# Preclinical Studies of Living Donor Islet-Kidney Allograft Tolerance

> **NIH NIH U19** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2020 · $651,494

## Abstract

Project Summary: Project 2 is specifically designed toward the development of a tolerance induction strategy
for curative treatment of end-stage diabetic nephropathy, using living donor composite Islet-Kidney (IK)
transplantation (Tx). Many diabetic patients in renal failure, especially children, have potential donors willing to
provide both a kidney and islets for transplantation. Unfortunately, the quantity of islets obtained through partial
pancreatectomy from living donors is often insufficient to achieve insulin independence following isolated islet
Tx. We have previously demonstrated that the strategy of 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. Both renal and islet function were restored by IK tx across fully allogeneic barriers in
nephrectomized diabetic baboons using a clinically relevant immunosuppression protocol. More recently, we
reported the successful induction of tolerance of IKs in rhesus monkeys using a novel, reduced intensity,
hematopoietic cell Tx protocol in a “parent-to-offspring” combination. These data demonstrated “proof of
principle” for the approach of induction of tolerance of allogeneic islet-kidneys. However, although allograft
tolerance was achieved, chimerism was transient and insulin supplementation was required early post
transplantation. We hypothesize that components of the conditioning regimen and/or donor cell source
may have had an early negative impact on islet function. We also hypothesize that induction of tolerance
through durable mixed chimerism may be more effective than transient chimerism in reversing
autoimmunity associated with T1D, as has been demonstrated recently in an NOD mouse model. We
therefore propose here to: 1) optimize the conditioning protocol and mobilized cell product in ways that are
expected to improve preservation of islet function during the tolerance induction phase (Aim 1), including
replacement of CyA with Rapamycin and anti-CD40 mAb and. If needed, use of purifed HSC; 2) add ex-vivo
expanded donor-specific Tregs to the induction regimen, in order to facilitate the establishment of durable mixed
chimerism (Aim 2). This approach is possible with the use of living-related donors, from whom one can generate
donor-specific Tregs in advance of the transplant; and 3) study the fate of both effector and regulatory T cells in
recipients of IKs (Aim 3), in order to determine the mechanism of tolerance and identify potential biomarkers
predicting tolerance vs rejection. These studies will involve assessment of the deletion or expansion of effector
and regulatory T cells using a high-throughput TCR sequencing approach developed in Core B. Islets will be
provided by Core A and collaboration with Project 1 and both cores will be coordinated through Core C.

## Key facts

- **NIH application ID:** 9988362
- **Project number:** 5U19AI131474-04
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** KAZUHIKO YAMADA
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $651,494
- **Award type:** 5
- **Project period:** 2017-08-18 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9988362

## Citation

> US National Institutes of Health, RePORTER application 9988362, Preclinical Studies of Living Donor Islet-Kidney Allograft Tolerance (5U19AI131474-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9988362. Licensed CC0.

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