Reactivations of Cytomegalovirus, Human Herpes Virus 6, and Epstein-Barr Virus Differ with Respect to Risk Factors and Clinical Outcome after Hematopoietic Stem Cell Transplantation

Jaskuła, Emilia; Dłubek, Dorota; Sędzimirska, Mariola; Duda, Dorota; Tarnowska, Agnieszka; Lange, Andrzej

doi:10.1016/j.transproceed.2010.07.027

Cited by 46 publications

(66 citation statements)

References 17 publications

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“…Besides CMV-induced pneumonitis, CMV reactivation is associated with increased risk of GvHD, while GvHD is also a risk factor for viral reactivations (62,(65)(66)(67)(68). CMV is the most frequent reactivation, but other viruses also hamper survival.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…Although latency is usually asymptomatic, HHV6 reactivates in Ͼ 50% of allogeneic HSCT recipients and can produce clinically significant manifestations, including encephalitis, delayed engraftment, and an increased rate of graft-versus-host disease, substantially increasing mortality. 10,11,14,[17][18][19] Thus, while HHV6 might be a suitable candidate virus to benefit from adoptive immunotherapy, such treatments can only be developed if there is evidence that T cells recognizing the virus exist in (or can be generated from) the peripheral blood of healthy seropositive individuals. If such cells exist, then it is important to know the antigens and HLA-restricted epitopes they recognize, so that the most effective T cells can be identified and prepared.…”

mentioning

confidence: 99%

“…13 Although not usually associated with disease in the immunocompetent, in immunocompromised individuals, such as solid-organ or HSCT recipients, reactivation of HHV6 can produce CNS disease (including encephalitis and meningitis), pneumonitis, transplant rejection, or delayed engraftment. [10][11][12][17][18][19]34,35 Reactivation has also been associated with seizures, 36 myocarditis, and pityriasis rosea. Beyond the immunocompromised host, HHV6 has been proposed to have a pathogenic role in multiple sclerosis, chronic fatigue syndrome, and drug-induced hypersensitivity syndrome, but these associations remain controversial.…”

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confidence: 99%

Immunotherapeutic strategies to prevent and treat human herpesvirus 6 reactivation after allogeneic stem cell transplantation

Gerdemann

Keukens

Keirnan

et al. 2013

Blood

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Key Points• We have characterized, for the first time, the cellular immune response to HHV6 and defined a hierarchy of immunodominance.• We have developed a GMPcompliant approach to generate polyfunctional T-cell lines that effectively kill HHV6-infected cells and are suitable for clinical use.Human herpesvirus (HHV) 6 causes substantial morbidity and mortality in the immunocompromised host and has no approved therapy. Adoptive transfer of virus specific T cells has proven safe and apparently effective as prophylaxis and treatment of other virus infections in immunocompromised patients; however, extension to subjects with HHV6 has been hindered by the paucity of information on targets of cellular immunity. We now characterize the cellular immune response from 20 donors against 5 major HHV6B antigens predicted to be immunogenic and define a hierarchy of immunodominance of antigens based on the frequency of responding donors and the magnitude of the T-cell response. We identified specific epitopes within these antigens and expanded the HHV6 reactive T cells using a GMP-compliant protocol. The expanded population comprised both CD4 ؉ and CD8 ؉ T cells that were able to produce multiple effector cytokines and kill both peptide-loaded and HHV6B wild-type virus-infected target cells. Thus, we conclude that adoptive T-cell immunotherapy for HHV6 is a practical objective and that the peptide and epitope tools we describe will allow such cells to be prepared, administered, and monitored in human subjects. (Blood. 2013;121(1):207-218) IntroductionAdoptive T-cell immunotherapy can successfully prevent and treat otherwise fatal infections in the immunocompromised host. At present, these benefits have been restricted to adenovirus, CMV and EBV. [1][2][3][4][5][6][7][8][9] However, it is increasingly apparent that a distinct herpesvirus, human herpesvirus 6 (HHV6) is also a significant cause of morbidity and mortality, particularly after hematopoietic stem cell transplantation (HSCT). To date, there have been no controlled studies on the use of antivirals as treatment for HHV6, but foscarnet, ganciclovir, and cidofovir have been used clinically, with variable results. [10][11][12][13][14] HHV6 is a member of the ␤-herpesvirus subfamily and exists as 2 species, HHV6A and HHV6B, which share 75%-95% nucleotide sequence identity. 15 Primary infection occurs in Ͼ 90% of individuals before the age of 2 years and is associated with clinical symptoms, including acute febrile illness and roseola infantum or exanthem subitum. 16 The virus subsequently persists in latent form, in an analogous way to other herpesviruses. Although latency is usually asymptomatic, HHV6 reactivates in Ͼ 50% of allogeneic HSCT recipients and can produce clinically significant manifestations, including encephalitis, delayed engraftment, and an increased rate of graft-versus-host disease, substantially increasing mortality. 10,11,14,[17][18][19] Thus, while HHV6 might be a suitable candidate virus to benefit from adoptive immunotherapy, such treatments can onl...

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“…Nonostante i molti progressi sia in ambito diagnostico che terapeutico nella gestione delle infezioni da virus erpetici nei soggetti sottoposti a trapianto di midollo, la morbilità e la mortalità risultano essere ancora piuttosto elevate, soprattutto se si considerano le problematiche legate alla riattivazione del CMV che è il virus più frequentemente rilevato in questo gruppo di pazienti (5). È stato osservato come la riattivazione da CMV, comporti la presenza in circolo del DNA virale anche per lunghi periodi in assenza di una terapia mirata, mentre di contro, la riattivazione del HHV6 è in genere correlata con la presenza di un solo risultato positivo (2).…”

Section: Discussione E Conclusioniunclassified

Evaluation of reactivation of HSV1, HHV6, CMV and EBV in a population of patients undergoing allogeneic bone marrow transplantation

Matinato¹,

Lunghi²,

Orlandi³

et al. 2011

Microbiol Med

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Reactivations of Cytomegalovirus, Human Herpes Virus 6, and Epstein-Barr Virus Differ with Respect to Risk Factors and Clinical Outcome after Hematopoietic Stem Cell Transplantation

Cited by 46 publications

References 17 publications

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

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

Immunotherapeutic strategies to prevent and treat human herpesvirus 6 reactivation after allogeneic stem cell transplantation

Evaluation of reactivation of HSV1, HHV6, CMV and EBV in a population of patients undergoing allogeneic bone marrow transplantation

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