Treating human autoimmunity: current practice and future prospects

Abstract

Autoimmune diseases are caused by immune cells attacking the host tissues they are supposed to protect. Recent advances suggest that maintaining a balance of effector and regulatory immune function is critical for avoiding autoimmunity. New therapies, including costimulation blockade, regulatory T cell therapy, antigen-specific immunotherapy, and manipulating the interleukin-2 pathway, attempt to restore this balance. This review discusses these advances as well as the challenges that must be overcome to target these therapies to patients suffering from autoimmune disease while avoiding the pitfalls of general immunosuppression.

Fig. 1

Costimulatory blockade as a method to treat autoimmunity. T cells require two signals to become fully activated. The first signal (“signal 1”) is provided through the TCR upon recognition and binding of specific antigen presented in the context by MHC (major histocompatibility complex) molecules on APCs. The second signal (“signal 2”) is a costimulatory signal provided by engagement of costimulatory ligands expressed on APCs with costimulatory receptors expressed on T cells. If T cells receive signal 1 without signal 2, they fail to be fully activated and are rendered functionally anergic. CD80 (B7-1) and CD86 (B7-2) binding to CD28 provides a robust costimulatory signal to T cells. Abatacept and belatacept are chimeric fusion proteins consisting of the extracellular domain of CTLA-4 and human IgG1. They bind to CD80 and CD86 with high affinity, preventing binding of these costimulatory ligands to CD28. Through blocking this potent costimulatory pathway, these reagents inhibit the activation of auto-reactive T cells in patients with autoimmunity.

Fig. 2

Augmentation of T_regs to treat human autoimmunity. Both in vivo and ex vivo approaches have been used to enhance the relative numbers of T_regs to treat autoimmune disease. Adoptive T_reg therapy is a method by which polyclonal T_regs are purified from peripheral blood or cord blood via fluorescence-activated cell sorting using cell surface markers preferentially expressed on T_regs. Purified cells are expanded ex vivo by culturing in the presence of TCR stimulation (with or without costimulation) in combination with exogenous IL-2 and, in some cases, rapamycin (which preferentially inhibits conventional T cell proliferation in vitro). Expanded cells are then adoptively transferred to the patient. The process of self-antigen–specific tolerance is aimed at enhancing the T_reg–to–pathogenic T cell (T_eff) ratio in vivo. In this approach, self-peptide is repeatedly administered in increasing doses to induce the preferential expansion of antigen-specific T_regs. Attempts to improve the efficacy of self-antigen tolerance include coupling antigen to autologous cells before injection. Polyclonal T_regs can be expanded in vivo by signaling through the IL-2 receptor (CD25), which is constitutively expressed on T_regs. Attempts to improve the efficacy of this approach in animal models have used recombinant IL-2 and monoclonal anti–IL-2 antibody immune complexes. The overall goal of both ex vivo and in vitro approaches is to increase the relative T_reg-to-T_eff ratio in an attempt to restore tissue-specific or systemic immune homeostasis.