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  • The data in our manuscript confirm previous

    2019-09-10

    The data in our manuscript confirm previous data on the origin of CMV-specific T cAMPS-Rp, triethylammonium salt mass following TCD alloSCT in CMV seropositive patients transplanted with a CMV seronegative donor (R+D−) and demonstrate that also recipient CMV-specific memory T-cells are able to survive alemtuzumab based TCD and are the main actors supplying protective immunity to prevent CMV disease in these patients [5,17]. However, the demonstration of donor-derived CMV-specific T-cells, as indicator of the development of a donor-derived primary immune response after TCD alloSCT in R+D− patients, adds an important novel insight to the findings made in previous studies. It may provide a rationale for adoptive cell transfer (ACT) of CMV-specific T-cells from healthy third party donors or autologous CMV-specific T cells harvested prior to the transplant for bridging the period of severe T-cell deficiency prior to development of the primary T-cell response [[18], [19], [20]]. Although these strategies imply a risk of rapid rejection, a short-term protective effect may be sufficient to prevent CMV disease while allowing the development of donor-derived CMV-specific T-cells. In previous studies, analysis of CMV-specific T-cells after alloSCT consistently demonstrated mainly cells of patient origin [5,17]. A possible explanation for the better detection of donor-derived CMV-specific T-cells in our study may be the utilized methodology for detection and purification of virus-specific T-cells. Whereas previous studies were focused only on CMV-specific CD8+ T-cells, isolated using peptide/MHC multimers, in our study we analyzed both CMV-specific CD4+ and CD8+ T-cells, isolated based on expression of the activation marker CD137 upon stimulation with CMV-derived pp65 and IE1 protein spanning peptides, which allows the analysis of a broader repertoire of CMV-specific T-cells [[11], [12], [13]]. In conclusion, we demonstrated a significantly increased duration of CMV reactivation and a significantly increased incidence of CMV disease in CMV seropositive patients transplanted with a CMV seronegative donor (R+D−) compared to CMV seropositive patients transplanted with a CMV seropositive donor (R+D+) following TCD alloSCT, illustrating that despite alemtuzumab-based TCD, memory T-cells can be transferred from the graft to provide protective anti-viral immunity. Furthermore, we demonstrated that protective immunity against CMV was predominantly mediated by T-cells from recipient origin in patients transplanted with a CMV seronegative donor (R+D−) within the first year after TCD alloSCT, but that a primary donor-derived CMV-specific T-cell response was frequently observed within the first year following TCD alloSCT, even as early as 3 months following TCD alloSCT.
    Declarations of interest
    Introduction Cytomegalovirus (CMV) infection is considered the major cause of morbidity in solid organ transplant (SOT) recipients [1]. CMV is efficiently transmitted to recipients during transplantation and the risk of infection post transplantation increases in the absence of a pre-existing CMV specific immunity and with the amount of transplanted lymphoid tissue (being particularly high for lung and small intestine transplant) [2]. Additionally, long-term immunosuppression therapy, necessary to prevent graft rejection, poses an additional risk of CMV reactivation among recipients with previously acquired infection [2]. The pretransplant evaluation of donor and recipient serological status for CMV has been used as a marker of previous infection and as a risk factor for donor-derived transmission. It is assumed that patients with positive pretransplant CMV serology have also acquired a CMV-specific cell-mediated immunity and the ability to control infection. Thus, although individual susceptibility to CMV infection is modulated by several factors (type of transplant, type of immunosuppression, or coinfection, among others), stratification according to the serological status D/R is the pillar of risk stratification. Consensus guidelines recommend that immunoglobulin G (IgG) anti-CMV antibody tests before SOT in both donors and recipients should be performed [1], [3]. The D/R serological combination differentiates between three main risk categories: (a) patients at high risk, when seronegative patients receive an organ from a seropositive donor (D+/R–); (b) patients at intermediate risk, seropositive recipients (R+); and (c) Patients at low risk, seronegative patients that receive an organ from a seronegative donor (D–/R–) [2], [4], [5].