Enumeration of cytomegalovirus-specific interferon  CD8+ and CD4+ T cells early after allogeneic stem cell transplantation may identify patients at risk of active cytomegalovirus infection

Solano, Carlos; Benet, Isabel; Clari, María Ángeles; Nieto, José; Cámara, Rafael de la; López, Javier; Hernández‐Boluda, Juan Carlos; Remigia, María José; Jarque, Isidro; Calabuig, María L; García‐Noblejas, Ana; Alberola, Juan; Tamarit, Alicia; Gimeno, Concepción; Navarro, David

doi:10.3324/haematol.12880

Cited by 52 publications

(62 citation statements)

References 11 publications

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“…We defined earlier levels of pp65 and IE-1-specific IFNg CD8 þ and IFNg CD4 þ T cells providing protection against the development of viremic CMV infection (41 IFNg CD8 þ cell/ml and 41.2 IFNg CD4 þ T cells/ml). 8 Comparable levels of pp65-specific IFNg or TNFa-producing CD8 þ T cells (range, 1-5 cells/ml) and IFNg/IL-2-producing CD4 þ T cells (1 cell/ml) conferring protection against CMV antigenemia or DNAemia have been reported earlier. [15][16][17][18] In this study, we enumerated peripheral levels of these T-cell subsets, both before and after the initiation of pre-emptive antiviral treatment, in a number of type A and type B episodes.…”

Section: Discussionmentioning

confidence: 99%

“…8 The number of CMV-specific functional cells at that time point might have been sufficient to control CMV replication in the presence of antivirals, but insufficient to protect from subsequent CMV reactivation in the absence of antiviral treatment.…”

Section: Discussionmentioning

confidence: 99%

“…8 In this study, we report on the frequency of the different antigenemia kinetic patterns observed during preemptive antiviral therapy in our setting and investigated whether a lack of expansion of CMV pp65 and IE-1-specific IFNg CD8 þ and CD4 þ T in response to virus replication was associated with rising levels of antigenemia and DNAemia during pre-emptive therapy. At present, there are no consensus criteria for the therapeutic management of such episodes of active CMV infection.…”

Section: Introductionmentioning

confidence: 99%

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Lack of prompt expansion of cytomegalovirus pp65 and IE-1-specific IFNγ CD8+ and CD4+ T cells is associated with rising levels of pp65 antigenemia and DNAemia during pre-emptive therapy in allogeneic hematopoietic stem cell transplant recipients

Tormo

Solano

Benet

et al. 2009

Bone Marrow Transplant

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Rising levels of cytomegalovirus (CMV) DNAemia and/or pp65 antigenemia have been observed during pre-emptive ganciclovir therapy in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-SCT). We assessed the incidence of this event in our series, and investigated whether its occurrence was associated with an impairment in the CMV-specific T-cell response. A total of 36 allo-SCT recipients experienced one or more episodes of active CMV infection (n ¼ 68) that were preemptively treated with val(ganciclovir). Rising levels of antigenemia and DNAemia, and an isolated increase in antigenemia, were observed in 39.7 and 2.9% of all episodes, respectively. Receipt of corticosteroids was associated with rising levels of antigenemia and DNAemia. Median increases of 12-and 6.8-fold of IFNc CD8 þ T and IFNc CD4 þ T cells, respectively, were observed at a median of 16.5 days after initiation of therapy in episodes with decreasing levels in antigenemia and DNAemia. In contrast, the numbers of both T-cell subsets at a median of 13.5 days after initiation of therapy did not differ significantly from those of pre-treatment samples in episodes with rising levels of antigenemia and DNAemia. Lack of prompt expansion of CMV pp65 and IE-1-specific IFNc CD8 þ and CD4 þ T cells is associated with rising levels in antigenemia and DNAemia during pre-emptive therapy.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Lack of prompt expansion of cytomegalovirus pp65 and IE-1-specific IFNγ CD8+ and CD4+ T cells is associated with rising levels of pp65 antigenemia and DNAemia during pre-emptive therapy in allogeneic hematopoietic stem cell transplant recipients

Tormo

Solano

Benet

et al. 2009

Bone Marrow Transplant

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“…ϩ T-helper cell population, we next measured IFN-␥ production in CD4 ϩ T cells after stimulation with a CMVpp65-overlapping peptide mix as described previously (3,18,34) (also data not shown). We observed expansion of the primary CMV-specific CD4…”

Section: Cd4mentioning

confidence: 99%

Cognate CD4 T-Cell Licensing of Dendritic Cells Heralds Anti-Cytomegalovirus CD8 T-Cell Immunity after Human Allogeneic Umbilical Cord Blood Transplantation

