Early detection of cytomegalovirus-specific cytotoxic T lymphocytes against cytomegalovirus antigenemia in human leukocyte antigen haploidentical hematopoietic stem cell transplantation

Abstract

Human leukocyte antigen (HLA)-haploidentical stem cell transplantation (haplo-SCT) is associated with a high incidence of cytomegalovirus (CMV) infection, probably originating from the delayed reconstitution of CMV-specific T cell immunity. There have been few reports on the presence of CMV-specific cytotoxic T lymphocytes (CMV-CTLs) after haplo-SCT. We have studied CMV-specific immune reconstitution by measuring the absolute number of CMV-CTLs using a flow cytometry method with HLA-A2-restricted NLVPMVATV peptide dextramers. We examined the association between reconstitution patterns of CMV-CTLs and the duration of CMV antigenemia in 15 patients who underwent first allogeneic SCT from HLA-haploidentical-related donors with HLA-A2. In seven and eight patients, CMV antigenemia consecutively resolved for more than 4 weeks (the CMV antigenemia 'resolved' group) and intermittently persisted (the CMV antigenemia 'persistent' group) during a 100-day observation period, respectively. The group of the seven patients, in whom levels of CMV antigenemia were reduced to zero, had a significantly lower maximum level of CMV antigenemia than the CMV antigenemia persistent group. In contrast, the CMV antigenemia persistent group had a significantly higher maximum level of CMV-CTLs, but the levels took longer to peak. Despite no difference in general lymphocyte recovery between the two groups, the CMV antigenemia resolved group had significantly higher median CMV-CTL counts than the CMV antigenemia persistent group at 6 weeks after onset of CMV infection. Flow cytometry analysis of CMV-CTLs is a convenient method of monitoring reconstitution of CMV-specific lymphocyte immunity following haplo-SCT.

Treatment of CMV infection after allogeneic hematopoietic stem cell transplantation

“…Soon after transplant, most CMV-CTLs are of donor origin, while newly "educated" endogenous T cells from thymic output appear only later [86]. In haploidentical HSCT, early T-cell recovery is primarily based on peripheral expansion of naïve T cells and it appears delayed when compared with that of HSCT from HLA-identical siblings [87][88][89][90] Long-term immune reconstitution, however, mostly thymus-dependent, appears appropriate to maintain an adequate naïve T cell pool [91][92][93][94]. Adoptively transferred CMV-CTL can be detected long after HSCT and up to 2 years after infusion [95].…”

Peptide Presentation Is the Key to Immunotherapeutical Success

“…Best studied are the pp65-derived peptides NLVPMVATV and TPRVTGGGAM, restricted to HLA-A*02:01 and HLA-B*07:02, respectively. Those peptides are described to induce extremely strong T-cell responses [37][38][39][40][41][42]. Yet, these peptides have been computationally predicted [43] but not been isolated from HLA molecules.…”

Releasing the concept of HLA‐allele specific peptide anchors in viral infections: A non‐canonical naturally presented human cytomegalovirus‐derived HLA‐A*24:02 restricted peptide drives exquisite immunogenicity

“…Most peptides that have been studied are derived from the well‐characterized phosphoprotein (pp)65 or the immediately‐early (IE)1 protein, but not in all individuals responses against these two proteins are immunodominant . Best studied are the pp65 peptides NLVPMVATV and TPRVTGGGAM restricted to HLA‐A*02:01 and HLA‐B*07:02 , respectively, that usually induce strong T‐cell responses . However, the majority of these and other applied peptides are predicted by computational analysis .…”

“…36,37 Best studied are the pp65 peptides NLVPMVATV and TPRVTGGGAM restricted to HLA-A*02:01 and HLA-B*07:02, respectively, that usually induce strong T-cell responses. [38][39][40][41][42][43] However, the majority of these and other applied peptides are predicted by computational analysis. 36,44,45 It remains questionable if these peptides would ever be recruited through the patients peptide loading complex, selected by one HLA subtype and naturally presented by HCMV infected cells.…”