No abstract

Adenoviral vectors efficiently target normal liver cells

Improvements in radiochemotherapy have correspondingly improved the prognosis of patients with HodgkinЈs lymphoma. 1 However, patients resistant to the standard therapeutic approaches have a poor outcome. Moreover, both life expectancy and quality of life of patients cured of Hodgkin's lymphoma are significantly reduced by treatment-related mortality and morbidity. 2,3 These limitations of current treatment protocols illustrate the need for more effective and less toxic therapeutic approaches.In HodgkinЈs lymphomas, up to 49% of specimens have been shown to carry EBV DNA and to express EBV genes. 4,5 Adoptive immunotherapy with donor-derived, EBV-specific CTLs has significantly improved the clinical outcome of patients with EBV ϩ immunoblastic lymphoma after T cell-depleted allogeneic stemcell transplantation. 6,7 In an ongoing study, our group has successfully generated EBV-specific CTLs in patients with EBV ϩ Hodgkin's lymphoma. 8 After infusion, these CTLs home to the tumor sites, persist in the circulation for up to 9 months and produce transient clinical benefits. In this protocol, LCLs are used as EBV antigen-presenting cells. LCLs activate polyclonal CTL populations that are preferentially directed against the immunodominant EBNA3A, -3B and -3C EBV proteins. 9 These immunogenic proteins are not expressed in HRS cells. Instead, the EBV antigens on HRS cells are restricted to the expression of a subset of latent proteins, EBNA1, LMP1, LMP2A and BARF0. 10 -12 LCLs have limited efficacy at stimulating CTLs directed against these subdominant proteins.Targeting the EBV proteins expressed in EBV ϩ HRS cells is further complicated by their limited immunogenicity. EBNA1 is not processed for HLA class I presentation due to an internal glycine-alanine repeat region. 13 LMP1-specific CTL clones are rare in EBV ϩ donors, 14 and very few LMP1 epitopes have been identified. 15 Moreover, LMP1 displays heterogeneity between viral strains, 16 and CTLs raised against B cell (B95-8 prototype) derived LMP1 may not recognize LMP1 tumor variants. 17 BARF0 is a protein expressed from the BamHI A rightward transcript. Attempts to identify BARF0-specific CTLs have produced lymphocytes that recognized target cells expressing BARF0 at high levels but failed to recognize the antigen expressed at lower levels in LCLs. 18 LMP2A epitopes were shown to be conserved among Hodgkin's lymphoma biopsy samples displaying little heterogeneity between viral strains. 19,20 Also, most donors have a low but measurable frequency of circulating LMP2A-specific CTLs that can be activated and expanded in vitro. 14 Hence, LMP2A may be the protein of choice to be targeted by CTLs in patients with Hodgkin's lymphoma.To stimulate LMP2A-specific CTLs, LMP2A peptide-pulsed DCs have been successfully used, but this approach is limited to known MHC-restricted peptides. 21,22 A more promising strategy is the production of CTLs by genetically modified DCs that direct the CTL response to virally transduced genes. [23][24][25] This approach allows expression of t...

An adequate immune and antioxidant response is a key to the resolution of sepsis. Heme oxygenase-1 (HMOX1) is a stress protein with a polymorphic (GT)n repeat in its gene promoter that regulates its expression in response to oxidative injury, such as that present in sepsis. HMOX1 is the rate-limiting enzyme of heme degradation, and the heme breakdown products, CO, Fe, and bilirubin, are considered to be biologically active metabolites with direct or indirect antioxidant and anti-inflammatory properties. In this study, we investigated the inflammatory and antioxidant response and the relationship with the HMOX1 levels and HMOX1 polymorphism in Mexican septic pediatric patients. In a case-control pilot study, we enrolled 64 septic patients and 72 hospitalized control patients without a diagnosis of sepsis. DNA extracted from buffy coat was genotyped for HMOX1 (GT)n polymorphism by PCR and markers of antioxidant and inflammatory status were quantified in plasma by analysis of the oxygen radical absorbance capacity (ORAC), protein carbonyl (PC), interleukin (IL) 6, IL10, and HMOX1 levels. In septic children, oxidative and inflammatory markers were elevated, and HMOX1 levels were positively correlated with IL10 levels. Genotypic and allelic distribution of HMOX1 polymorphism showed no difference between groups. HMOX1 short-allele septic carriers (< 25 GT repeats) presented favorable ORAC, PC and IL10 levels. This study confirms that an active response against pediatric sepsis involves the expression of HMOX1 and IL10, suggesting that the high antioxidant status associated with HMOX1 short-allele septic carriers might provide a beneficial environment for sepsis resolution.

We conclude that adenoviral HSV TK gene therapy in combination with adjuvant radiotherapy does not generate increased toxic side effects in glioblastoma treatment. The prolonged survival time of animals receiving gene therapy and the reduced occurrence of neurological symptoms in irradiated mice constitute promising features of the combined treatment.

No abstract

No abstract

No abstract