Abstract
Pediatric hematopoietic stem cell transplantation (HSCT) is challenged by chronic graft-versus-host disease (cGvHD) significantly affecting survival and long-term morbidity, but underlying mechanisms including the impact of post-HSCT CMV infection are sparsely studied.
We first investigated the impact of CMV infection for development of cGvHD in 322 children undergoing standard myeloablative HSCT between 2000 and 2018. Clinically significant CMV infection (n = 61) was an independent risk factor for chronic GvHD in a multivariable Cox regression analysis (HR = 2.17, 95% CI = 1.18–3.97, P = 0.013). We next explored the underlying mechanisms in a subcohort of 39 children. CMV infection was followed by reduced concentration of recent thymic emigrants (17.5 vs. 51.9 × 106/L, P = 0.048) and naïve CD4+ and CD8+ T cells at 6 months post-HSCT (all P < 0.05). Furthermore, CD25highFOXP3+ Tregs tended to be lower in patients with CMV infection (2.9 vs. 9.6 × 106/L, P = 0.055), including Tregs expressing the naivety markers CD45RA and Helios. CD8+ T-cell numbers rose after CMV infection and was dominated by exhausted PD1-expressing cells (66% vs. 39%, P = 0.023).
These findings indicate that post-HSCT CMV infection is a main risk factor for development of chronic GvHD after pediatric HSCT and suggest that this effect is caused by reduced thymic function with a persistently impaired production of naïve and regulatory T cells in combination with increased peripheral T-cell exhaustion.
We first investigated the impact of CMV infection for development of cGvHD in 322 children undergoing standard myeloablative HSCT between 2000 and 2018. Clinically significant CMV infection (n = 61) was an independent risk factor for chronic GvHD in a multivariable Cox regression analysis (HR = 2.17, 95% CI = 1.18–3.97, P = 0.013). We next explored the underlying mechanisms in a subcohort of 39 children. CMV infection was followed by reduced concentration of recent thymic emigrants (17.5 vs. 51.9 × 106/L, P = 0.048) and naïve CD4+ and CD8+ T cells at 6 months post-HSCT (all P < 0.05). Furthermore, CD25highFOXP3+ Tregs tended to be lower in patients with CMV infection (2.9 vs. 9.6 × 106/L, P = 0.055), including Tregs expressing the naivety markers CD45RA and Helios. CD8+ T-cell numbers rose after CMV infection and was dominated by exhausted PD1-expressing cells (66% vs. 39%, P = 0.023).
These findings indicate that post-HSCT CMV infection is a main risk factor for development of chronic GvHD after pediatric HSCT and suggest that this effect is caused by reduced thymic function with a persistently impaired production of naïve and regulatory T cells in combination with increased peripheral T-cell exhaustion.
| Originalsprog | Engelsk |
|---|---|
| Artikelnummer | 110302 |
| Tidsskrift | Clinical Immunology |
| Vol/bind | 265 |
| Antal sider | 9 |
| ISSN | 1521-6616 |
| DOI | |
| Status | Udgivet - 2024 |
Bibliografisk note
Funding Information:This study was supported by unrestricted grants from the Research Council at Copenhagen University Hospital Rigshospitalet (grant #R85-A3157), the Danish Childhood Cancer Association (grant #2015-30), the Dagmar Marshall Foundation, \u00C5se and Ejnar Danielsen's Foundation, and T\u00F8mrermester J\u00F8rgen Holm og Hustru Elisa f. Hansens Mindelegat. We thank Winnie Hansen (Institute for Inflammation Research, Copenhagen University Hospital Rigshospitalet) for excellent technical assistance in the laboratory.
Funding Information:
This study was supported by unrestricted grants from the Research Council at Copenhagen University Hospital Rigshospitalet (grant #R85-A3157 ), the Danish Childhood Cancer Association (grant #2015-30 ), the Dagmar Marshall Foundation , \u00C5se and Ejnar Danielsen's Foundation , and T\u00F8mrermester J\u00F8rgen Holm og Hustru Elisa f. Hansens Mindelegat .
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