Flinsenberg

Spel

Jansen

et al. 2015

J Virol

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Reactivation of human cytomegalovirus (CMV) is hazardous to patients undergoing allogeneic cord blood transplantation (CBT), T-cell-mediated immunity and fight off viral reactivation in CBT patients. IMPORTANCE Survival rates after stem cell transplantation are lowered by 25% when patients undergo reactivation of cytomegalovirus (CMV) that they harbor. Immune protection against CMV is mostly executed by white blood cells called killer T cells. We here show that for generation of optimally protective killer T-cell responses that respond to CMV, the early elicitation of help from a second branch of CMV-directed T cells, called helper T cells, is required.C ytomegalovirus (CMV)-seropositive patients who are immunocompromised are at increased risk for developing potentially life-threatening CMV reactivation. Especially after allogeneic cord blood (CB) transplantation (CBT), the first weeks of immune reconstitution are hazardous for developing CMV reactivation, which is associated with decreased survival rates (1, 2). Antiviral treatment can reduce CMV viremia, but effective viral control requires induction of CMV-directed immunity by T lymphocytes. In particular, CD8 ϩ cytotoxic T lymphocytes (CTLs) fulfill a predominant role in protection against CMV disease (2-4). Therefore, strategies that increase early CMV-specific adaptive immune responses after transplantation are currently being explored, which could ultimately help to establish full clearance of, and long-term immunological memory against, CMV. In the human setting, cell-based therapy is being explored, geared toward dendritic cell (DC)-mediated activation of CTLs (5, 6). The elicitation of antigen-specific CTL immunity was in mouse models shown to require cognate CD4 ϩ T-cell licensing (7-10). Furthermore, priming of naive CD8 ϩ T cells requires both the CD4 ϩ T-helper cells and CD8 ϩ T cells to recognize antigen on the same antigen-presenting cell (5,11,12). Such CD4 ϩ T-cell help can involve CD40 ligand (CD40L) binding to CD40 on DCs (9,13,14). For humans, a requirement for CD4 CMV-specific CD4ϩ T-cell clones are present in the healthy population, suggesting a role for antigen-specific CD4 ϩ T cells in immunity against CMV, as 50 to 80% of adults experience CMV infection in their lifetime (6,15). Moreover, effective control of CMV infection was attained in patients when CMV-specific T cells, of which 77% were CD4 ϩ T cells, were infused (16). Further, human DCs loaded with both HLA class I and II/peptide complexes were more effective at generating antigen-specific CTL responses than were those loaded with solely major histocompatibility complex (MHC) class I/peptide complexes (17). In a different setting, not only the absence of antigen-specific CTLs but also the absence of specific CD4 ϩ T-helper cells resulted in higher

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“…1,2 Results of immune monitoring studies have generally shown that CMV-specific T-cell immune reconstitution is associated with the spontaneous resolution of CMV viraemia 3 and protection from recurrent or complicated CMV reactivation. [2][3][4] However, unlike solid-organ transplantation, the relationship between CMV-specific immune reconstitution and protection from a first episode of CMV reactivation is unclear in allo-HSCT with some 5,6 but not all 2,7 studies showing protection. As CMV-specific T-cell immune reconstitution is influenced by both homoeostatic proliferation and antigen-driven expansion, we hypothesise that the predictive value of CMV-specific immune monitoring can be improved if these contrasting driving forces can be separated.…”

mentioning

confidence: 99%

Post transplant CMV-specific T-cell immune reconstitution in the absence of global T-cell immunity is associated with a high risk of subsequent virus reactivation

Tey

Davenport²,

Hill

et al. 2014

Bone Marrow Transplant

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Enumeration of cytomegalovirus-specific interferon CD8+ and CD4+ T cells early after allogeneic stem cell transplantation may identify patients at risk of active cytomegalovirus infection

Cited by 52 publications

References 11 publications

Lack of prompt expansion of cytomegalovirus pp65 and IE-1-specific IFNγ CD8+ and CD4+ T cells is associated with rising levels of pp65 antigenemia and DNAemia during pre-emptive therapy in allogeneic hematopoietic stem cell transplant recipients

Lack of prompt expansion of cytomegalovirus pp65 and IE-1-specific IFNγ CD8+ and CD4+ T cells is associated with rising levels of pp65 antigenemia and DNAemia during pre-emptive therapy in allogeneic hematopoietic stem cell transplant recipients

Cognate CD4 T-Cell Licensing of Dendritic Cells Heralds Anti-Cytomegalovirus CD8 T-Cell Immunity after Human Allogeneic Umbilical Cord Blood Transplantation

Post transplant CMV-specific T-cell immune reconstitution in the absence of global T-cell immunity is associated with a high risk of subsequent virus reactivation

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