Immune Tolerance for Autoimmune Disease and Cell Transplantation

Abstract

The undesired destruction of healthy cells, either endogenous or transplanted, by the immune system results in the loss of tissue function or limits strategies to restore tissue function. Current therapies typically involve nonspecific immunosuppression that may prevent the appropriate response to an antigen, thereby decreasing humoral immunity and increasing the risks of patient susceptibility to opportunistic infections, viral reactivation, and neoplasia. The induction of antigen-specific immunological tolerance to block undesired immune responses to self- or allogeneic antigens, while maintaining the integrity of the remaining immune system, has the potential to transform the current treatment of autoimmune disease and serve as a key enabling technology for therapies based on cell transplantation.

Keywords: cell therapies; immunomodulation; inverse vaccines; nanotechnology; tolerance.

Figure 1

Tolerance by antigen (Ag) presentation without costimulation. Antigens are internalized by antigen-presenting cells (APCs), and after processing, a peptide of 7–10 amino acids or 14–20 amino acids can be presented on major histocompatibility complex (MHC) I or II, respectively, for recognition by the T cell receptor (TCR) on T cell subsets. The plasticity of T cell subsets enables their response resulting in either immunity or the induction of tolerance. (a) Immunity. The T cell clones mediating the undesired response contain a TCR that recognizes the Ag presented by an APC presenting the MHC/Ag complex (signal 1). The interaction between costimulatory factors present on APCs and cognate receptors on T cells is also needed to cause T cell activation (signal 2). The final stage of T cell activation involves the interaction of soluble mediators (such as interleukins or other factors) with receptors on the T cell surface (signal 3). (b) Blockade of the positive costimulatory CD28/B7 signaling axis between T cells and APCs by the cytotoxic T lymphocyte antigen 4 (CTLA-4)–Ig fusion protein serves as a constitutive regulatory control switch, and it has been exploited as a tolerogenic regimen for autoimmunity treatment. Programmed death 1 (PD-1) signaling on T cells by its ligands PD-L1 and PD-L2 represents another regulatory mechanism of immune responses, and it has been extensively studied in the context of autoimmunity and T cell exhaustion and deletion. Selective blockade of the PD-1/PD-L1 signaling axis can disrupt tolerance induction by blocking T cell receptor stop signals, thereby decreasing T cell motility and increasing physical interactions with APCs, resulting in enhanced immune responses. (c) Induction of regulatory T cells (T_regs) as a mechanism to achieve Ag-specific immunoregulation. In the presence of transforming growth factor β (TGF-β) and interleukin-2 (IL-2), naïve T cells can be differentiated into T_regs that release immunosuppressive cytokines such as IL-10 to diminish the induction and proliferation of effector T cells.

Figure 2

Schematic illustrating tolerogenic approaches being developed for delivery (a) subcutaneously, (b) to the lymphatics, or (c) intravenously. Factors delivered subcutaneously can release factor locally, be internalized by cells within the subcutaneous space, or travel to the lymphatics. Intravenous delivery can involve soluble antigen (Ag) or modified Ag or nanoparticles that can associate with cells in the blood, or it can be internalized by antigen-presenting cells in organs such as the liver or spleen. Abbreviation: Ag-SP, antigen coupled to splenocytes.