Restoring the balance: immunotherapeutic combinations for autoimmune disease

Abstract

Autoimmunity occurs when T cells, B cells or both are inappropriately activated, resulting in damage to one or more organ systems. Normally, high-affinity self-reactive T and B cells are eliminated in the thymus and bone marrow through a process known as central immune tolerance. However, low-affinity self-reactive T and B cells escape central tolerance and enter the blood and tissues, where they are kept in check by complex and non-redundant peripheral tolerance mechanisms. Dysfunction or imbalance of the immune system can lead to autoimmunity, and thus elucidation of normal tolerance mechanisms has led to identification of therapeutic targets for treating autoimmune disease. In the past 15 years, a number of disease-modifying monoclonal antibodies and genetically engineered biologic agents targeting the immune system have been approved, notably for the treatment of rheumatoid arthritis, inflammatory bowel disease and psoriasis. Although these agents represent a major advance, effective therapy for other autoimmune conditions, such as type 1 diabetes, remain elusive and will likely require intervention aimed at multiple components of the immune system. To this end, approaches that manipulate cells ex vivo and harness their complex behaviors are being tested in preclinical and clinical settings. In addition, approved biologic agents are being examined in combination with one another and with cell-based therapies. Substantial development and regulatory hurdles must be overcome in order to successfully combine immunotherapeutic biologic agents. Nevertheless, such combinations might ultimately be necessary to control autoimmune disease manifestations and restore the tolerant state.

Keywords: Autoimmune; Biologic; Tolerance.

Fig. 1

Tolerance mechanisms in T cells and B cells. Central tolerance occurs when high-affinity self-reactive T cells and B cells are eliminated in the thymus and bone marrow, respectively. Low-affinity self-reactive T cells and B cells escape central tolerance and enter the periphery, where they are kept in check by complementary and non-redundant peripheral tolerance mechanisms.

Fig. 2

Tolerance pathways are targets for immune intervention in autoimmune states. A variety of mechanisms influence the balance of the regulatory and effector arms of the immune system. Strategies for treating autoimmunity target these pathways, such that insufficient regulatory mechanisms are enhanced and inappropriate activation mechanisms are diminished.

Fig. 3

Examples of combination therapy for autoimmunity. Successful treatment of autoimmune disease is likely to require novel combinations of pathway-targeted cell-based therapies and biologic agents. (A) Manifestations of autoimmune disease could be reduced with an anti-inflammatory cytokine, and recurrence prevented by co-stimulatory blockade. (B) Pathogenic T or B cells could be depleted, and re-emergence of autoreactive cells during homeostatic proliferation could be prevented by an antibody that targets a homeostatic cytokine. (C) Tregs that have been expanded ex vivo could be infused with a cytokine that prevents their pathogenic conversion to an inflammatory phenotype. (D) Manifestations of autoimmune disease could be reduced with an anti-inflammatory cytokine, in combination with antigen-specific tolerance induction using antigen-containing nanoparticles.