Stimulating Immune Responses

 STIMULATING IMMUNE RESPONSES


Some differences in chemical structure between genetic information of pathogenic microorganisms and mammals form a recognition signal for immune activation. Specific receptors exist that recognize pathogenic DNA or RNA that subsequently activate a series of genetic programs. This broad pro-inflam-matory activation can have applications in antiviral, immune activating, vaccine adjuvant, and antitumor applications.

 

Prokaryotic DNA contains many CpG dinucleo-tide sequences, while mammalian DNA has very few, which are usually methylated. Synthetic ONs contain-ing CpG motifs can mimic prokaryotic DNA, and induce immune responses (Krieg, 2006). The CpG sequence is a strong recognition signal for mamma-lian cells through interaction with Toll-like receptor 9 in the endosomes leading to B-cell proliferation and activation of cells of myeloid lineage (Rothenfusser et al., 2003). CPG 7909 is currently in clinical trials for cancer, while CPG 10101 is developed for hepatitis C virus by Coley Pharmaceutical Group Inc. The difference between the two sequences, which essen-tially share the same mechanism of action is that CPG 10101 appears a more potent inducer of the interferon-a pathway, particularly important to fight viralinfections. The same firm also develops VaxImmune as a support for vaccination protocols, which is based on the same immunostimulatory principle.

In a similar manner, dsRNA can be a predictor of viral infection and Toll-like receptor 3 recognizes dsRNA in the endosomes. In particular, synthetic dsRNA composed of poly-inosinic and poly-cytidylic acids are strong activators (poly-IC). It is clinically tested as poly-ICLC (HiltonolTM) by Oncovir Inc., a poly-lysine complexed formulation of poly-IC, to protect the dsRNA from nuclease action. The system is being developed for the treatment of glioma patients with or without supportive chemotherapy.

Comments

Post a Comment

Popular posts from this blog

Adenoviral Vectors - Viral Vectors for Gene Transfer

Image
  Viral Vectors for Gene Transfer   Viruses, natural parasites that efficiently enter cellular targets and hijack cellular machinery for propagation, are currently the most effective vectors for gene therapy. Approximately 70% of all gene therapy clinical trials employ viral vectors (Table 4). Many viruses with divergent properties have been devel-oped for gene transfer. Retroviruses, adenoviruses and adeno-associated viruses (AAVs) are the most extensively studied to date. Characteristics of each are summarized in Table 5.   Adenoviral Vectors Biology   Adenoviruses are non-enveloped, lytic, DNA viruses with a linear double-stranded genome and icosahedral symmetry. Since the isolation of the first human adenovirus in 1953 from tonsils and adenoid tissue (Rowe, 1953), 50 additional serotypes have been identified and grouped into six species (A–F) based on genome size, composition and homology, hemag-glutinating properties and oncogenicity in rodents. Because the subg...
Read more

Direct Binding to Non-Nucleic Acids

Image
  DIRECT BINDING TO NON-NUCLEIC ACIDS The ability of nucleic acids to fold into complex three-dimensional structures through regions of (partial) complementarity allows them to bind to virtually any molecule with nano- to picomolar affinity (Proske et al., 2005). This high affinity is supported by data on their extreme specificity. A nucleic acid sequence specifically binding theophylline has a million times higher affinity for theophylline than caffeine, mole-cules which differ by only one methyl group.   Aptamers/Riboswitches   Aptamers and riboswitches are single-stranded ONs of either DNA or RNA, generally about 60 nucleotides long, which fold into well-defined three-dimensional structures. They bind to their target molecule by complementary shape interactions accompanied by charge and hydrophobic interactions and hydrogen bridges. The target can be small molecules or macromolecules. Aptamers are isolated artificially, whereas riboswitches occur naturally (Tucker and ...
Read more

Uptake - Immunological Principles of Vaccines

  Uptake   Every immune reaction against a pathogen starts with its uptake by specialized phagocytic cells in the infected tissue. These cells carry receptors on their surface; pattern-recognition receptors (PRRs) that recognize common features of pathogens called pathogen associated molecular patterns (PAMPs). Binding of PAMPs to these PRRs results in phagocy-tosis of the pathogens. Examples of PRRs are toll-like receptors (TLRs), scavenger receptors and C-type lectins (Table 2). TLRs consist of a family of receptors, with each member recognizing different patterns on the surface of pathogens ( Akira et al., 2006). TLRs canbe found on many cells including macrophages and dendritic cells (DCs). DCs can also engulf materials from their extracellular environment by a receptor independent process called micropinocytosis.
Read more