Immunosuppression in Vivo by a Soluble Form of the CTLA-4 T Cell Activation Molecule

Abstract

In vitro, when the B7 molecule on the surface of antigen-presenting cells binds to the T cell surface molecules CD28 and CTLA-4, a costimulatory signal for T cell activation is generated. CTLA4Ig is a soluble form of the extracellular domain of CTLA-4 and binds B7 with high avidity. CTLA4Ig treatment in vivo suppressed T cell-dependent antibody responses to sheep erythrocytes or keyhole limpet hemocyanin. Large doses of CTLA4Ig suppressed responses to a second immunization. Thus, costimulation by B7 is important for humoral immune responses in vivo, and interference with costimulation may be useful for treatment of antibody-mediated autoimmune disease.

Blunting of immune responses to adenoviral vectors in mouse liver and lung with CTLA4Ig

“…23,26 In contrast, however, suppression of cellmediated immunity could be achieved when CTLA4-Ig was used in different experimental settings. [27][28][29][30] The latter observation is supported by data presented in this study, which demonstrate inhibition of T and B cell activation by an adenoviral recombinant in animals treated with huCTLA4Ig.…”

“…The safety of CTLA4Ig for human application is unknown although it is likely to have a more specific effect on immune function than general immune suppressants, such as cyclophosphamide and cyclosporin A. Moreover, all studies published utilizing CTLA4Ig as an immunosuppressive reagent have demonstrated some level of inhibition of both the cellular and humoral arm of the immune response, [27][28][29] making this drug an attractive tool for human application. The data, however, demonstrating only partial blockade of the immune responses, such as neutralizing antibody following intravenous vector delivery, suggest that more potent blockers of these accessory, costimulatory molecules may be required.…”

New TCR Transgenic Model for Tracking Allospecific CD4 T-Cell Activation and Tolerance in Vivo

“…The finding that the antigen-specific TCR-tg CD4 + T cells in transplanted mice treated with CTLA4Ig retained a naive phenotype supports previous observations that naive T cells require CD28 costimulation to become activated (26). Taken together, these data suggest that CTLA4Ig inhibits priming of CD4 + T cells (31) and their ability to acquire phenotypic and functional characteristics of effector or memory cells.…”

Locally expressed CTLA4-Ig in a pancreatic beta-cell line suppresses accelerated graft rejection response induced by donor-specific transfusion

“…Administration of a high dose of CTLA4-Ig was previously reported to suppress immune responses systemically [14,15,16,17], and several preceding studies indicate that local delivery of CTLA4-Ig prolongs the survival of islet allografts in mice [8,9,18]. Using adenovirus-mediated expression of CTLA4-Ig, investigators [26] recently reported that the production of CTLA4-Ig by islet cells themselves, but not by cells located in remote sites, is effective in prolonging islet allograft survival.…”

“…A chimeric fusion protein, CTLA4-Ig, which is composed of the extracellular region of CTLA4 and the Fc portion of IgG1, similarly blocks the CD28-mediated co-stimulatory pathways, and down-regulates the immune response in various experimental transplantation models. When administered systemically [14,15,16,17] or expressed in engrafted tissues by gene transfer [8,9,18], CTLA4-Ig prolongs graft survival, and occasionally induces graft-specific unresponsiveness. However, it has not yet been established whether the prolongation of graft survival is obtained by a local or systemic immunoregulatory mechanism.…”