Successful treatment of posttransplantation lymphoproliferative disorder (PTLD) following renal allografting is associated with sustained CD8+ T-cell restoration

Porcu, Pierluigi; Eisenbeis, Charles F.; Pelletier, Ronald P.; Davies, Elizabeth; Baiocchi, Robert A.; Roychowdhury, Sameek; Vourganti, Srinivas; Nuovo, Gerard J.; Marsh, W.; Ferketich, Amy K.; Henry, Mitchell L.; Ferguson, Ronald M.; Caligiuri, Michael A.

doi:10.1182/blood-2002-01-0210

Cited by 55 publications

(50 citation statements)

References 43 publications

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“…Conversely, several studies have shown the central role of CD8+ CTL in cell-mediated containment of EBV infection (4,5,21) and data in the mouse model documented that transfer of CD8+ T cells raised against human LCL can prevent the formation of tumors after infusion of LCL from the same individual (22). Moreover, recovery from PTLD after antiviral therapy and reduction of immunosuppression in renal transplant recipients were shown to be associated with a sustained recovery of circulating EBVspecific CD8+ T cells (23), and, in our clinical experience, SOT patients with poor response to EBV-specific CTL infusions had a majority of CD4+ CTL in the infused line [(12) and Comoli P, personal observation].…”

Section: Introductionmentioning

confidence: 99%

Successful In Vitro Priming of EBV-Specific CD8+ T Cells Endowed with Strong Cytotoxic Function from T Cells of EBV-Seronegative Children

Comoli

Ginevri

Maccario

et al. 2006

American Journal of Transplantation

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Epstein-Barr virus (EBV)-seronegative transplant recipients are at high risk of developing EBV-associated post-transplant lymphoproliferative disorder (PTLD), and would maximally benefit from an EBV-directed T-cell therapy for prevention or treatment of PTLD. So far, efforts to activate CD8+ EBV-specific cytotoxic T lymphocytes (CTL) endowed with high specific cytotoxicity from EBV-seronegative children have failed. We compared the CD8+ CTL priming efficiency of three different modified activation protocols, based on lymphoblastoid cell lines (LCL) stimulation potentially enhanced by either LCL presentation through dendritic cells, or selection of IFN-c + cultured cells, or culture in the presence of rhIL-12 and rhIL-7, according to the standard protocol for reactivation of EBVspecific CTL. We found that only specific LCL stimulation in the presence of rhIL-12 and rhIL-7 was able to reproducibly expand EBV-specific CD8+ CTL endowed with strong cytotoxic activity from truly EBVseronegative children. The lines thus activated, which included specificities toward EBV latent and lytic proteins, showed high percentage CD8+ T cells, with <10% naïve CD8+/CCR7+/CD45RA+ cells. Overall, the total number of CD8+ central memory cells, and of CCR7 T-cell effectors was comparable to that observed in healthy EBV-seropositive controls. In conclusion, it is feasible to activate EBV-specific CD8+ CTL with suitable characteristics for in vivo employment from EBVseronegative children.

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Section: Introductionmentioning

confidence: 99%

Successful In Vitro Priming of EBV-Specific CD8+ T Cells Endowed with Strong Cytotoxic Function from T Cells of EBV-Seronegative Children

Comoli

Ginevri

Maccario

et al. 2006

American Journal of Transplantation

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“…[38][39][40][41][42] Despite these caveats, the hu-PBL-SCID model remains one of the few mouse models with which to assess spontaneous human tumor development and the resultant antitumor immune response. More recently, evidence has accumulated that the control of EBV-lymphoproliferative disorder is mediated by CD8 cytotoxic T lymphocytes in patients with PTLD 43,44 and in hu-PBL-SCID mice. 26,45 With the identification of EBV latent and lytic antigens, it has been demonstrated that specific CD8 T-cell responses to these EBV antigens can be detected in seropositive patients 34,46,47 and in hu-PBL-SCID mice.…”

Section: Discussionmentioning

confidence: 99%

Anti–human CTLA-4 monoclonal antibody promotes T-cell expansion and immunity in a hu-PBL-SCID model: a new method for preclinical screening of costimulatory monoclonal antibodies

