The Presence of a Marked Imbalance Between Regulatory T Cells and Effector T Cells Reveals That Tolerance Mechanisms Could Be Compromised in Heart Transplant Children.

Regulatory T cells (Treg) are crucial for the induction and maintenance of graft tolerance. In pediatric heart transplant procedures, the thymus is routinely excised, removing the primary source of T-cell replenishment. Consequently, thymectomy joined to the effects of immunosuppression on the T-cell compartment may have a detrimental impact on Treg values, compromising the intrinsic tolerance mechanisms and the protective role of Treg preventing graft rejection in heart transplant children. METHODS: A prospective study including 7 heart transplant children was performed, and immune cell populations were evaluated periodically in fresh peripheral blood at different time points before and up to 3 y posttransplant. RESULTS: Treg counts decreased significantly from the seventh-month posttransplant. Furthermore, there was a significant increase in effector memory and terminally differentiated effector memory T cells coinciding with the fall of Treg counts. The Treg/Teffector ratio, a valuable marker of the tolerance/rejection balance, reached values around 90% lower than pretransplant values. Additionally, a negative correlation between Treg count and T effector frequency was observed. Particularly, when Treg count decreases below 50 or 75 cells/µL in the patients, the increase in the frequency of T effector CD4+ and CD8+, respectively, experiences a tipping point, and the proportion of T-effector cells increases dramatically. CONCLUSIONS: These results reveal that interventions employed in pediatric heart transplantation (immunosuppression and thymectomy) could induce, as an inevitable consequence, a dysregulation in the immunologic status characterized by a marked imbalance between Treg and T effector, which could jeopardize the preservation of tolerance during the period with the higher incidence of acute rejection.

Basiliximab impairs regulatory T cell (TREG) function and could affect the short-term graft acceptance in children with heart transplantation.

CD25, the alpha chain of the IL-2 receptor, is expressed on activated effector T cells that mediate immune graft damage. Induction immunosuppression is commonly used in solid organ transplantation and can include antibodies blocking CD25. However, regulatory T cells (Tregs) also rely on CD25 for their proliferation, survival, and regulatory function. Therefore, CD25-blockade may compromise Treg protective role against rejection. We analysed in vitro the effect of basiliximab (BXM) on the viability, phenotype, proliferation and cytokine production of Treg cells. We also evaluated in vivo the effect of BXM on Treg in thymectomized heart transplant children receiving BXM in comparison to patients not receiving induction therapy. Our results show that BXM reduces Treg counts and function in vitro by affecting their proliferation, Foxp3 expression, and IL-10 secretion capacity. In pediatric heart-transplant patients, we observed decreased Treg counts and a diminished Treg/Teff ratio in BXM-treated patients up to 6-month after treatment, recovering baseline values at the end of the 12-month follow up period. These results reveal that the use of BXM could produce detrimental effects on Tregs, and support the evidence suggesting that BXM induction could impair the protective role of Tregs in the period of highest incidence of acute graft rejection.

Immune dysregulation and Th2 polarization are associated with atopic dermatitis in heart-transplant children: A delicate balance between risk of rejection or atopic symptoms.

Atopic dermatitis (AD) has a high incidence in heart-transplant children, and the reason why there is more AD after transplantation is still unknown. We conducted a cross-sectional study comparing 11 AD and 11 non-AD age-matched heart-transplant children, to assess which immune alterations are related to AD in these patients. AD patients had been transplanted at a younger age compared to non-AD, indicating that age at transplant may be determinant in the onset of AD. The earlier thymectomy in AD heart-transplant children favored the presence of more differentiated phenotypes in the T cell compartment. We observed a clear reduction in the T-helper 1/T-helper 2 (Th1/Th2) ratio in AD children. This Th2 polarization was related to eosinophilia and high immunoglobulin E levels, but also to an impaired regulatory T cell (Treg) suppression, which could be secondary to an exhaustion of the Treg compartment. Interestingly, AD patients were free of rejection episodes (0/11) in comparison to non-AD children (4/11). We propose that a predominant Th2 phenotype may prevent the emergence of Th1 responses associated with graft rejection. A more differentiated Treg phenotype could also play a role in preventing acute rejection in the first year posttransplant. Our findings provide useful insights and knowledge for the better understanding of atopic disorders in transplanted children.