurately quantify deletion/expansion of donor-reactive effector T 
cells and donor-specific Tregs. Islets will be provided...

## Key facts

- **NIH application ID:** 9988361
- **Project number:** 5U19AI131474-04
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Adam David Griesemer
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $758,403
- **Award type:** 5
- **Project period:** 2017-08-18 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9988361

## Citation

> US National Institutes of Health, RePORTER application 9988361, Using Polyclonal Tregs to Develop a Compressed BMT Regiment for Deceased Donor Islets and Kidneys (5U19AI131474-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9988361. Licensed CC0.

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