Abstract
Cytomegalovirus (CMV) infection represents a vital complication after Hematopoietic Stem Cell Transplantation (HSCT). We screened the entire CMV proteome to visualize the humoral target epitope-focus profile in serum after HSCT. IgG profiling from four patient groups (donor and/or recipient +/− for CMV) was performed at 6, 12 and 24 months after HSCT using microarray slides containing 17174 of 15mer-peptides overlapping by 4 aa covering 214 proteins from CMV. Data were analyzed using maSigPro, PAM and the ‘exclusive recognition analysis (ERA)’ to identify unique CMV epitope responses for each patient group. The ‘exclusive recognition analysis’ of serum epitope patterns segregated best 12 months after HSCT for the D+/R+ group (versus D−/R−). Epitopes were derived from UL123 (IE1), UL99 (pp28), UL32 (pp150), this changed at 24 months to 2 strongly recognized peptides provided from UL123 and UL100. Strongly (IgG) recognized CMV targets elicited also robust cytokine production in T-cells from patients after HSCT defined by intracellular cytokine staining (IL-2, TNF, IFN and IL-17). High-content peptide microarrays allow epitope profiling of entire viral proteomes; this approach can be useful to map relevant targets for diagnostics and therapy in patients with well defined clinical endpoints. Peptide microarray analysis visualizes the breadth of B-cell immune reconstitution after HSCT and provides a useful tool to gauge immune reconstitution.
Highlights
Patients after hematopoietic stem cell transplantation (HSCT) remain at increased risk to cytomegalovirus (CMV) disease despite advances in clinical management [1]; a similar situation is true for patients after solid organ transplantation [2]
Identification of biologically relevant CMV epitopes may aid to develop improved strategies to boost anti-CMV directed immune responses in CMV-discordant transplant situations. ii) Post-Hematopoietic Stem Cell Transplantation (HSCT) vaccination CMV-strategies lack epitope recognition patterns which would help to differentiate between already existing antiCMV humoral responses and new CMV epitope recognition patterns associated with CMV infection(s) or CMV vaccines. iii) CMV2 epitope mapping may help to decipher the quality of immune responses in CMV-discordant transplant recipients; iv) Mapping anti-CMV humoral reactivity will aid to reflect the breadth of B-cell immune-reconstitution in transplant recipients and possibly perturbations in the B-cell compartment associated with graft-versus-host-disease (GVHD) [17]
In the D2R2 group, one patient developed a primary CMV infection at 8 months after HSCT and was removed from the analysis No patient developed CMV disease and no pre-emptive antiviral therapy was provided since the viral load was below the intervention limit
Summary
Patients after hematopoietic stem cell transplantation (HSCT) remain at increased risk to cytomegalovirus (CMV) disease despite advances in clinical management [1]; a similar situation is true for patients after solid organ transplantation [2]. The importance of specific antibodies (Abs) as part of the immune protection against CMV has been controversial in the stem cell transplant setting [4,5,6,7], yet anti-CMV directed serum antibodies may be clinically relevant in the post-transplant setting in the absence of antibody producing B-cells due to the half-life of serum IgG of 40–60 days. Identification of biologically relevant CMV epitopes may aid to develop improved strategies to boost anti-CMV directed immune responses in CMV-discordant transplant situations. Iii) CMV2 epitope mapping may help to decipher the quality of immune responses in CMV-discordant transplant recipients; iv) Mapping anti-CMV humoral reactivity will aid to reflect the breadth of B-cell immune-reconstitution in transplant recipients and possibly perturbations in the B-cell compartment associated with graft-versus-host-disease (GVHD) [17] Identification of biologically relevant CMV epitopes may aid to develop improved strategies to boost anti-CMV directed immune responses in CMV-discordant transplant situations. ii) Post-HSCT vaccination CMV-strategies lack epitope recognition patterns which would help to differentiate between already existing antiCMV humoral responses and new CMV epitope recognition patterns associated with CMV infection(s) or CMV vaccines. iii) CMV2 epitope mapping may help to decipher the quality of immune responses in CMV-discordant transplant recipients; iv) Mapping anti-CMV humoral reactivity will aid to reflect the breadth of B-cell immune-reconstitution in transplant recipients and possibly perturbations in the B-cell compartment associated with graft-versus-host-disease (GVHD) [17]
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