Co‐Stimulatory Blockade in the Treatment of Murine Systemic Lupus Erythematosus (SLE)

Abstract

Although the life span of patients with systemic lupus erythematosus (SLE) has improved considerably over the last several decades, the toxicities of chronic immunosuppressive therapy are major causes of morbidity and mortality. Safer and more effective therapies for SLE are clearly needed. SLE is characterized by excessive activation of both B and T lymphocytes. Activation of these cells requires both antigen engagement and co-stimulatory signals from interacting lymphocytes (Carreno, B.M. M. Collins, 2002, Annu. Rev. Immunol. 20: 29-53; Grewal, I.S. R.A. Flavell, 1998, Annu. Rev. Immunol. 16: 111-135). Thus, blockade of co-stimulatory signals offers a new therapeutic approach to SLE. Our short-term goal has been to understand the effect of co-stimulatory blocking reagents on the development, selection, and activation of pathogenic anti-dsDNA antibody producing B cells in mice genetically pre-determined to develop SLE and showing signs of either early or advanced disease activity. Our long-term goal is to use the knowledge we gain to design therapeutic regimens for humans that avoid the complications of long-term immunosuppression. As new co-stimulatory molecules are discovered, studying their mechanism of action in animal models and their clinical utility in human autoimmune disease should lead both to a new understanding of disease pathogenesis and also to safer and more effective therapies.

Mechanism of Action of Transmembrane Activator and Calcium Modulator Ligand Interactor-Ig in Murine Systemic Lupus Erythematosus

“…In preventive studies neither CTLA4-Ig, anti-CD40L, nor the combination of the two agents induced either a change in serum levels of Ig or a decrease in titers of IgM anti-DNA Abs, even in young mice (17,20,31). In contrast, these treatments inhibited class switching and somatic mutation and appeared to alter selection of autoreactive V region genes, consistent with their effect on delivery of T cell help to B cells (37). In remission induction studies, a 2-wk course of combination anti-CD40L and CTLA4-Ig did not induce remission in nephritic NZB/W F 1 mice (22).…”

Interferon‐γ–dependent inhibition of B cell activation by bone marrow–derived mesenchymal stem cells in a murine model of systemic lupus erythematosus

“…Steroids and immunosuppressants are currently used to treat many patients with SLE (20). The efficacy of these agents lies in their ability to suppress inflammation and to block or partially reduce abnormal T cell and B cell activation (21). Therefore, targeting both the B lymphocytes and the T lymphocytes as well as their interaction could represent an alternative approach to the currently available pharmacologic methods.…”

B cell targeted therapy in autoimmunity

“…Long-term administration of CTLA4Ig as a fusion protein or expressed in adenovirus, to NZB/NZW F1 mice, prevented the onset of [9,10]. Gene therapy using this approach has also been shown to be beneficial in the MRL lpr/ lpr lupus mice [11]. Clinical studies with CTLA4Ig fusion protein showed improvement in rheumatoid arthritis activity when added to methotrexate therapy [12].…”