Homoharringtonine Promotes Heart Allograft Acceptance by Enhancing Regulatory T Cells Induction in a Mouse Model
Heart transplantation remains a critical intervention for end-stage heart failure, yet post-transplant immune rejection continues to challenge long-term success. Current immunosuppressive regimens, including calcineurin inhibitors, antimetabolites, and corticosteroids, effectively reduce acute rejection rates but carry significant risks of toxicity, infections, and metabolic complications. These limitations underscore the urgent need for novel therapeutic strategies that mitigate rejection while preserving immune competence. A recent study investigating homoharringtonine (HHT), a plant-derived alkaloid, provides compelling evidence for its immunomodulatory potential in promoting cardiac allograft acceptance through selective enhancement of regulatory T (Treg) cells.
HHT Inhibits T Cell Proliferation and Induces Apoptosis in a Dose-Dependent Manner
The study first characterized the impact of HHT on T cell responses using ex vivo and in vivo models. Activated CD4+ and CD8+ T cells were exposed to varying HHT concentrations (10, 30, and 50 nmol/L) to assess proliferation and apoptosis. At 10 nmol/L, HHT significantly suppressed the proliferation of both CD4+ and CD8+ T cells. This inhibitory effect intensified at 30 nmol/L, with CD4+ T cells additionally exhibiting early apoptosis. At 50 nmol/L, HHT induced substantial apoptosis in CD8+ T cells, though CD4+ apoptosis plateaued compared to lower doses. These findings highlighted HHT’s dual role: it dampens T cell activation at lower concentrations while triggering apoptosis at higher doses, particularly in CD8+ subsets.
To translate these findings into a therapeutic context, the authors determined the optimal in vivo dose. Wild-type mice receiving 0.5 mg/kg HHT showed no structural or functional abnormalities in vital organs, as confirmed by histopathological analysis of the liver, kidneys, and spleen. Hematological parameters, including white blood cell counts, remained within normal ranges, suggesting minimal systemic toxicity at this dose.
Low-Dose HHT Prolongs Graft Survival Without Broad Immunosuppression
In a mouse model of heterotopic heart transplantation, recipients were treated with 0.5 mg/kg HHT for either 10 days (short-term) or 4 weeks (long-term). Both regimens significantly extended mean survival time (MST) of allografts compared to untreated controls. Strikingly, despite HHT’s in vitro suppression of T cells, in vivo analyses revealed no reduction in splenic or graft-infiltrating T cell populations. Furthermore, CD8+ T cells within allografts retained their cytotoxic function, as evidenced by unaltered expression of granzyme B and perforin. This dissociation between in vitro and in vivo effects suggested that HHT’s graft-protective mechanism operates independently of global T cell suppression.
HHT Enhances Treg Cell Differentiation and Function
The study identified Treg cells as central mediators of HHT’s therapeutic effect. Flow cytometry revealed a significant increase in FoxP3+ Treg cells within the spleens and cardiac allografts of HHT-treated mice. RNA sequencing of graft-infiltrating T cells further elucidated the molecular underpinnings of this shift. HHT downregulated genes associated with T cell receptor (TCR) signaling pathways, which are critical for effector T cell activation. Concurrently, it upregulated signature Treg genes, including FoxP3, Il10, and Tgfb1, as well as pathways linked to interleukin-10 (IL-10) and transforming growth factor-beta (TGF-β).
Functional assays demonstrated that Treg cells from HHT-treated mice exhibited enhanced suppressive capacity. When co-cultured with effector T cells, these Tregs significantly inhibited proliferation in a contact-independent manner, implicating soluble factors like IL-10 and TGF-β. In vivo depletion of Tregs using anti-CD25 antibodies abolished HHT’s graft-prolonging effects, confirming their indispensability.
Mechanistic Insights: Balancing Immune Regulation and Tolerance
The study proposed a model wherein low-dose HHT skews the immune microenvironment toward tolerance by two synergistic mechanisms:
- Attenuation of TCR Signaling: By dampening TCR-driven activation, HHT reduces the priming of alloreactive effector T cells.
- Amplification of Treg Activity: Enhanced IL-10 and TGF-β secretion by Tregs creates a suppressive milieu that restrains residual effector responses.
This dual action allows HHT to prevent rejection without inducing broad immunosuppression. Notably, the preservation of CD8+ T cell function suggests that pathogen-specific immunity may remain intact, potentially lowering infection risks compared to conventional therapies.
Clinical Implications and Unresolved Questions
The findings position HHT as a promising adjunct to current immunosuppressive regimens. Its ability to selectively expand Tregs could complement calcineurin inhibitors, which lack specificity and impair Treg function. However, the study flagged two critical considerations:
- Leukopenia Risk: HHT-treated mice exhibited mild leukopenia, raising concerns about hematopoietic toxicity during prolonged use.
- IL-10 Signaling: While IL-10 was upregulated, the downstream pathways mediating its suppressive effects remain uncharacterized.
Future studies must address these gaps, particularly the long-term safety of HHT and its interactions with established immunosuppressants. Additionally, translating these findings to large-animal models or humanized systems will be essential to validate clinical applicability.
Conclusion
This investigation provides a robust preclinical foundation for repurposing HHT in transplantation immunology. By harnessing Treg cells to enforce graft tolerance, HHT offers a paradigm shift from nonspecific immunosuppression to precision immunomodulation. While challenges persist, the study illuminates a path toward safer, more effective strategies for preventing cardiac allograft rejection.
doi.org/10.1097/CM9.0000000000003492
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