CD28/CD154 Blockade Prevents Autoimmune Diabetes by Inducing Nondeletional Tolerance After Effector T-Cell Inhibition and Regulatory T-Cell Expansion

Abstract

OBJECTIVE—Blocking T-cell signaling is an effective means to prevent autoimmunity and allograft rejection in many animal models, yet the clinical translation of many of these approaches has not resulted in the success witnessed in experimental systems. Improved understanding of these approaches may assist in developing safe and effective means to treat disorders such as autoimmune diabetes.RESEARCH DESIGN AND METHODS—We studied the effect of anti-CD154 and CTLA4-Ig on diabetes development, and the requirements to induce tolerance in nod.scid mice after transfer of transgenic β-cell reactive BDC2.5.NOD T-cells.RESULTS—Nod.scid recipients of diabetogenic BDC2.5.NOD cells were protected indefinitely from diabetes by a short course of combined costimulation blockade, despite the continued diabetogenic potential of their T-cells. The presence of pathogenic T-cells in the absence of disease indicates peripheral immune tolerance. T-cell maturation occurred in protected recipients, yet costimulation blockade temporarily blunted early T-cell proliferation in draining pancreatic nodes. Tolerance required preexisting regulatory T-cells (Tregs), and protected recipients had greater numbers of Tregs than diabetic recipients. Diabetes protection was successful in the presence of homeostatic expansion and high T-cell precursor frequency, both obstacles to tolerance induction in other models of antigen-specific immunity.CONCLUSIONS—Immunotherapies that selectively suppress effector T-cells while permitting the development of natural regulatory mechanisms may have a unique role in establishing targeted long-standing immune protection and peripheral tolerance. Understanding the mechanism of these approaches may assist in the design and use of therapies for human conditions, such as type 1 diabetes.

TGF-β Blockade Does Not Improve Control of an Established Persistent Viral Infection

“…SB 431542 (Tocris Bioscience, Ellisville, MI) was dissolved in 100% DMSO and administered intraperitoneally to persistently infected mice starting from day 21 post-infection at a dose of 400 lg (50 lL of a 19 lmol solution) every 2-3 d for a total of 4 to 5 treatments. In one control experiment, mice additionally received 4-5 doses of 250 lg of a TGF-b antibody intraperitoneally (clone 1D11.16.8; BioXcell, West Lebanon, NH), which has been widely used to block TGF-b in vivo (19)(20)(21)(22). As we have not observed any differences between SB 431542-treated and SB 431542 + 1D11.16.8-treated mice in the parameters analyzed in this study, we have integrated the results from the control experiments into the graphs throughout the article.…”

Central memory CD8+ T lymphocytes mediate lung allograft acceptance

“…We have previously demonstrated that immunosuppression through blockade of the CD28/B7 and CD40/CD154 costimulatory pathways leads to long-term lung allograft acceptance in the BALB/c→B6 (31, 33) as well as other strain combinations (30). Regulatory CD4 + T cells have been shown to play a critical role in costimulatory blockade-mediated acceptance of heart, skin, and islet allografts as well as amelioration of autoimmune diseases (4,5,(34)(35)(36)(37)(38). However, recipient bulk CD4 + T cell antibody-mediated depletion did not affect the fate of immunosuppressed lung allografts with rejection grades comparable to wild-type costimulatory blockade-treated hosts ( Figure 2, A and B).…”

“…Costimulatory blockade has been described to mediate graft acceptance through the generation of regulatory T lymphocytes (4,5,(34)(35)(36)(37)(38). In order to evaluate whether CD8 + T lymphocytes with regulatory capacity develop in costimulatory blockade-treated lung recipients, we isolated CD8 + T cells from the lung grafts and spleens of such mice and used them as "regulators" in in vitro mixed lymphocyte reactions (MLRs) ( Figure 4A).…”

GVHD after haploidentical transplantation: a novel, MHC-defined rhesus macaque model identifies CD28− CD8+ T cells as a reservoir of breakthrough T-cell proliferation during costimulation blockade and sirolimus-based immunosuppression

“…[2][3][4][5][6] CD28-directed therapies have moved the farthest clinically, with the CD28-blockade agent cytotoxic T-lymphocyte-associated antigen 4 immunoglobulin (CTLA4Ig) approved for rheumatoid arthritis, 7 and a secondgeneration compound, belatacept, that has just completed phase 3 clinical trials for renal transplantation. 8 Although blockade of both sides of the CD40:CD154 pathway have shown promise in murine models of transplantation, [9][10][11][12][13][14] platelet-mediated thromboembolic complications have slowed clinical development of CD154-directed therapies. 15 Fortunately, several studies have shown that blockade of CD40 may also have significant potency for inhibiting alloreactivity while avoiding risks of thrombosis.…”