CMV-Seropositive Patients Allografted with a CMV-Seronegative Donor Show Delayed or Missing CMV-Specific T-Cell Immune Response and Are at Higher Risk for CMV-Viremia and CMV-Disease.

Abstract

The human cytomegalovirus (CMV) is an important cause for mortality and morbidity after allogeneic stem cell transplantation (allo SCT) especially in patients without a CMV-specific T cell response. CMV seropositive patients allografted with a CMV seronegative donor do not rise up specific CMV-T cell immunity posttransplant and are therefore at great risk for CMV viremia and disease. In a prospective manner, we analyzed blood samples of 38 HLA-A2+ patients with different haematological malignancies for CMV specific T cells.Methods: Frequency of T cells with reactivity against the pp65-peptide (NLVPMVATV) was assessed by ELISPOT assay in 38 patients at defined time points after allo SCT. In patients with high CMV specific T cell frequencies, the T cell phenotype was determined by flow cytometry. Surveillance of CMV viremia was carried out by routine PCR-technique or pp65 Ag staining.Results: In high-risk patients (donor-/recipient+) viremia was observed in 7/9 patients, 3/7 developed clinical severe CMV-disease. In this group, only one patient presented a weak CMV-specific T cell response in the first year after transplantation, although CMV-specific T cells were demonstrated in 5/9 patients before transplantation. In contrast, 64% (11/17) of the CMV seropositive patients having had a CMV seropositive donor showed CMV-specific T cells around day 30. Their T cell frequencies remained stable at a relative high level during the whole time of our investigation period and no CMV disease was observed. CMV seronegative patients allografted with either a CMV seronegative or seropositive donor also remained disease-free. CMV specific T cells were detectable in 2/7 patients of the d+/r− group. FACS analysis revealed that most of the responding cells were of the activated effector phenotype CD8+/CD45RA+/HLA-DR+ with a low expression of CCR7 and CD27.Conclusion: CMV-seropositive patients receiving graft from a seronegative donor are at a high risk and therefore prone for CMV-viremia and -disease. The development of CMV-specific T cells i.e. immune reconstitution in high risk patients remains delayed or is completely missing during the first year post transplant. In contrast, seropositive recipients grafted with a seropositive donor develop a durable T cell response within 3–4 weeks and show no viremia at all. New strategies as donor vaccination and adoptive T cell transfer are warranted to prevent CMV-disease in CMV seropositive patients for whom only a seronegative donor can be found.