Treating autoimmune diseases through restoration of antigen-specific immune tolerance

Abstract

The first line of treatment for many human autoimmune diseases involves the use of anti-inflammatory or immunosuppressive drugs such as prednisone or other steroids that not only suppress the underlying autoimmune disease, but lead to global suppression of the immune system. The sequelae of this approach include increased risk of infection, carcinogenesis, and osteoporosis. Moreover, such broad spectrum immunosuppression tends to have transient therapeutic benefit, as in many cases the disease becomes refractory to these drugs. There is a clear need for more specific means to restore immune tolerance to the specific autoantigens implicated in disease pathology. This review provides an overview of some of these newer, more specific therapeutic approaches to restoring immune tolerance to autoantigens, with an emphasis on those approaches that have been or will soon be tested in controlled clinical trials. Covered here are peptide- or protein-based therapeutics, oral tolerance, and cellular and gene therapy approaches to restoring antigen-specific immune tolerance.

Selective gene silencing in activated leukocytes by targeting siRNAs to the integrin lymphocyte function-associated antigen-1

“…Selective targeting of activated lymphocytes would likely be sufficient to suppress inflammatory tissue injury. By leaving resting and naïve cells untouched, selective targeting would reduce iatrogenic immunodeficiency, a major problem associated with current immunosuppressive drugs (15). Moreover, the siRNA dose required to target a small subset of disease-causing cells is likely to be substantially less than that needed for indiscriminate targeting.…”

“…Other activation makers, such as CD69, CD25, CD40L, or OX40, could also be used for selective targeting of activated lymphocytes (15,32,33). The expression profiles of cell surface molecules after activation vary greatly depending on timing and the character and strength of the activating stimulus (32).…”

“…Silencing gene expression only in activated cells during a disease could provide the possibility of interfering with unwanted pathogenic immune stimulation without global immunosuppressive effects on bystander immune cells that complicate most current immunosuppressive therapies (15). We designed an AL-57 single-chain variable region fragment (scFv)-protamine fragment fusion protein (AL-57-PF) and tested its ability to deliver siRNAs and silence gene expression in activated cells.…”

Emerging Opportunities for Site-Specific Molecular and Cellular Interventions in Autoimmune Hepatitis

“…2). These focused actions promise to preserve adaptive immune defenses, reduce treatment-related complications, ensure prompt onset of action, and allow better regulation of the duration and intensity of the immunosuppressive effect [45]. …”

Effects of structural modification of anti-inflammatory steroidal antedrug on pro-inflammatory mediators and inhibitory cytokines in human alveolar epithelial cells

“…However, these drugs display a number of serious systemic side effects such as suppression on pituitary-adrenal axis and on the immune system, aggravation of diabetes, hypertension, retardation of growth in children and osteoporosis. These systemic side effects limit the clinical use of corticosteroids [5][6][7][8][9]. Therefore, the main focus of present research is to modify the structure of corticosteroids by reducing the systemic side effects without losing their anti-inflammatory function.…”