The very drugs that make hematopoietic cell transplantation (HCT) possible also give a dormant virus its chance to strike. In HCT, a patient’s blood-forming stem cells, which give rise to the immune system, are replaced with healthy donor cells to treat blood cancers and other blood disorders. Powerful immunosuppressive medications are crucial for preventing the newly transplanted immune system from attacking the patient’s body, but they can also awaken cytomegalovirus (CMV), a widespread virus that is kept in check by a healthy immune system, which most people carry without any symptoms.
HCT was pioneered at Fred Hutch over 50 years ago, transforming fatal blood cancers into treatable diseases. Since then, researchers have worked to understand and control CMV, which was a leading cause of death in the early days of HCT. While CMV-related mortality rates have decreased, the virus still poses risks for HCT recipients today.
Increased immunosuppression is the main driver of CMV reactivation, but researchers have a limited understanding of precisely how different drugs shape the recovery of CMV-specific antiviral immunity. At the heart of this immune recovery are polyfunctional CMV-specific T cells, specialized immune cells that target and attack the virus from multiple angles to keep CMV in check after HTC.
A recent study from the Boeckh Group examined how commonly used immunosuppressive agents, and the specific timing and doses in which they’re given, influence the recovery of these protective responses. The team analyzed samples from 243 CMV-seropositive HCT recipients, tracking how different immunosuppressive agents, alongside factors like CMV reactivation and antiviral administration, shaped immune recovery and protection against CMV.
Dr. Boeckh explained, “This deep interrogation of CMV-specific T cell function in HCT recipients gave us important novel insights into the effects of dose and timing of commonly used immunosuppressive drugs”. Prolonged exposure to intermediate or high doses of corticosteroids, for example, strongly impaired CMV-specific T cell function, but this effect was reversible when steroid doses were quickly tapered, highlighting the importance of both timing and dosage. The team also uncovered differences in immune recovery between two immunosuppressants belonging to the same drug class – patients treated with cyclosporine showed stronger polyfunctional CMV-specific T cell responses, even at higher doses, whereas tacrolimus had a more dose-dependent suppressive effect.
By teasing apart these nuances, the study highlights how carefully tailored treatment regimens could better protect patients from CMV while still preventing transplant complications. Beyond standard HCT care, this work could also guide emerging virus-specific T cell therapies, in which donor-derived CMV-targeting T cells are used to treat stubborn infections, by revealing how common immunosuppressants shape the survival and function of these therapeutic cells. As immunosuppressive strategies become increasingly complex, this kind of fine-tuning may help clinicians better balance the delicate trade-offs between preventing immune complications and preserving the antiviral defenses that keep latent threats in check.
Fred Hutch/University of Washington/Seattle Children’s Cancer Consortium Members Drs. Wendy M. Leisenring, Stephen C. De Rosa, Marco Mielcarek, and Michael Boeckh contributed to this research.
The spotlighted research was funded by the Medical University of Gdansk, the Joel D. Meyers Scholarship Endowment, and the National Institutes of Health.
Sadowska-Klasa A, Edmison BC, Lim FY, De Rosa SC, Xie H, Zamora D, Stevens-Ayers T, Mielcarek M, Boeckh M. 2026. New Insights Into Factors Shaping CMV-Specific T-Cell Polyfunctionality After Hematopoietic Cell Transplantation. American Journal of Hematology. DOI: 10.1002/ajh.70152
Science Spotlight writer Thamiya Vasanthakumar is a postdoctoral research fellow in the Campbell Lab at Fred Hutch. As a structural biologist, she uses cryogenic electron microscopy (cryoEM) to visualize the molecular structures of receptors found on the surface of immune cells.
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