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Regulatory (FOXP3 + ) T cells (T regs ) comprise a subpopulation of CD4I ntense research has shown that regulatory T cells (T regs ) play a fundamental role in providing peripheral tolerance against auto and foreign antigens, whereas impairment of T reg function seems to be associated with different autoimmune diseases like systemic lupus erythematodes,(1) type 1 diabetes, (2) rheumatoid arthritis (3,4) and multiple sclerosis.(5) Particularly stimulating for oncologic research was that increased frequencies of T regs with suppressive activity were found in malignant tumors and in the blood of cancer patients.(6-9) Blocking of T reg function in murine tumor models resulted in strong cellular antitumor immunity and even complete tumor destruction, (10)(11)(12)(13)(14)(15) indicating a crucial role for T regs in tumor immunity.T regs represent a subpopulation of CD4 + T cells and account for approximately 10-15% of all CD4 + T cells. The most specific marker for T regs currently available is the transcription regulator FOXP3. + T regs an evolutionary conserved region within the foxp3 locus upstream of exon-1 displays complete DNA demethylation, known as the T reg -specific demethylated region (TSDR), whereas T cells with transient FOXP3 expression and thus non-permanent suppressive function, such as transforming growth factor-β induced T regs and recently activated conventional human T cells show a fully methylated TSDR. (18)(19)(20)(21) Little is known about factors that mediate homing of T regs in different organs or tumor tissue, but experimental data suggest that an interaction between organ-specific factors and T regs is required for their expansion and homing. (22)(23)(24) A highly selective switch for specific inactivation of murine T regs was identified by Shimon Sakaguchi and his colleagues.(25) He developed an agonistic antibody that binds to murine glucocorticoidinduced tumor necrosis factor receptor family-related protein (GITR). Activation of GITR in concert with antigen-specific stimulation of T regs abrogates their suppressive activity. Applying the anti-GITR antibody to BALB/c mice 8 days after inoculation of 2 × 10 5 Meth-A fibrosarcoma cells induced a strong antitumor immune response followed by complete tumor eradication in all treated animals.(25) One concern regarding possible side-effects of GITR activation was the unintended induction of autoimmune reactions, but organ function in mice remained unaltered during therapy and no autoimmune reactions were detected. (25) Despite their viral origin and well-defined target genes, clinical trials for immune therapy of cervical intraepithelial neoplasia (CIN) lesions and cervical cancer have been mostly ineffective. (26)(27)(28)(29)(30)(31)(32)(33)(34)(35) Potentially acting as a tumor-protective shield, T reg may constitute an important reason for these failures, as their accumulation at the tumor site might render intended immunostimulation ineffective.In order to elucidate the prevalence of FOXP3 + T cells in CIN lesions, cervical cancer, colon can...

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Recombinant human adenoviruses (hAd) have become widely used as tools to achieve efficient gene transfer. However, successful application of hAd-derived vectors in clinical trials is limited due to immunological and potential safety problems inherent in their human origin. In this study, we describe a recombinant ovine adenovirus (OAV) as an alternative vector for gene transfer in vivo. In contrast to an hAd vector, the OAV vector was not neutralized by human sera. An OAV vector which contained the cDNA of the human α1-antitrypsin (hAAT) gene linked to the Rous sarcoma virus promoter was generated and administered systemically to mice. The level and duration of hAAT gene expression was similar to that achieved with an hAd counterpart in both immunocompetent and immunodeficient mice. However, the tissue distribution of the OAV vector differed from that observed for hAd vectors in that the liver was not the dominant target. Significantly, we demonstrated efficient gene transfer with the OAV vector into mice immunized with hAd vectors and vice versa. We also confirm that the immune response to a transgene product can prevent its functional expression following sequential application of a vector. Our results suggest a possible solution to endemic humoral immunity against currently used hAd vectors and should therefore have an impact on the design of improved gene therapy protocols utilizing adenovirus vectors.

Vaccines play a critical role in combating the COVID-19 pandemic. Future control of the pandemic requires improved vaccines with high efficacy against newly emerging SARS-CoV-2 variants and the ability to reduce virus transmission. Here we compare immune responses and preclinical efficacy of the mRNA vaccine BNT162b2, the adenovirus-vectored spike vaccine Ad2-spike and the live-attenuated virus vaccine candidate sCPD9 in Syrian hamsters, using both homogeneous and heterologous vaccination regimens. Comparative vaccine efficacy was assessed by employing readouts from virus titrations to single-cell RNA sequencing. Our results show that sCPD9 vaccination elicited the most robust immunity, including rapid viral clearance, reduced tissue damage, fast differentiation of pre-plasmablasts, strong systemic and mucosal humoral responses, and rapid recall of memory T cells from lung tissue after challenge with heterologous SARS-CoV-2. Overall, our results demonstrate that live-attenuated vaccines offer advantages over currently available COVID-19 vaccines.

The non-physiological constitutive overexpression of an LDL receptor gene induces an imbalance between the speed of LDL uptake and metabolism which leads to pathological accumulation of lipids and cholesterol in hepatocytes. To protect cells from negative effects of LDLr overexpression, future vector design should consider the use of physiologically controlled expression elements.