Treatment of solid organ transplant recipients with autologous Epstein Barr virus-specific cytotoxic T lymphocytes (CTLs)

Department of Pediatrics, Baylor College of Medicine, Houston, Texas, United States
Blood (Impact Factor: 10.45). 12/2006; 108(9):2942-9. DOI: 10.1182/blood-2006-05-021782
Source: PubMed

ABSTRACT We have investigated the in vivo safety, efficacy, and persistence of autologous Epstein Barr virus (EBV)-specific cytotoxic T lymphocytes (CTLs) for the treatment of solid organ transplant (SOT) recipients at high risk for EBV-associated posttransplantation lymphoproliferative disease (PTLD). EBV-CTLs generated from 35 patients expanded with normal kinetics contained both CD8 and CD4 lymphocytes and produced significant specific killing of autologous EBV-transformed B lymphoblastoid cell lines (LCLs). Twelve SOT recipients at high risk for PTLD, or with active disease, received autologous CTL infusions without toxicity. Real-time polymerase chain reaction (PCR) monitoring of EBV-DNA showed a transient increase in plasma EBV-DNA suggestive of lysis of EBV-infected cells, although there was no consistent decrease in virus load in peripheral-blood mononuclear cells. Interferon-gamma enzyme-linked immunospot (ELISPOT) assay and tetramer analysis showed an increase in the frequency of EBV-responsive T cells, which returned to preinfusion levels after 2 to 6 months. None of the treated patients developed PTLD. One patient with liver PTLD showed a complete response, and one with ocular disease has had a partial response stable for over one year. These data are consistent with an expansion and persistence of adoptively transferred EBV-CTLs that is limited in the presence of continued immunosuppression but that nonetheless produces clinically useful antiviral activity.

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Available from: Stephan Schubert, Jan 12, 2014
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    • "Clinical management of PTLD typically involves reducing iatrogenic immunosuppression so that natural immunity against EBV and the neoplastic clone is restored [71, 82]. Complementary interventions include infusing donor lymphocytes, infusing EBV-specific cytotoxic T cells that are grown ex vivo by exposing HLA-matched T cells to EBV antigens [83–85] and infusing anti-CD20 monoclonal antibody (e.g., rituximab) [86–88]. If initial intervention is insufficient, more traditional cancer treatment with radiation and multidrug chemotherapy is used [72]. "
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    ABSTRACT: Viruses are among the most common causes of opportunistic infection after transplantation. The risk for viral infection is a function of the specific virus encountered, the intensity of immune suppression used to prevent graft rejection, and other host factors governing susceptibility. Although cytomegalovirus is the most common opportunistic pathogen seen in transplant recipients, numerous other viruses have also affected outcomes. In some cases, preventive measures such as pretransplant screening, prophylactic antiviral therapy, or posttransplant viral monitoring may limit the impact of these infections. Recent advances in laboratory monitoring and antiviral therapy have improved outcomes. Studies of viral latency, reactivation, and the cellular effects of viral infection will provide clues for future strategies in prevention and treatment of viral infections. This paper will summarize the major viral infections seen following transplant and discuss strategies for prevention and management of these potential pathogens.
    The Scientific World Journal 05/2012; 2012:820621. DOI:10.1100/2012/820621 · 1.73 Impact Factor
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    • "Humoral immunity to EBV could be boosted by vaccination with gp350 or administration of humanized or human monoclonal antibody against gp350. CD8+ T-cell immunity could be boosted by the intravenous infusion of autologous EBV-specific cytotoxic CD8+ T cells after expansion in vitro [201] or by the administration of agents such as interleukin-7, which expands the population of functional virus-specific CD8+ T cells in chronic viral infection [202]. With regard to antiviral drugs, treatment with aciclovir and related drugs, which inhibit herpesvirus DNA polymerase, is likely to have only a limited beneficial effect in chronic autoimmune diseases because these drugs act on EBV only when it is using its own DNA polymerase to replicate its DNA. "
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    ABSTRACT: CD8+ T-cell deficiency is a feature of many chronic autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, Sjögren's syndrome, systemic sclerosis, dermatomyositis, primary biliary cirrhosis, primary sclerosing cholangitis, ulcerative colitis, Crohn's disease, psoriasis, vitiligo, bullous pemphigoid, alopecia areata, idiopathic dilated cardiomyopathy, type 1 diabetes mellitus, Graves' disease, Hashimoto's thyroiditis, myasthenia gravis, IgA nephropathy, membranous nephropathy, and pernicious anaemia. It also occurs in healthy blood relatives of patients with autoimmune diseases, suggesting it is genetically determined. Here it is proposed that this CD8+ T-cell deficiency underlies the development of chronic autoimmune diseases by impairing CD8+ T-cell control of Epstein-Barr virus (EBV) infection, with the result that EBV-infected autoreactive B cells accumulate in the target organ where they produce pathogenic autoantibodies and provide costimulatory survival signals to autoreactive T cells which would otherwise die in the target organ by activation-induced apoptosis. Autoimmunity is postulated to evolve in the following steps: (1) CD8+ T-cell deficiency, (2) primary EBV infection, (3) decreased CD8+ T-cell control of EBV, (4) increased EBV load and increased anti-EBV antibodies, (5) EBV infection in the target organ, (6) clonal expansion of EBV-infected autoreactive B cells in the target organ, (7) infiltration of autoreactive T cells into the target organ, and (8) development of ectopic lymphoid follicles in the target organ. It is also proposed that deprivation of sunlight and vitamin D at higher latitudes facilitates the development of autoimmune diseases by aggravating the CD8+ T-cell deficiency and thereby further impairing control of EBV. The hypothesis makes predictions which can be tested, including the prevention and successful treatment of chronic autoimmune diseases by controlling EBV infection.
    01/2012; 2012(7691):189096. DOI:10.1155/2012/189096
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    • "As EBV-transformed LCLs can be readily generated from any donor, they are used as APCs for preparing clinical grade polyclonal anti-EBV CD4+ and CD8+ effector T lymphocytes, recognizing multiple latent and lytic viral antigens. In this way high numbers, that is, >107/m2 of EBV-reactive CTLs can be produced, which are sufficient for repeated cycles of their adoptive transfer [76, 77]. Such adoptively transferred CTL effectors survive up to eight years in the recipient and can expand up to 2–4 logs after infusion [68]. "
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    ABSTRACT: Adoptive transfer of effector antigen-specific immune cells is becoming a promising treatment option in allogeneic transplantation, infectious diseases, cancer, and autoimmune disorders. Within this context, the important role of CD 8 + cytotoxic T cells (CTLs) is objective of intensive studies directed to their in vivo and ex vivo induction, detection, selection, expansion, and therapeutic effectiveness. Additional questions that are being addressed by the scientific community are related to the establishment and maintenance of their longevity and memory state as well as to defining critical conditions underlying their transitions between discrete, but functionally different subtypes. In this article we review and comment latest approaches and techniques used for preparing large amounts of antigen-specific CTLs, suitable for clinical use.
    BioMed Research International 03/2010; 2010(5):705215. DOI:10.1155/2010/705215 · 2.71 Impact Factor
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