Innate immune response modulators

Investigators

Abstract

Our laboratory is focused on identification and characterization of modulators of the innate immune response as they relate to potential vaccines and therapies for infection, particularly with agents of bioterrorism. Current areas of development include the use of synthetic CpG oligogeoxynucleotides (ODN) type D as well as novel DNA sequences that act on Toll-like receptors expressed by dendritic and B cells resulting in improved antigen uptake/presentation by antigen presenting calls, and the secretion of polyreactive Ig, chemokines and cytokines by B cells, NK cells, dendritic cells, and monocytes. To assert protection, the laboratory utilizes animal models of infection with Leishmania major, Herpes and Tacaribe virus, a new world Arenavirus in mice and non-human primates. This work not only has applications in the area of Bioterrorism, but also in reducing the susceptibility of immunosuppressed subjects to opportunistic infections. Particular areas of interest include: a) Establishing the safety and effectiveness of CpG ODN as immunoprotective agents against Class A Bioterrorist agents in healthy murine and primate models. 1. We have shown that CpG ODN are effective in non-human primates as vaccine adjuvants for vaccines against hepatitis B and Leishmaniasis. For Leishmaniasis, we have shown that D ODN administered in conjunction with a heat killed leishmania vaccine afford protection from cutaneous leishmaniasis in macaques. Recent work shows that CpG ODN accelerate and increase the titers of antibodies to Hbs Ag relative to the existing HBV vaccine Engerix 2. As immunoprotective agents, we have shown that CpG ODN administered locally can significantly reduce the lesions caused by a L.major challenge in macaques. 3. Our studies in primates show no weight loss, no significant changes in blood chemistries, erythrosedimentation or CBC and differential as well as no changes in gross pathology except for mild enlargement of draining lymph nodes upon administration of CpG ODN at therapeutic doses. 4. One of the concerns when utilizing a strong immune stimulant is the development of autoimmune disease or the induction of tolerance. Intraarticular administration of CpG ODN had been shown to induce a reactive arthritis. Of considerable interest, this adverse side effect was blocked by the co-administration of "suppressive" oligonucleotides. This provides insight into the role of CpG-containing bacterial DNA to the pathogenesis of autoimmune disease, and raises the possibility of such diseases being treated using suppressive ODN. b) Assessing the effects of age, gender, and immunecompetence on the immunostimulatory effects of CpG ODN in in vitro and in vivo models.1. Comparative studies are underway to characterize the immunostimulatory effects of CpG ODN in pre-, post menopausal and pregnant females compared to males in mice, human and non-human primates. Our studies show that CpG ODN induce higher cytokine and Ig secretion in response to CpG ODN. Moreover, upon administration in vivo they provide a higher degree of protection against leishmania infection in female than male mice. c) Determine the effectiveness of these compounds on selected at-risk populations including subjects with primary and secondary immunodeficiencies. 1. There is considerable interest in developing novel agents that improve resistance against infectious microorganisms in immunosuppressed patients. Our studies show that CpG ODN can stimulate PBMC from HIV infected patients or SIV infected macaques. Further, we have shown that CpG ODN can protect SIV infected monkeys from a super-infection with L.major. CpG-treated monkeys had significantly reduced lesions and parasite numbers. 2. Recent studies from our lab also show that in SIV infected macaques that usually mount a suboptimal response to the licensed HBV vaccine use of CpG ODN as vaccine adjuvants can significantly improve the immunogenicity of the vaccine to induce protective antibody titers. This project incorporates FY2002 projects 1Z01BN002029-01 and 1Z01BN002030-01.