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  • br Disclosures br Introduction The

    2019-08-12


    Disclosures
    Introduction The presence of anti-viral T-cell immunity is crucial for effective and sustained protection against Cytomegalovirus (CMV) following allogeneic stem cell transplantation (alloSCT) [1]. In vitro and in vivo T-cell depletion (TCD) via addition of the anti-CD52 monoclonal antibody alemtuzumab to the stem cell graft (alemtuzumab “in the bag”) is used to reduce the incidence of acute Graft versus Host Disease (GVHD) following alloSCT [[2], [3], [4]]. Alemtuzumab does not exclusively eliminate alloreactive T-cells, but affects presumably all T-cells, including donor-derived CMV-specific T-cells in the graft and residual CMV-specific T-cells of the recipient. Despite the profound TCD, protection against CMV is observed early after TCD alloSCT in CMV seropositive recipients (R+) transplanted with a CMV seropositive donor (R+D+) mediated by CMV-specific T-cells that can either originate from the donor via transfer with the graft or from the recipient as residual memory T-cells. In CMV seropositive recipients (R+) transplanted with a CMV seronegative donor (R+D−) donor-derived CMV-specific memory T-cells are not present in the graft and R+D− patients must therefore rely on residual CMV-specific T-cells of recipient origin and/or a donor-derived primary CMV-specific T-cell response to control CMV reactivations. If despite the in vivo T-cell depletion mediated by the free alemtuzumab transferred with the graft, recipient-derived T-cell immunity predominates in the protection against CMV, the incidence and severity of CMV reactivation and disease would not differ between R+D+ and R+D− patients. Because the function of the thymus is likely to be impaired after TCD alloSCT [5], it P7C3 is not known if or when to expect a donor-derived primary immune response after TCD alloSCT. Demonstrating donor derived CMV-specific T-cells after transplantation with a CMV seronegative donor (R+D−) would be indicative of a newly developed CMV-specific primary T-cell response. In this study we analyzed the effect of donor CMV serostatus on the incidence of CMV reactivation and CMV disease in R+D− patients versus R+D+ patients following TCD alloSCT using alemtuzumab in the bag (20 mg). Furthermore we analyzed the origin of circulating CMV-specific CD4+ and CD8+ T-cell populations in R+D− patients by chimerism analysis to detect donor derived CMV-specific T-cells indicative of a donor derived primary CMV-specific T-cell response.
    Objectives or hypothesis The objectives of this studies were to analyze the effect of donor CMV serostatus on the incidence of CMV reactivation and CMV disease following T-cell depleted allogeneic stem cell transplantation and to detect CMV-specific primary T-cell responses by demonstrating donor derived CMV-specific CD4+ and CD8+ T-cell populations in seropositive recipients transplanted with stem cells from a CMV seronegative allogeneic donor.
    Material and methods
    Results
    Discussion The observed effect of the donor serostatus on the course of CMV reactivations in CMV seropositive patients suggests that in vitro TCD by addition of 20 mg of alemtuzumab to the bag is not 100% effective in fully depleting grafts from T-cells. This importance of donor-derived CMV-specific memory T-cells for sustained control of CMV reactivation has been demonstrated in previous studies [5]. Our clinical data on CMV reactivation are in agreement with these studies and suggest that donor-derived CMV-specific memory T-cells are able to survive profound TCD and provide protective immunity. Indeed, chimerism analysis to assess the origin of CMV-specific T-cells circulating in R+D+ patients demonstrated that CMV-specific immunity in these patients can be mediated by CMV-specific T-cells of donor origin, patient origin or a mixture of these. A recent study [16] described loss of expression of the Alemtuzumab target antigen CD52 as a possible escape mechanism allowing survival of T-cells (including virus-specific donor T-cells) following alemtuzumab based TCD alloSCT.