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Peer-reviewedCC BY-NC-ND 4.0Cell Reports Medicine

Combining pro-resolving therapy with cyclosporine A restores immune homeostasis and reduces toxicity in autoimmune bone marrow failure

  • Rachel Grazda1
  • Amber Bahr1
  • Lily Nti-kyeremeh1
  • Christina Nickerson2
  • Gabrielle Fredman2
  • Katrin D. Mayer-Barber3
  • Katherine C. MacNamara1
  1. 1Department of Immunology and Microbiology, Albany Medical College, Albany, NY 12208, USA
  2. 2Department of Molecular and Cellular Physiology, Albany Medical College, Albany, NY 12208, USA
  3. 3Inflammation and Innate Immunity Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), National Institute of Health (NIH), Bethesda, MD 20892, USA
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Abstract

Immunosuppressive therapies (ISTs), including calcineurin inhibitors like cyclosporine A (CsA), are essential therapeutics for autoimmunity; however, they often fail and cause dose-limiting toxicity. Severe aplastic anemia (SAA) is a fatal autoimmune bone marrow (BM) failure disorder that is treated with ISTs. BM single-cell RNA sequencing (scRNA-seq) from SAA patients reveals enhanced T cell effector programs, maladaptive myelopoiesis, and impaired inflammation resolution despite standard-of-care therapy, suggesting incomplete restoration of immune homeostasis with ISTs. In murine SAA, CsA improves survival but induces persistent inflammatory T cells, emergency myelopoiesis, and nephrotoxicity following withdrawal. The pro-resolving lipid mediator resolvin E1 (RvE1) similarly prevents SAA-induced mortality but without toxicity or persistent inflammation. Co-treatment with RvE1, concurrently or after CsA, achieves complete survival, restores immune and hematopoietic homeostasis, and reduces toxicity in a ChemR23-dependent manner. These findings support a paradigm shift toward curative therapies that simultaneously engage endogenous repair programs and suppress pathogenic responses to enhance treatment safety and durability.

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Cite

BibTeXRIS
BibTeX
@article{grazda2026combining,
  title = {{Combining pro-resolving therapy with cyclosporine A restores immune homeostasis and reduces toxicity in autoimmune bone marrow failure}},
  author = {Rachel Grazda and Amber Bahr and Lily Nti-kyeremeh and Christina Nickerson and Gabrielle Fredman and Katrin D. Mayer-Barber and Katherine C. MacNamara},
  journal = {Cell Reports Medicine},
  year = {2026},
  month = sep,
  doi = {10.1016/j.xcrm.2026.103074},
  url = {https://doi.org/10.1016/j.xcrm.2026.103074},
  note = {CC BY-NC-ND 4.0},
}
RIS
TY  - JOUR
TI  - Combining pro-resolving therapy with cyclosporine A restores immune homeostasis and reduces toxicity in autoimmune bone marrow failure
AU  - Rachel Grazda
AU  - Amber Bahr
AU  - Lily Nti-kyeremeh
AU  - Christina Nickerson
AU  - Gabrielle Fredman
AU  - Katrin D. Mayer-Barber
AU  - Katherine C. MacNamara
PY  - 2026
DA  - 2026/09/24
JO  - Cell Reports Medicine
DO  - 10.1016/j.xcrm.2026.103074
UR  - https://doi.org/10.1016/j.xcrm.2026.103074
AB  - Immunosuppressive therapies (ISTs), including calcineurin inhibitors like cyclosporine A (CsA), are essential therapeutics for autoimmunity; however, they often fail and cause dose-limiting toxicity. Severe aplastic anemia (SAA) is a fatal autoimmune bone marrow (BM) failure disorder that is treated with ISTs. BM single-cell RNA sequencing (scRNA-seq) from SAA patients reveals enhanced T cell effector programs, maladaptive myelopoiesis, and impaired inflammation resolution despite standard-of-care therapy, suggesting incomplete restoration of immune homeostasis with ISTs. In murine SAA, CsA improves survival but induces persistent inflammatory T cells, emergency myelopoiesis, and nephrotoxicity following withdrawal. The pro-resolving lipid mediator resolvin E1 (RvE1) similarly prevents SAA-induced mortality but without toxicity or persistent inflammation. Co-treatment with RvE1, concurrently or after CsA, achieves complete survival, restores immune and hematopoietic homeostasis, and reduces toxicity in a ChemR23-dependent manner. These findings support a paradigm shift toward curative therapies that simultaneously engage endogenous repair programs and suppress pathogenic responses to enhance treatment safety and durability.
SN  - 2666-3791
ER  -