# Optimized bone marrow conditioning and tolerance assays to advance cell-based therapies for diabetes

> **NIH NIH F32** · STANFORD UNIVERSITY · 2024 · $74,284

## Abstract

PROJECT SUMMARY
 Type 1 diabetes mellitus (T1D) is an incurable autoimmune disease that results in the destruction of insulin
producing β cells and affects nearly 10% of the global population. T1D most commonly affects young children
and adolescents and can lead to irreparable and deadly complications if not properly treated. Current treatments
and management strategies require time-intensive exogenous insulin administration, with incredible onus on
patients and their caregivers. Islet transplantation to replace β cells is an attractive and FDA-approved alternative
to insulin therapy in T1D. However, the widespread acceptance of this approach faces formidable challenges,
including the absence of safe, non-toxic methods to shield transplanted allogeneic donor islets from immune
rejection and a scarcity of donor material. To surmount these hurdles, the field must accomplish two critical
objectives: 1) establish an effective, non-toxic strategy to induce tolerance toward donor tissues and 2) identify
a readily obtainable source of donor material for transplantation.
 An emerging field for transplant tolerance is mixed chimerism achieved by hematopoietic cell transplant
(HCT), establishing tolerance toward donor-matched tissues and correction of defects that cause autoimmunity.
Unfortunately, this requires high doses of radiation and/or chemotherapy to prepare and condition the host prior
to HCT, resulting in undesirable toxicities. The development of low intensity conditioning protocols with reduced
toxicity, adverse effects, and risk for graft vs. host disease (GVHD) is necessary to increase access to HCT for
patients without imminent fatal illness or malignancy. Additionally, pluripotent stem cell (PSC)-derived β-like cells
offer an attractive and unlimited source of material for islet cell replacement therapy. However, the
immunogenicity of PSC derivatives and the potential for mixed hematopoietic chimerism to induce tolerance to
these derivatives remains unexplored.
 In recent exciting work, we show that a novel low intensity conditioning protocol using monoclonal antibodies
for T cell and hematopoietic stem cell (HSC) depletion combined with a non-myeloablative dose of total body
irradiation allows for stable mixed chimerism and donor-matched allogeneic islet transplant tolerance. Here, we
propose to 1) optimize our conditioning protocol to significantly reduce, or eliminate, the radiation dose required
for conditioning and generation of mixed hematopoietic chimerism across full MHC barriers, and 2) evaluate the
immunogenicity of mouse PSC-derived β-like cells and tolerance induction in mixed hematopoietic chimeras.
 Collectively, this research will develop reduced intensity conditioning regimens to produce sustained mixed
chimerism and islet transplant tolerance. This will allow for use of this technique beyond patients with fatal
malignancy or autoimmunity, including in patients with T1D, as well as provide the necessary training for me to
be...

## Key facts

- **NIH application ID:** 10999248
- **Project number:** 1F32DK141209-01
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Stephan Anthony Ramos
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $74,284
- **Award type:** 1
- **Project period:** 2024-08-01 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10999248

## Citation

> US National Institutes of Health, RePORTER application 10999248, Optimized bone marrow conditioning and tolerance assays to advance cell-based therapies for diabetes (1F32DK141209-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10999248. Licensed CC0.

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