# Mixed Chimerism-Dependent Tolerance After Myeloablative Bone Marrow Transplantation

> **NIH VA I01** · IOWA CITY VA MEDICAL CENTER · 2022 · —

## Abstract

Graft-versus-host disease (GVHD) is a lethal and devastating complication of hematopoietic cell
transplantation (HCT) or bone marrow transplantation (BMT), where HCT/BMT constitutes a predominant and
curative approach for the treatment of hematological malignancies and other disorders. Because of exposure
to environmental agents, such as the carcinogen agent orange, members of the US Military are under risk to
develop hematological malignancies during their years as active soldiers or later as veterans. GVHD is caused
by donor (graft) T cell-mediated immune attack of recipient (host) tissues and also complicates the clinical
picture after combined transplantation of bone marrow and a solid organ. Veterans are also under higher risk
to develop end-stage solid organ failure that requires transplantation. Novel treatment strategies are needed in
BMT/HCT patients to maintain the donor T lymphocyte-mediated anti-tumor immune (graft-versus-tumor (GVT)
response and suppress the GVHD. In this context, therapeutic achievement of mixed chimerism, which is
characterized by the presence of donor and recipient hematopoietic cell after transplantation, results in
immune tolerance by donor T cells against the recipient and in regulation of GVHD. Mixed chimerism also
tolerizes recipient’s immune cells against the donor, suppressing the rejection of solid organ graft after
combined transplantation and reduces the use of toxic immune suppressive medications. Current clinical
protocols mostly use nonmyeloablative preparation (lower dose of chemotherapy and/or radiation without
completely eradicating recipient’s bone marrow cells) before the BMT/HCT to achieve mixed chimerism. This
approach carries a high risk of tumor relapse. By contrast, we use myeloablative preparation (higher dose of
chemotherapy and/or radiation with complete eradication of recipient’s bone marrow cells) in our BMT model
with mixed chimerism, where the GVT response is preserved and the risk of cancer relapse is reduced. We
induce mixed chimerism-dependent regulation of GVHD by modulation of intestinal immune pathways using a
completely novel approach and with self-limited helminth colonization of the gut. We have shown before that
helminths promote the generation of mixed chimerism by stimulating recipient cell Th2 signaling and Th2-
dependent generation of TGFβ. In this application, in Aim #1 we propose to investigate the elements of
Th2/TGFβ pathways critical to generation of mixed chimerism. In Aim #2, we will explore the role of different
immune regulatory circuitries relevant to mixed chimerism-dependent regulation of GVHD and solid organ
rejection. In Aim #3, we will investigate the effect of mixed chimerism-induced immune regulation on the GVT
response using a mouse leukemia/lymphoma model syngeneic with the BMT recipient strain. Our long-term
goals are to dissect immune regulatory pathways important in helminth-induced mixed chimerism and apply
the knowledge to clinical transplantation...

## Key facts

- **NIH application ID:** 10449110
- **Project number:** 5I01BX002906-06
- **Recipient organization:** IOWA CITY VA MEDICAL CENTER
- **Principal Investigator:** Mirac Nedim Ince
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2017-01-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10449110

## Citation

> US National Institutes of Health, RePORTER application 10449110, Mixed Chimerism-Dependent Tolerance After Myeloablative Bone Marrow Transplantation (5I01BX002906-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10449110. Licensed CC0.

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