# Core-002

> **NIH NIH U19** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2022 · $354,251

## Abstract

This U19 proposal aims to achieve islet and kidney allograft tolerance through mixed chimerism in two
complementary cynomolgus monkey projects that are supported by three cores. Both projects have relevance
for end-stage renal disease (ESRD) and curative therapy for Type 1 diabetes (T1D). They employ related
approaches to achieve tolerance for deceased and living donor grafts, respectively. Project 1 aims to use
expanded polyclonal recipient Tregs to develop a compressed conditioning regimen that induces tolerance of
simultaneous bone marrow, kidney and islet allografts from deceased donors. We have previously used a 6-
day conditioning protocol that is relevant only for living donors, to achieve transient chimerism and kidney
allograft tolerance in monkeys and humans. We now aim to develop a conditioning protocol that could be initiated
after identification of a deceased donor, allowing transplantation (Tx) within 24 hours. Our approach builds on
our demonstration that expanded polyclonal recipient Tregs can achieve far more prolonged chimerism and more
robust tolerance than has previously been possible in the cynomolgus model. Tolerance obviates the need for
long-term immunosuppressive therapy with its destructive effects on islet grafts. Moreover, our studies in NOD
mice have shown that non-myeloablative induction of durable mixed chimerism reverses advanced anti-islet
autoimmunity, simultaneously avoiding the alloimmunity, autoimmunity and drug toxicity that currently limit the
efficacy of islet Tx in T1D. Project 2 aims to develop a tolerance induction strategy for curative treatment of
end-stage diabetic nephropathy using living related donor (LRD) composite Islet-Kidney (IK) Tx. The project
builds on our observation that transplanting pre-vascularized islets as part of composite IKs in large animal
models requires far fewer islets to achieve insulin independence than Tx of free, non-vascularized islets. We
recently achieved tolerance of IKs in rhesus monkeys using a novel, low intensity, hematopoietic cell transplant
protocol in a “parent-to-offspring” combination. Project 2 aims to adjust components of the conditioning regimen
and/or donor cell source that may have an early negative impact on islet function. Taking advantage of the ability
to generate potent donor-specific Tregs prior to LRD Tx, we will test the ability of these cells to promote durable
mixed allogeneic chimerism, with its potential to reverse T1D. Both projects will include extensive mechanistic
analyses that build on a high-throughput TCR sequencing-based approach for tracking the alloreactive T cell
repertoire that we have developed in humans and will apply to cynomolgus monkeys in Core B. Thus, we aim
to achieve durable mixed chimerism in both projects to cure autoimmunity while simultaneously preventing
alloimmune attack by inducing tolerance. Core A will provide monkey islets for both projects and Core B will
develop a high throughput T cell receptor (TCR) sequencin...

## Key facts

- **NIH application ID:** 10596885
- **Project number:** 4U19AI131474-06
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Megan Sykes
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $354,251
- **Award type:** 4C
- **Project period:** 2017-08-18 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10596885

## Citation

> US National Institutes of Health, RePORTER application 10596885, Core-002 (4U19AI131474-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10596885. Licensed CC0.

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