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Introduction
Influenza virus represents a significant source of morbidity and mortality in solid organ transplant (SOT) recipients [1,2] . Vaccination is the most effective intervention to prevent influenza infection and its complications in this population [3,4] . However, the immunogenicity of seasonal influenza trivalent inactivated vaccine (TIV) in SOT recipients is lower than those reported for healthy subjects or non-immunocompromised patients with chronic conditions [2] . It has been suggested that a number of clinical variables--type of transplant, time interval since transplantation or immunosuppressive regimen--influence the odds of achieving protective antibody titers following vaccination [5-8] . Nevertheless, there remains the need for identifying immune biomarkers that could predict vaccine efficacy in the transplant setting.
Influenza vaccine elicits both cellular and humoral adaptive responses, with the later being directly correlated with post-vaccination antibody levels against the hemagglutinin (HA) antigen [9] . Cytokines, in their key role as regulators of the immune system, are essential for the establishment and maintenance of immunological memory [10] . The differentiation of antigen-primed B-cells to long-lived plasma cells in the germinal centers (GCs) is supported by a subset of CD4+ T-cells termed T follicular helper (TFH) cells, which act as a major source of interleukin (IL)-21 [11] . It has been shown that IL-21 is instrumental for inducing B-cell differentiation and proliferation [12,13] . Other cytokines are also involved in modulating antibody response to antigenic challenge. For instance, IL-4 is produced by the specialized subpopulation of GC-resident TFH cells and seems to exert redundant functions with IL-21 [14] . Some TH1 (IL-12) and proinflammatory cytokines (IL-6) promote TFH cell differentiation and IL-21 production, respectively [15,16] , whereas IL-2 impairs long-lived antibody responses [17] .
The analysis of baseline levels of these cytokines, as well as of the distinct kinetic changes in such profiles following vaccination, might provide a useful insight into the mechanisms contributing to generate a protective antibody response against influenza antigens [18] . We have recently reported the results from a randomized clinical trial that compared high doses of intradermally administered influenza TIV with the standard intramuscular (IM) formulation in SOT recipients [19] . Serum samples from this study offered the opportunity to evaluate changes in cytokine levels in individuals undergoing different influenza vaccination strategies and its...