Chronic antibody-mediated rejection is the major cause of fading allograft function and loss after renal transplantation. Currently, pharmacological agents for the suppression of chronic antibody-mediated rejection are lacking. Non-selective proteasome inhibitors suppress antibody-mediated allograft rejection. However, extensive adverse side effects of these inhibitors severely limit their application. In contrast, immunoproteasome inhibition is effective in preclinical models of autoimmune diseases and was applied over weeks without obvious adverse side effects. ONX 0914, an immunoproteasome subunit LMP7 (β5i)-selective inhibitor, impeded the chronic rejection of kidneys transplanted from Fischer to allogeneic Lewis rats. ONX 0914 inhibited immunoproteasome induction both in immune organs and renal allografts. Selective immunoproteasome inhibition reduced the numbers of B and plasma cells, and suppressed donor-specific alloantibody production. The infiltration of T cells, B cells and macrophages as well as interferon-γ, interleukin-17, IgG and complement deposition were reduced in renal allografts of ONX 0914-treated recipients. Chronic nephropathy was ameliorated and renal allograft function preserved, enabling long-term survival of recipients. Thus, our studies define a critical role of the immunoproteasome in chronic kidney allograft rejection and suggest immunoproteasome inhibition as a promising therapeutic approach to suppress chronic antibody-mediated rejection.
ABSTRACT.Hawksbill sea turtles (Eretmochelys imbricata) inhabiting the eastern Pacific Ocean are one of the world's most threatened marine turtle management units. Despite the fact that knowledge about the status of sea turtles at foraging grounds is a key element for developing the effective conservation strategies, comprehensive studies of hawksbills at foraging habitats in the eastern Pacific remain lacking. For many years anecdotal information indicated Coiba Island National Park in Panama as a potentially important hawksbill foraging ground, which led to the initiation of monitoring surveys in September 2014. Ongoing mark-recapture surveys to assess population status, generate demographic data and identify key foraging sites have been conducted every six months in the park since that time. To date, a total of six monitoring campaigns consisting of four days each have been conducted, leading to the capture and tagging of 186 hawksbills, 51 of which were recaptured at least once. The size range of captured individuals was 30.0 to 75.5 cm and largely comprised of juveniles. Somatic growth rates of individual hawksbills were highly variable, ranging from -0.78 to 7.1 cm year -1 . To our knowledge, these are the first published growth rates for juvenile hawksbill turtles in the eastern Pacific Ocean. When these growth data are combined with information on hawksbill demography and distribution, our findings indicate Coiba Island National Park is one of the most important known foraging sites for hawksbill sea turtles in the eastern Pacific Ocean.
Therapeutic DNA vaccination is an attractive adjuvant option to conventional methods in the fight against cancer, like surgery radiotherapy and chemotherapy. Despite strong antitumor effects that were observed in small animals with different antigens, DNA-based vaccines remain weakly immunogenic in large animals and primates compared to protein-based vaccines. Here, we sought to enhance the immunogenicity of a therapeutic nontransforming cervical cancer DNA vaccine (HPV-16 E7SH) by introduction of a highly optimized CpG cassette into the plasmid backbone as well as by an optimized DNA delivery using an advanced electroporation (EP) technology. By integrating the means for agent administration and EP into a single device, this technology enables a simple, one-step procedure that facilitates reproducibility. We found that highly optimized CpG motifs alone triggers an enhanced IFN-c and granzyme B response in Elispot assays as well as stronger tumor regression. Furthermore, these effects could be dramatically enhanced when the CpG cassette containing plasmid was administered via the newly developed EP technology. These data suggest that an optimized application of CpG-enriched DNA vaccines may be an attractive strategy for the treatment of cancer. Collectively, these results provide a basis for the transfer of preclinical therapeutic DNA-based immunization studies into successful clinical cancer trials.Cervical cancer (cc) is the second largest cause of cancer deaths amongst women around the world. In a global perspective, 370,000 cc cases and 200,000 cc related deaths are diagnosed each year.1 Despite the successful prevention of cc by monitoring Pap smears in industrial countries, the impact of cc is still growing in economically disadvantaged population areas, due to inadequate access to screening. Therefore, 80% of all cc caused deaths occur in developing countries. But even under optimal treatment (mainly surgery but also chemotherapy and radiotherapy), 40% of cc patients die of the disease. Because a persistent infection with high-risk Human Papillomaviruses (HPVs) is necessary for the development of cc, therapeutic vaccination against HPV antigens could be an attractive adjuvant option. One HPV type (HPV-16) alone is responsible for about 50% of all cc. 3 The etiological principle for the transforming activity of the high-risk HPV types has been mainly assigned to the oncoprotein E7, 4 which interferes with the cell cycle mainly through interaction with the Retinoblastom protein (pRb). 5 The exclusive and consistent expression of the E7 in cc tumor cells and in all precancerous lesions renders this antigen to an ideal target for tumorspecific immunotherapy.Particularly, the usage of DNA vaccination has several potential advantages over vaccines based on recombinant proteins as they are relatively easy to design according to different needs, production cost are relatively low and predictable and DNA is stable. Moreover, there are no unwanted immune reactions against other components of the vaccine observed as...
