Oral vaccines can induce both systemic and mucosal immunity. Mucosal immunity, especially regional cell-mediated immunity, plays an important role in protecting individuals from infectious diseases such as acquired immunodeficiency syndrome. In this study, a recombinant adeno-associated virus vector expressing human immunodeficiency virus type 1 env gene (AAV-HIV) was orally administered to BALB/c mice. Systemic and regional immunity was induced in the mice. Furthermore, the immunization significantly reduced viral load after an intrarectal challenge with a recombinant vaccinia virus expressing HIV env gene. Moreover, we also show that dendritic cells might contribute to the AAV-HIV vector-induced immune responses.
AAV ITRs enhance CMV-dependent up-regulation of transgene expression and immunogenicity of DNA vaccine.
4018 CD26 is a 110-kDa multifunctional membrane-bound glycoprotein with dipeptidyl peptidase IV (DPPIV) enzyme activity present on a wide variety of cells, and is critical in T cell biology, as a marker of T cell activation. The role of CD26 in immune regulation has been extensively characterized, with our recent findings elucidating its linkage with signaling pathways and structures involved in T cell activation as well as antigen presenting cell (APC)-T cell interaction. CD26 in human T cells has a costimulatory function and is upregulated after activation. On the other hand, in murine lymphocytes, CD26 is expressed in CD4-CD8- thymocytes and its expression level is not changed by various stimulation procedures. Moreover, murine T cells are not observed to be activated via CD26. Therefore, for the analysis of CD26-mediated immuneregulation leading to clinical applications, it is necessary to use a pathological model system caused by human T cells but not murine T cells. For this purpose, we used a xenogeneic graft-versus-host disease (x-GVHD) murine model, which is generated by transplantation of human T cells into NOG-Scid mice (hu-PBL-NOG). In this model mouse, x-GVHD is developed by manifesting rough hair, loss of weight and motility, since transplanted human T cells become effector cells in murine organs. By examining the cytotoxic functions of human CD8+ T cells after CD26-mediated costimulation in vitro, we have shown that CD26-mediated costimulation induced vigorous secretion of inflammatory cytokines, TNF-a, IFN-g and soluble Fas Ligand, and strongly enhanced the expression of Granzyme B. These results suggested that cytotoxic function in human CD8+ T cells activated via CD26-mediated costimulation has a key role in developing x-GVHD. In the present study, we showed that CD26 blockade by humanized anti-CD26 monoclonal antibody (huCD26mAb) reduced development of x-GVHD, and that this effect of CD26 blockade was exerted by suppression of cytotoxic activity of human CD8+ T cells in vivo. Moreover, huCD26mAb showed as same effect on suppression of x-GVHD as clinically available drug, abatacept (CTLA4-Ig), a blockade of CD28-mediated costimulation. While increased dose of CTLA4-Ig showed more suppressive effect on x-GVHD but sustained suppression of engraftment of transplanted human T cells, the same dose of huCD26mAb showed no delay in engraftment. We performed a further analysis of peripheral human lymphocytes in hu-PBL-NOG after administration of huCD26mAb or CTLA4-Ig. Although CD26 expression on both human CD4+ T cells and CD8+ T cells was markedly increased in control mice with human IgG administration as compared with those before transplantation, the engraftment of human CD26+ T cells was completely inhibited in huCD26mAb administered hu-PBL-NOG. As a result of analysis of human T cells engrafted in spleen of NOG-Scid mice transplanted with carboxyfluorescein diacetate succinimidyl ester (CFSE)-labeled human lymphocytes, huCD26mAb administration preferentially suppressed the priming of human CD8+ T cells rather than CD4+ T cells, while CTLA4-Ig strongly suppressed the cell division of both human CD4+ T cells and CD8+ T cells. Our data strongly suggested that CD26-mediated costimulatory activation in human CD8+ T cells was deeply involved in the pathogenesis of x-GVHD, and blocking the CD26-mediated costimulation resulted in prophylaxis and treatment of x-GVHD. Taken together, our results support the notion that CD26 blockade by huCD26mAb may become a promising therapeutic strategy for GVHD and other refractory immune-mediated disorders. Disclosures: No relevant conflicts of interest to declare.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.