ABSTRACT
BACKGROUND: Extracorporeal photopheresis (ECP) has emerged as a prophylactic and therapeutic immunomodulatory option for managing acute rejection in heart transplants (HTx). The underlying mechanisms through which ECP exerts its immunomodulatory effects remain under investigation. Regulatory T cells (Treg) are a heterogeneous subset of immune lymphocytes that ensure the maintenance of tissue homeostasis, avoiding graft rejection. The transcription factor forkhead box protein 3 (FoxP3) is an essential molecular marker of Treg, acting as a "master regulator" of their genesis, stability, and functions. No study has investigated whether ECP impacts FoxP3 expression and its highly suppressive variants containing the exon 2 (FoxP3-E2), particularly in HTx. METHODS: In the current study, we recruited 14 HTx participants who had undergone ECP therapy. We explored the effect of in vivo ECP on CD4+FoxP3+ Treg frequency and in vitro suppressive function in 8 HTx participants before (T0) and after 3 (T1), 6 (T2), and 12 (T3) mo of treatment. As a control group, we included 4 HTx individuals who had not undergone ECP therapy. RESULTS: We found that ECP increases the frequency of CD4+FoxP3+ Treg subset with highly suppressive phenotype, including CD4+FoxP3-E2+ Treg. At functional levels, we observed that ECP treatment in HTx individuals effectively improves Treg suppressive ability in controlling the proliferation of autologous conventional CD4+ T lymphocytes. CONCLUSIONS: Our findings collectively suggest that ECP exerts its immunomodulatory effects in HTx individuals by positively impacting the frequency and regulatory function of the FoxP3+ Treg compartment.
ABSTRACT
AIMS/HYPOTHESIS: Type 1 diabetes is an autoimmune disorder that is characterised by destruction of pancreatic beta cells by autoreactive T lymphocytes. Although islet autoantibodies (AAb) are an indicator of disease progression, specific immune biomarkers that can be used as target molecules to halt development of type 1 diabetes have not been discovered. Soluble immune checkpoint molecules (sICM) play a pivotal role in counteracting excessive lymphocyte responses, but their role in type 1 diabetes is unexplored. In this longitudinal study, we measured sICM levels in AAb-positive (AAb+) children to identify molecules related to type 1 diabetes progression. METHODS: We measured the levels of 14 sICM in the sera of AAb+ children (n=57) compared to those with recent-onset type 1 diabetes (n=79) and healthy children (n=44), obtained from two cohorts. AAb+ children were followed up and divided based on their progression to type 1 diabetes (AAbP) or not (AAbNP) (if they lost islet autoimmunity and did not develop disease in subsequent years). sICM were also measured in the sample taken at the visit closest to disease onset in AAbP children. RESULTS: We found that AAb+ children had a distinct sICM profile compared with healthy children and those with recent-onset type 1 diabetes. In addition, AAb+ children who progressed to type 1 diabetes (AAbP) had higher sICM concentrations than non-progressors (AAbNP). Further, sICM levels decreased in AAbP children close to disease onset. Application of Cox regression models highlighted that high concentrations of soluble programmed cell death protein 1 (sPD-1) are associated with type 1 diabetes progression (HR 1.71; 95% CI 1.16, 2.51; p=0.007). CONCLUSIONS/INTERPRETATION: This study reveals an sICM profile that is dysregulated during the preclinical stage of type 1 diabetes, and identifies sPD-1 as a pathophysiologically-relevant molecule that is associated with disease progression, offering a potential target for early interventions in autoimmune diabetes.