Targeting Dendritic Cells with Antigen-Delivering Antibodies for Amelioration of Autoimmunity in Animal Models of Multiple Sclerosis and Other Autoimmune Diseases

Abstract

The specific targeting of dendritic cells (DCs) using antigen-delivering antibodies has been established to be a highly efficient protocol for the induction of tolerance and protection from autoimmune processes in experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS), as well as in some other animal disease models. As the specific mechanisms of such induced tolerance are being investigated, the newly gained insights may also possibly help to design effective treatments for patients. Here we review approaches applied for the amelioration of autoimmunity in animal models based on antibody-mediated targeting of self-antigens to DCs. Further, we discuss relevant mechanisms of immunological tolerance that underlie such approaches, and we also offer some future perspectives for the application of similar methods in certain related disease settings such as transplantation.

Keywords: antigen targeting; autoimmunity; chimeric antibodies; dendritic cells; diabetes; multiple sclerosis; tolerance.

Figure 1

The delivery of self-antigens to dendritic cells induces tolerance and ameliorates autoimmunity. Antibodies specific for cell surface molecules expressed by dendritic cells (DCs) are fused with or conjugated to self-antigens. Upon In Vivo administration, these antibodies target the antigens to DCs. DCs then internalize, process, and present the delivered antigens to T cells. Natural tolerogenic DCs (ntDCs) are good inducers of peripheral regulatory T cells (pTreg cells) and are often selected for antigen targeting purposes. This results in the induction of pTreg cells and, ultimately, in immune tolerance to the specific self-antigens and amelioration of autoimmune disease symptom severity. Additionally, antigens presented by some tolerance-inducing DCs may also promote the expansion of pre-existing regulatory T cells (Treg cells) as well as the anergy or deletion of autoreactive T cells.

Figure 2

Defined antigens are delivered to dendritic cells In Vivo using recombinant chimeric and other types of antibodies. (a) Recombinant chimeric antibodies, which deliver defined peptide or protein antigens (shown in yellow in panels (a–c)) to specific dendritic cell (DC) cell surface molecules, are comprised of the variable (V) regions derived from monoclonal antibodies specific for cell surface molecules expressed on DCs and the species-specific heavy and light constant (C) regions derived from separate immunoglobulins. The peptide antigen of choice is genetically fused to the C regions. This recombinant chimeric antibody design enhances the targeting specificity In Vivo by minimizing non-specific binding to Fc receptors, and it also helps to avoid stoichiometric differences in the amounts of antigenic materials present in such reagents. (b) Antibody–antigen conjugates are comprised of antigenic proteins chemically conjugated to native antibodies specific for cell surface molecules expressed on DCs. Such conjugates have been successfully used to deliver defined antigens to DCs, although they may lack some of the targeting specificity-enhancing modifications found in recombinant chimeric antibody designs. (c) Single-chain fragment variable (scFv) constructs provide yet another means of delivering antigen In Vivo. scFv constructs are comprised of a linker joining the corresponding V regions genetically fused to the antigen for targeting.