The Cytomegalovirus-Specific IL-21 ELISpot Correlates with Allograft Function of Kidney Transplant Recipients

Abstract

In kidney transplant recipients, the cytomegalovirus (CMV) is frequently causing infection/reactivation and can trigger allograft rejection. To assess the risk of reactivation, the cellular immune response against CMV is increasingly assessed by cellular in vitro methods, such as the interferon (IFN)-γ ELISpot. In the current study we compared the IFN-γ ELISpot with our newly established CMV-specific ELISpot assays determining IL-17A, IL-21, IL-22, granzyme B, and perforin and correlated the results with flow cytometric data and clinical parameters. In 77 kidney transplant recipients, the highest frequency was observed for CMV pp65-specific cells secreting IFN-γ, followed by cells secreting IL-21 (62.9 and 23.2 Δ spot forming cells/105 cells). We observed a positive correlation between the percentage of CMV-specific CD3+ CD4+ CD154+ cells and results of the CMV-specific IL-21 ELISpot (p = 0.002). Results of the CMV pp65-specific IL-21 ELISpot correlated negatively with kidney function (estimated glomerular filtration rate, p = 0.006) and were significantly higher in women (p = 0.005). IL-21, a cytokine involved in aging that is secreted by activated CD4+ T cells, may also impact on allograft function. Thus, the CMV-specific IL-21 ELISpot could become a new tool to assess if CMV seropositivity represents a hazard for the graft.

Sex-associated differences in cytomegalovirus prevention: Prophylactic strategy is associated with a strong kidney function impairment in female renal transplant patients

“…36 In transplantation, several complications are associated with sex, including acute rejection, graft loss and viral (re)activations. 11,13,37,38 However, the underlying reasons for these sex differences are not well understood; possible causes include the hormonal regulation of the immune system, the effects of pregnancy, and differences in the metabolism of drugs routinely employed in transplantation. 11 For example, there is tentative evidence of sexrelated differences in the pharmacokinetics of (val)ganciclovir.…”

“…11,12 Furthermore, it has been shown repeatedly that women and men have different anti-CMV immunological profiles, with an impact in the graft function and even the phenotype of the immune system as a whole. 13,14,18 Notably, in a recent publication, Lindemann et al have observed an association of high numbers of IL-21-secreting anti-CMV T cells with female sex and lower eGFR in a clinical transplantation context. 13 Our analyses may provide some evidence on the nature of the observed association of eGFR-1y with prevention strategies in female patients.…”

“…13,14,18 Notably, in a recent publication, Lindemann et al have observed an association of high numbers of IL-21-secreting anti-CMV T cells with female sex and lower eGFR in a clinical transplantation context. 13 Our analyses may provide some evidence on the nature of the observed association of eGFR-1y with prevention strategies in female patients. Although the impaired graft function in the female prophylactic strategy group can be partly explained through the higher incidence of BKV severe (re)activation and rejection, the results of the multi-parameter analysis showed an independent association of prevention strategy with graft function, regardless of these adverse events.…”

“…Interestingly, there is evidence of sex differences in both ganciclovir pharmacokinetics and the anti-CMV immune response. [11][12][13][14][15][16][17][18] Thus, female patients have been shown to have a faster ganciclovir clearance, and distinct anti-CMV immunological profiles e.g. higher number of secreting anti-CMV T cells.…”

“…higher number of secreting anti-CMV T cells. [11][12][13][14]18 In spite of this, there are to our knowledge still no studies on the influence of sex on the clinical outcomes of CMV prevention strategies. In this work, we provide evidence that prophylaxis might be associated with inferior transplantation outcomes in female patients.…”