Treatment of patients with cervical cancer by conventional methods (mainly surgery, but also radiotherapy and chemotherapy) results in a significant loss in quality of life. A therapeutic DNA vaccine directed to tumor-specific antigens of the human papilloma virus (HPV) could be an attractive treatment option. We have developed a nontransforming HPV-16 E7-based DNA vaccine containing all putative T cell epitopes . DNA vaccines, however, are less immunogenic than protein-or peptidebased vaccines in larger animals and humans. In this study, we have investigated an adjuvant gene support of the HPV-16 E7SH therapeutic cervical cancer vaccine. DNA encoded cytokines (IL-2, IL-12, GM-CSF, IFN-c) and the chemokine MIP1-a were coapplied either simultaneously or at different time points pre-or post-E7SH vaccination. In addition, sequence-optimized adjuvant genes were compared to wild type genes. Three combinations investigated lead to an enhanced IFN-c response of the induced T cells in mice. Interestingly, IFN-c secretion of splenocytes did not strictly correlate with tumor response in tumor regression experiments. Gene-encoded MIP-1a applied 5 days prior to E7SH-immunization combined with IFN-c or IL-12 (3 days) or IL-2 (5 days) postimmunization lead to a significantly enhanced tumor response that was clearly associated with granzyme B secretion and target cells lysis. Our results suggest that a conditioning application and combination with adjuvant genes may be a promising strategy to enhance synergistically immune responses by DNA immunization for the treatment of cervical cancer. ' UICCKey words: gynecology; virology; immunology; gene shuffling; cervical cancer; immunotherapy; tumor regression; DNA vaccine; genetic adjuvants Around 370,000 cases of cervical cancer are newly diagnosed each year worldwide and nearly 200,000 deaths are related to this disease.1 Moreover, in Third World countries cervical cancer is one of the major cause of cancer-associated deaths. Even under optimal circumstances of medical care 40% of patients with cervical cancer die of the disease.2 The human papilloma virus (HPV) high-risk type 16 (HPV-16) is responsible for about 50% of the cancers. 3 The transforming activity of the high-risk HPV types has been mainly assigned to the oncoprotein E7 4 that interferes with the cell cycle control by interaction with pRb.5 Because the E7 is exclusively and consistently expressed by the HPV-infected tumor cells and all precancerous lesions it represents an ideal target for a tumor-specific immune therapy.A new and very promising approach in vaccine development is the application of naked DNA. As compared to protein-or peptide-based vaccines a DNA vaccine has remarkable advantages making it of potential interest for Third World countries: (i) production costs are relatively low and predictable, (ii) DNA is stable and does not require refrigeration for storage, (iii) no unwanted immune reactions against other components of the vaccine are observed as it can be the case in vector-based vaccines, thus D...
Prostate cancer (PCa) is the most commonly diagnosed type of cancer in men in western industrialized countries. As a public health burden, the need for the invention of new cost-saving PCa immunotherapies is apparent. In this study, we present a DNA vaccine encoding for the prostate-specific antigen prostatic acid phosphatase (PAP) linked to the J-domain and the SV40 enhancer sequence. The PAP DNA vaccine induced a strong PAP-specific cellular immune response after electroporation (EP)-based delivery in C57BL/6 mice. Splenocytes from mice immunized with PAP recognized the naturally processed PAP epitopes, indicating that vaccination with the PAP-J gene broke its self-tolerance against PAP. Remarkably, DNA vaccination with PAP-J inhibited tumor growth in the Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) mouse model that closely resembled human PCa. Therefore, this study highlights a novel cancer immunotherapy approach with the potential to control PCa in clinical settings.
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