Prevention of Graft-Versus-Host Diseases by in Vivo supCD28mAb-Expanded Antigen-Specific nTreg Cells

Abstract

Naturally occurring CD4+ CD25 + Treg cells (nTregs) can be exploited to establish an immunologic tolerance to non-self-antigens. The in vivo administration of a single superagonistic CD28-specific monoclonal antibody (supCD28mAb) to naive rat preferentially expanded the nTregs, which induced a potent inhibition of lethality of the graft-versus-host (GvH) diseases. The appearance of increased Foxp3 molecules was accompanied with a polarization towards a Th2 cytokine profile with a decreased production of IFN-γ and increased production of IL-4 and IL-10 in the serum of the antibody-treated rat. The peripheral Foxp3 nTregs are decreased in acute GvHD, while supCD28mAb administration showed that nTregs were preferentially proliferating in vivo, thus resulting in the significant prevention of the GvH disease. Furthermore, antigen-specific nTregs could suppress conventional T-cell proliferation stimulated with alloantigen in vitro. Taken together, our findings demonstrate that the potent regulatory functions of the Tregs for the treatment of GvHD are antigen specific. These data also provide evidence that GvHD is associated with decrease of Tregs in the periphery of the host. The determination of the Foxp3 Tregs can be a helpful tool to discriminate GvHD severity and lethality after allogeneic stem cell transplantation.

The effects of Foxp3-expressing regulatory T cells expanded with CD28 superagonist antibody in DSS-induced mice colitis

“…CD4+Foxp3+Treg cells play a critical role in the maintenance of self tolerance, control of autoimmune diseases, transplant rejection and have also been documented to offer a therapeutic option in severe inflammatory colitis [5,8,[17][18][19][20]. Therefore, therapeutic agents that are capable of enhancing the number and activity of this T-cell subset are highly desirable.…”

Immune Reconstitution and Graft-Versus-Host Reactions in Rat Models of Allogeneic Hematopoietic Cell Transplantation

“…In a number of these models, engraftment, reconstitution, chimerism, cell trafficking, and tolerance toward donor cells has been studied (Clancy et al, 1983; Oaks and Cramer, 1985; Ohajekwe et al, 1995; Engh et al, 2001; Foster et al, 2001; Okayama et al, 2004; Itakura et al, 2007; Klimczak et al, 2007; Nestvold et al, 2008; Zhou et al, 2008; Zhu et al, 2011; Zinöcker et al, 2011a;Lin et al, 2012). Furthermore, rat models have been employed to test prevention or treatment of GvHD by therapeutic regimens involving immunomodulatory drugs (Tutschka et al, 1979; Vogelsang et al, 1986; Vogelsang et al, 1988; Mrowka et al, 1994; Ohajekwe et al, 1995; Pakkala et al, 2001; Okayama et al, 2006; Wolff et al, 2006; Jäger et al, 2007), infusion or induction of various suppressive cell types (Itakura et al, 2007; Aksu et al, 2008; Nestvold et al, 2008; Kitazawa et al, 2010; Zinöcker et al, 2011b; Kitazawa et al, 2012; Zinöcker et al, 2012), UV irradiation (Ohajekwe et al, 1995; Gowing et al, 1998), serum transfusion (Shimizu et al, 1997), surgical techniques (Kobayashi et al, 1998), and prolonged distribution of a chemical agent with subcutaneously implanted osmotic pumps (Fidler et al, 1993). …”

Systemic Inflammatory Response Elicited by Superantigen Destabilizes T Regulatory Cells, Rendering Them Ineffective during Toxic Shock Syndrome

“…For example, Tregs have been shown to be protective in several acute systemic inflammatory conditions such as LPS-induced shock (20), zymosan-induced shock (21), graft-versus-host disease (22–24) sepsis caused by Gram-negative bacteria (25) and CD28 superagonist-induced inflammatory response syndrome (26), which are all analogous to SAg-induced TSS. Given these findings, Tregs are attractive candidates for the prevention and/or treatment of acute inflammatory diseases caused by SAg.…”