Publisher Summary Although interleukin-12 (IL-12) has been discovered only relatively recently, a remarkable level of knowledge has been obtained for this cytokine, and many possible therapeutic applications are being tested or have been proposed. It performs the dual function as a proinflammatory cytokine and as an immunomodulatory molecule. This chapter describes the structure, genetics, induction, and biological functions of IL-12. Being produced at the early times of inflammation in response to infection or other stimuli, IL-12 contributes via the production of IFN-γ and other cytokines to the inflammatory process itself and particularly to the activation of macrophages. IL-12 represents a bridge between innate resistance and adaptive immunity, with a central role in the regulation of the response to infection and tumor cells, as well as in autoimmunity and allergy. Because of these activities, its clinical use has been proposed in infections, both as an immunopotentiating agent or as an adjuvant in vaccination, against tumors, and for the prevention of severe allergic syndromes. The study of IL-12 has revealed much about the physiology of innate and adaptive immunity; however, harnessing its potent biological activities for efficient therapeutical applications is a challenge.

Interleukin-12: A Cytokine at the Interface of Inflammation and Immunity

Surviving a given infection requires the generation of a controlled immune response. Failure to establish or restore homeostatic conditions during or following the onset of an infection can lead to tissue damage. Investigation of the immunoregulatory network that arises in response to the infectious process or that is induced by the pathogen itself should provide insight into therapeutic approaches for the control of infection and any subsequent immunopathology. In this Review, I discuss current hypotheses and points of polemic associated with the origin, mode of action and antigen specificity of the various populations of regulatory T cells that arise during infection.

Regulatory T cells and infection: a dangerous necessity

Plasmid pRSVL persisted and expressed luciferase for at least 19 months in mouse skeletal muscle after intramuscular injection. Other injected plasmids also stably expressed long-term suggesting that any plasmid DNA could stably persist and express in muscle. Plasmid DNA was demonstrated by quantitative PCR in some of the muscle DNA samples for at least 19 months after injection. The methylation pattern of the plasmid DNA remained in its bacterial form indicating that the foreign DNA did not replicate in the muscle cells. The electroporation of total cellular DNA from injected muscles into bacteria indicated that the plasmid DNA was extrachromosomal. Chromosomal integration of plasmid DNA was searched for by electroporating the injected muscle DNA into bacteria after restriction enzyme digestion and ligation. No plasmids containing plasmid/chromosome junctions were observed in over 1800 colonies examined. Lack of integration increases the theoretical safety of this gene transfer technique. Long-term stability of plasmid DNA in muscle indicates that muscle is an attractive target tissue for the introduction of extrachromosomal plasmid or viral DNA for the purpose of gene therapy.

Very long term persistence of plasmid dna and foreign gene expression in mouse muscle

Leishmaniae are obligatory intracellular protozoa in mononuclear phagocytes. They cause a spectrum of diseases, ranging in severity from spontaneously healing skin lesions to fatal visceral disease. Worldwide, there are 2 million new cases each year and 1/10 of the world's population is at risk of infection. To date, there are no vaccines against leishmaniasis and control measures rely on chemotherapy to alleviate disease and on vector control to reduce transmission. However, a major vaccine development program aimed initially at cutaneous leishmaniasis is under way. Studies in animal models and humans are evaluating the potential of genetically modified live attenuated vaccines, as well as a variety of recombinant antigens or the DNA encoding them. The program also focuses on new adjuvants, including cytokines, and delivery systems to target the T helper type 1 immune responses required for the elimination of this intracellular organism. The availability, in the near future, of the DNA sequences of the human and Leishmania genomes will extend the vaccine program. New vaccine candidates such as parasite virulence factors will be identified. Host susceptibility genes will be mapped to allow the vaccine to be targeted to the population most in need of protection.

/pdf/leishmaniasis-current-status-of-vaccine-development-3rp6570msi.pdf

Leishmaniasis: Current Status of Vaccine Development

Genetic vaccination depends at least in part on the adjuvant properties of plasmids, properties that have been ascribed to unmethylated CpG dinucleotides in bacterial DNA. Because dendritic cells (DC) participate in the T cell priming that occurs during genetic vaccination, we reasoned that CpG-containing DNA might activate DC. Thus, we assessed the effects of CpG oligodeoxynucleotides (CpG ODN) on Langerhans cell (LC)-like murine fetal skin-derived DC (FSDDC) in vitro and on LC in vivo. Treatment with CpG ODN as well as LPS induced FSDDC maturation, manifested by decreased E-cadherin-mediated adhesion, up-regulation of MHC class II and costimulator molecule expression, and acquisition of enhanced accessory cell activity. In contrast to LPS, CpG ODN stimulated FSDDC to produce large amounts of IL-12 but only small amounts of IL-6 and TNF-α. Injection of CpG ODN into murine dermis also led to enhanced expression of MHC class II and CD86 Ag by LC in overlying epidermis and intracytoplasmic IL-12 accumulation in a subpopulation of activated LC. We conclude that immunostimulatory CpG ODN stimulate DC in vitro and in vivo. Bacterial DNA-based vaccines may preferentially elicit Th1-predominant immune responses because they activate and mobilize DC and induce them to produce large amounts of IL-12.

Activation of Cutaneous Dendritic Cells by CpG-Containing Oligodeoxynucleotides: A Role for Dendritic Cells in the Augmentation of Th1 Responses by Immunostimulatory DNA

http://www.cell.com/article/S2211124722000894/pdf

A Fc-enhanced NTD-binding non-neutralizing antibody delays virus spread and synergizes with a nAb to protect mice from lethal SARS-CoV-2 infection

To determine whether DNA immunization could elicit protective immunity to Leishmania major in susceptible BALB/c mice, cDNA for the cloned Leishmania antigen LACK was inserted into a euykaryotic expression vector downstream to the cytomegalovirus promoter. Susceptible BALB/c mice were then vaccinated subcutaneously with LACK DNA and challenged with L. major promastigotes. We compared the protective efficacy of LACK DNA vaccination with that of recombinant LACK protein in the presence or absence of recombinant interleukin (rIL)-12 protein. Protection induced by LACK DNA was similar to that achieved by LACK protein and rIL-12, but superior to LACK protein without rIL-12. The immunity conferred by LACK DNA was durable insofar as mice challenged 5 wk after vaccination were still protected, and the infection was controlled for at least 20 wk after challenge. In addition, the ability of mice to control infection at sites distant to the site of vaccination suggests that systemic protection was achieved by LACK DNA vaccination. The control of disease progression and parasitic burden in mice vaccinated with LACK DNA was associated with enhancement of antigen-specific interferon-γ (IFN-γ) production. Moreover, both the enhancement of IFN-γ production and the protective immune response induced by LACK DNA vaccination was IL-12 dependent. Unexpectedly, depletion of CD8+ T cells at the time of vaccination or infection also abolished the protective response induced by LACK DNA vaccination, suggesting a role for CD8+ T cells in DNA vaccine induced protection to L. major. Thus, DNA immunization may offer an attractive alternative vaccination strategy against intracellular pathogens, as compared with conventional vaccination with antigens combined with adjuvants.

https://rupress.org/jem/article-pdf/186/7/1137/1114395/97-1096.pdf

Vaccination with dna encoding the immunodominant lack parasite antigen confers protective immunity to mice infected with leishmania major

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A Fc-enhanced NTD-binding non-neutralizing antibody delays virus spread and synergizes with a nAb to protect mice from lethal SARS-CoV-2 infection

Vaccination with dna encoding the immunodominant lack parasite antigen confers protective immunity to mice infected with leishmania major