Reduced Frequency of Peripheral Th17-Precursors of the Phenotype CD4+CD161+ Following Kidney Transplantation and Long-Term Therapy with Belatacept

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Introduction: The co-stimulation blocker Belatacept recently has been approved by the FDA for the use in kidney transplantation. As clinical trials have pointed out, this newly developed drug is a promising candidate to help improve graft function and avoid undesired side-effects associated with chronic use of calcineurin-inhibitors (CNI). Unfortunately, so far almost no data exists to assess the effects of sustained application of this immunomodulator on the recipient's immune system as the worldwide availability of appropriate patients is highly limited. Aim of this study thus was to identify specific differences in the composition of immunologic subpopulations, especially those potentially involved in chronic graft rejection as well as the development of tolerance, following long-term treatment with Belatacept. Methods: Applying multi-colour flow-cytometry, the frequencies of various lymphocyte subsets in the peripheral blood of kidney recipients (n = 5) on long-term therapy with Belatacept (on average 7.8 years) were compared with cells from matched patients on CNI (n = 9) and healthy controls (n = 10). The number of T-cells capable of producing interleukin-17 (IL-17) likewise was determined following stimulation in vitro. Serum samples were used to detect the levels of soluble CD30 (sCD30). Results: Patients treated with CNI showed a higher frequency of Th17-precursor cells of the phenotype CD4+CD161+ than Belatacept-patients and healthy controls. Likewise, the number of IL-17 producing CD4+ T-cells was found to be increased in the former. In addition, evaluation of serum samples revealed significantly higher serum levels of sCD30 in patients on CNI-therapy as observed in the group of transplant recipients on Belatacept which showed comparable levels to untreated individuals. No differences between the groups were found concerning peripheral CD4+CD25+CD127lowFoxP3+ regulatory T-cells. Conclusion: Patients receiving Belatacept as a maintenance therapy following kidney transplantation did not show comparable Th17-profiles as observed for transplanted individuals on long-term treatment with CNI. If the mechanistic link between Belatacept and Th17-immunity can be confirmed, this recently approved drug thus might prove beneficial for the long-term outcome following kidney transplantation.