Aiming to specifically inactivate the cells of interest in vivo, we developed two novel technologies. Both strategies are based on the nature of chemokines to deliver antigens to the cytosol of cells expressing respective chemokine receptors. 1) The technology designated chemotoxin, a chimeric chemokine fused with toxic moieties, specifically kills cells expressing respective chemokine receptors. For example, using TARC-chemotoxin we could eradicates established leukemia in mice. This technology is for treatment of human T cell malignant diseases when patients immune system is severely immunocompromised. The results of this study was published (Baatar et al, 2007a). The technology can also be used to specifically deplete Tregs in mice and to augment immune responses to cancer vaccines. TARC-chemotoxin eliminated Tregs and enhanced CD8+ T cell responses to gp100-based vaccines in mice. This technology is also being successfully used to understand the role of regulatory immune cells in cancer metastasis in mice (see AG000443-02). The results generated using TARC-chemotoxin were published in several our papers (Baatar et al.,2009;Olkhanud et al., 2009). 2) We developed novel technology designated Chemoarp to specifically deliver siRNA/miRNA into immune cells in vivo. The technology overcomes the major stumbling block of siRNA/miRNA use, i.e. the lack of ways to deliver them into immune cells in vivo. We created chemokines modified to bind siRNA/miRNA by hypothesizing that this will enable us to specifically deliver siRNA/miRNA into immune cells. Indeed, we demonstrate that modified chemokine CCL17 (TARC-arp) efficiently silences expression of genes in immune cells by delivering inhibitory oligonucleotides via their chemokine receptors. In modeling studies using mice with established 4T1.2 breast cancer, we show that IL10 produced by FoxP3+CCR4+ Tregs plays an important role in lung metastasis. As such, TARC-arp-mediated silencing of IL-10 or FoxP3 in CCR4+ regulatory T cells (Tregs) is sufficient to block lung metastasis. Thus, we provide a simple solution that circumvents the problems of RNAi use in vivo, indicating that a disease outcome can be successfully controlled by delivering inhibitory oligonucleotides with chemokines to inactivate a selective subset of immune cells, such as CCR4+ Tregs. Overall, considering the simplicity of our chemoarp technology, chemoarp is a potent therapeutic strategy to modulate immune responses and to improve outcome of diseases by, for example, inactivating Tregs and other disease associated immune cells. This study was recently published (Biragyn et al., J. Immunotherapy, 2013). Recently, we also developed and successfully used BLC-arp (a CXCL13-based chemoarp) to inactivate tBregs in mice with breast cancer by delivering immunostimulatory CpG-ODN. This enabled us to abrogate lung metastasis via conversion of tBregs into T cell activating B cells expressing 4-1BBL . This study was recently published (Bodogai et al., 2012), see Report AG000443. We also successfully collaborated with Dr. Rivas-Santiago (Mexican Institute of Social Security, Mexico) on the development of chemoattractant-based vaccine for tuberculosis (Cervantes-Villagrana et al., 2013).
|Cervantes-Villagrana, Alberto R; Hernández-Pando, Rogelio; Biragyn, Arya et al. (2013) Prime-boost BCG vaccination with DNA vaccines based in ?-defensin-2 and mycobacterial antigens ESAT6 or Ag85B improve protection in a tuberculosis experimental model. Vaccine 31:676-84|
|Baatar, Dolgor; Olkhanud, Purevdorj B; Wells, Valerie et al. (2009) Tregs utilize beta-galactoside-binding protein to transiently inhibit PI3K/p21ras activity of human CD8+ T cells to block their TCR-mediated ERK activity and proliferation. Brain Behav Immun 23:1028-37|