Patients at high risk for CMV infection and disease show delayed CD8+ T-cell immune recovery after allogeneic stem cell transplantation

Abstract

Human cytomegalovirus (CMV) is a major cause of death after transplantation. The frequency of pp65-specific T cells was examined in 38 HLA-A2 þ stem cell recipients during the first year after transplantation. Patients were divided into four groups based on donor/recipientand dÀ/rÀ (n ¼ 5). Peripheral blood mononuclear cells were stimulated with the CMVpp65 peptide NLVPMVATV, and the specific T-cell frequency was assessed by interferon gamma (IFN-c) ELISPOT assay. Responding T cells were characterized by flow cytometry revealing a terminal differentiated effector phenotype. Surveillance of CMV infection was carried out by realtime polymerase chain reaction (n ¼ 26) or immunofluorescence (n ¼ 12). Infection was present in 7/9 dÀ/r þ high-risk patients, and CMV disease occurred exclusively in this group with delayed or absent virus-specific T-cell recovery. In contrast, 16/24 intermediate-risk patients showed CMV-specific T cells. Our data suggest that CMV infection and disease rates are elevated in high-risk patients with delayed CMV-specific T-cell immune reconstitution and lower in those with early recovery of T-cell immunity. We recommend preferring CMV seropositive donors for CMV seropositive recipients, as this should lead to durable CMV-specific T-cell responses soon after transplantation with consecutive protection from CMV disease.

Fludarabine-based reduced intensity conditioning transplants have a higher incidence of cytomegalovirus reactivation compared with myeloablative transplants

“…CD8 þ T lymphocytes and natural killer cells have an important function in maintaining cell-mediated immunity against CMV and suppressing viral replication, 21,22 and inadequate or defective recovery of CD8 þ T cells after transplant has been shown to contribute to a higher incidence of CMV reactivation and disease in transplant recipients. [23][24][25][26][27] Though previous studies have showed similar patterns of immune reconstitution after non-myeloablative transplantation compared with myeloablative transplants, 28 the use of ATG or alemtuzumab has been shown to delay CMV-specific immune reconstitution. 8,9,10,17 In this study, the OS among patients with CMV reactivation was not significantly lower than patients without CMV reactivation.…”

Cytomegalovirus in Hematopoietic Stem Cell Transplant Recipients

“…64 Although a CMV-seropositive recipient is at higher risk for transplant-related mortality than a seronegative recipient, 65,66 the impact of donor serostatus on nonrelapse mortality and survival when the recipient is seropositive remains controversial. [67][68][69][70][71][72][73][74][75][76][77][78] This combination, however, has been reported as a risk factor for delayed CMV-specific immune reconstitution, [79][80][81][82] repeated CMV reactivations, 80,83 late CMV recurrence, 84 and development of CMV disease. 46,80,85 Other risk factors for CMV infection after allogeneic HSCT include the use of high-dose corticosteroids, T-cell depletion, acute and chronic GVHD, and the use of mismatched or unrelated donors.…”

“…[67][68][69][70][71][72][73][74][75][76][77][78] This combination, however, has been reported as a risk factor for delayed CMV-specific immune reconstitution, 79-82 repeated CMV reactivations, 80,83 late CMV recurrence, 84 and development of CMV disease. 46,80,85 Other risk factors for CMV infection after allogeneic HSCT include the use of high-dose corticosteroids, T-cell depletion, acute and chronic GVHD, and the use of mismatched or unrelated donors. 43,46,[85][86][87][88][89] The use of sirolimus for GVHD prophylaxis seems to have a protective effect against CMV infection, possibly because of the inhibition of cellular signaling pathways that are co-opted by CMV during infection for synthesis of viral proteins.…”

Immunotherapy for opportunistic infections: Current status and future perspectives

“…[34][35][36] Lack of T cell immunity against CMV is associated with an increased risk of late onset/recurrent CMV antigenemia and CMV disease. 21,[23][24][25][26][27][28][29] In EBV and ADV infections, importance of T cell immunity against was also reported. [37][38][39] Therefore, if T cell immunity is found to be insufficient in patients with viral reactivation, adoptive immunotherapy to enhance T cell reconstitution could be an option to consider in order to treat or prevent the development of endorgan disease (Fig.…”

“…In terms of viral infections, it is well established that T cells play an important role. [21][22][23][24][25][26][27][28][29][30] In terms of mold infections, innate immunity alone was considered important historically in the control of mold infections. However, recent studies found that adaptive immunity, in particular Th1 cells, was relevant in the control of aspergillus infections.…”