May

Roychowdhury

Bhatt

et al. 2005

Blood

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When adopting basic principles learned in mice to clinical application in humans, it is often difficult to distinguish whether a "translation" fails because of an invalid target in the human disease or because the therapeutic agents are not optimal for the human target. It is, therefore, desirable to develop preclinical models to optimize therapies for human targets using in vivo settings. Although anti-mouse CTLA-4 antibodies are known to enhance immune responses in vivo, their effect on T-cell activation in vitro ranges from enhancement to inhibition. Here we use the hu-PBL-SCID mouse model of EpsteinBarr virus (EBV)-associated lymphoma development to screen a panel of antihuman CTLA-4 monoclonal antibodies (mAbs) for their effect on human lymphocytes in an in vivo "humanized" environment. We report significant heterogeneity of anti-human CTLA-4 mAbs in enhancing the expansion of human T cells in mice, and this heterogeneity cannot be attributed to immunoglobulin isotypes or affinity for CTLA-4. These data validate the development of additional screening tools, such as the one described, to further characterize functional activity of antihuman antibodies before proceeding with clinical translation to human studies.

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“…Because EBV-associated malignancies typically develop in the setting of latent, rather than lytic, infection, the role of antiviral treatments for these late complications of EBV infection is unclear. Though multiple case reports and small studies have suggested a possible role for antiviral treatment of post-transplant lymphoproliferative disorder (PTLD) and hemophagocytic syndrome [8][9][10][11][12], the lack of larger trials has hindered a better understanding of the impact of antiviral therapy in disease treatment. Further data elaborating the effect of antiviral prophylaxis and treatment for immunosuppressed patients at risk for complications of EBV infection could significantly reduce the burden of EBV-associated disease and are sorely needed.…”

Section: Background and Significancementioning

confidence: 99%

Valganciclovir for the Suppression of Epstein-Barr Virus Replication

Yager

Magaret

Kuntz³

et al. 2017

The Journal of Infectious Diseases

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Valganciclovir for the Suppression of Epstein-Barr Virus Replication Jessica Eve YagerChair of the Supervisory Committee:Professor Anna Wald Department of EpidemiologyEpstein-Barr virus (EBV), a common herpesvirus, is the main causative agent of infectious mononucleosis.Following primary infection, EBV persists in host cells and can cause B cell transformation, leading to the development of EBV-associated malignancies. The role for antiviral therapy in treating and preventing EBV-associated disease remains unclear. Using oral swabs collected from a randomized, double-blind, placebo-controlled crossover study that our group had previously conducted, we sought to determine the impact of valganciclovir on both the rate and quantity of oral EBV shedding. Twenty-six men were randomly assigned to receive either oral valganciclovir, 900mg daily, or oral placebo once daily for eight weeks. Participants then received no study drug for a two week "washout period," followed by the alternate treatment (valganciclovir or placebo) for a second eight-week period. Valganciclovir reduced the proportion of days on which EBV was detected by 72% (relative risk 0.28, 95% confidence interval 0.08-0.55; p=0.003), and reduced the quantity of virus detected by 0.77 logs (95% confidence interval 0.62-0.91 logs; p<0.001). These results were consistent regardless of participants' HIV status and use of antiretroviral therapy. These findings could have significant clinical applications in both the treatment and prevention of EBV-associated disease. 4Background and Significance:

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Successful treatment of posttransplantation lymphoproliferative disorder (PTLD) following renal allografting is associated with sustained CD8+ T-cell restoration

Abstract: Posttransplantation lymphoproliferative disorder (PTLD) is a life-threatening Ep

Cited by 55 publications

References 43 publications

Successful In Vitro Priming of EBV-Specific CD8+ T Cells Endowed with Strong Cytotoxic Function from T Cells of EBV-Seronegative Children

Successful In Vitro Priming of EBV-Specific CD8+ T Cells Endowed with Strong Cytotoxic Function from T Cells of EBV-Seronegative Children

Anti–human CTLA-4 monoclonal antibody promotes T-cell expansion and immunity in a hu-PBL-SCID model: a new method for preclinical screening of costimulatory monoclonal antibodies

Valganciclovir for the Suppression of Epstein-Barr Virus Replication

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