Screening, Action Mechanism And Adjuvanticity With T Cell Epitope Peptide Specific For SARS-CoV Of Immunopotentiators

MDP, muramyl dipeptide, the minimal bioactive unit of peptidoglycan of gram-negative and gram-positive bacterial cell wall, was known to have pleiotropic stimulatory effects on host immune system and further elicit defensive responses. However, MDP showed significant concomitant side effects in vivo, such as pyrogenicity, poor penetration of membranes and rapid elimination. MDP usally targets on APC (antigen presenting cells), such as macrophage and DC (dendritic cells), which is the most potent professional APC. In this paper, a model for assay the killing activity of macrophage to P388 tumor cells was established to screen the fifty seven MDP derivatives. As results, compound C7 (named MDP-C, N²-[α-O-benzyl-N-(acetylmuramyl)-L-alanyl-D-isoglutaminyl]-N⁶-trans-(m-nitrocin namoyl)-L-lysine) with low toxicity, apyrogenity and non-allergicity was shown to signifisintly potentiate killing activity of macrophage to P388 tumor cells. Additionally, MDP-C could significantly enhance proliferative response of murine splenic lymphocytes with EC50 of 5.7×10^-9mol/L. MDP-C also enhance the ability of DC, the most potent professional APCs and sensor of immune system, to induce cytolytic activities to P815 of CTL and level of IFN-γ produced by CTL. In the immunosuppressed mice model caused by cyclophosphamide, MDP-C significantly promoted the number of CD3⁺CD4⁺ T cell and the ratio of CD3⁺CD4⁺/CD3⁺CD8⁺ T cell, subsequently promoted the immunity of the mice. These data suggested that MDP-C, a potential immunopotentiator, may play important roles in immunotherapy to cancer and the immunodeficient diseases caused by virus infection.Further investigation of action mechanism indicated that MDP-C could enhance the levels of IL-2, TNF-a and IL-12 released by DC, up-regulate the expressions of MHC class II and ICAM-1 which might be through the pathway of TLR4/ NF-kB, subsequently induce native T cell into effector CTL, enhance their cytolytic activities and promote their abilities of presenting antigen. The immuno-adjuvancy...