Therapeutic strategies for SLE involving cytokines: mechanism-oriented therapies especially IFN-gamma targeting gene therapy

Abstract

Systemic lupus erythematosus (SLE: lupus) is a chronic complicated autoimmune disease and pathogenesis is still unclear. However, key cytokines have been recognized. Interferon (IFN)-γ and also IFNalpha/beta are of particular importance. Depending on the concept that lupus is a helper T(Th)1 disease and that dendritic cells (DCs) determine the direction of lupus, balance shift of Th1/Th2 and immunogenic/tolerogenic DCs is reviewed for therapy. (IFN)-gamma- and IFN-alpha/beta-targeted (gene) therapies are introduced. These consist of Th1/Th2 balance shift and elimination of IFN-gamma and IFN-gamma-related cytokines such as (interleukin)IL-12 and IL-18. Other approaches include suppression of immunocompetent cells, normalization of abnormal T-cell function, costimulation blockade, B lymphocyte stimulator (Blys) blockade, and suppression of nephritic kidney inflammation. Moreover, balance shift of IFN-alpha/beta and tumor necrosis factor (TNF)-alpha together with regulatory T(Treg) cells are briefly introduced. Clinical application will be discussed.

Figure 1

Class-switcing of immunoglobulin. Cognate contact of T-B interaction and following stimulation of cytokines determine Ig subclass switching in mouse.

Figure 2

Notion of IFN-α/β and TNF-α axis balance proposed by Banchereau and Pascual [26]. Environmental factors (e.g., viral infections), apoptotic bodies and immune complexes stimulate pDCs through the coengagement of FcγR and TLRs trigger the production of IFN-α/β from pDCs and following production of TNF-α occurs. Also IFN-α/β induces the generation of mature DCs. Banchereau and Pascud hypothesize that increased production of TNF-α may weaken IFN-α/β production, leading to prevention of lupus. Also tolerogenic peptide activates Treg cells leading to production of TGF-β may inhibit DCs activity, resulting in the suppression of lupus development [27]. These events suppress the lupus development, whereas immunogenic DCs suppress function of Treg cells. Thus Horwitz [22] proposed T reg regulation together with tolerogenic DCs for therapy. Important cytokines are shown in bold arrows letters.

Figure 3

Female B/WF₁ mice constitute one of the best-studied animal models of spontaneous systemic lupus erythematosus (SLE) in human. Their characteristic features include polyclonal B-cell activation, production of autoantibodies against autoantigens (e.g., notably dsDNA), which occur when the animals are 5-6 months of age, and development of glomerulonephritis with age which is the major cause of death due to renal failure. Moreover, animals respond to cortisone similar to human patients with SLE [51]. H-2: mouse MHC. ANA: antinuclear antibody.

Figure 4

Survival rate among three groups. Mice were treated intraperitoneally either with 100 μg of the IL-4pDNA, 100 μg of plasmid only or saline only at the age of 4, 6, 8, 12, 16, 20, 24, 28 and 32 weeks. *P < .001 (comparison between the IL-4pDNA group and two controls). Provided here is courtesy of NDT 2007, 22, 3131-8: Oxford University Press).

Figure 5

Cytokine targeted therapy will be expected to clinical application, but more detailed examination of side effects (e.g., development of infections, cancer, allergic diseases, and autoimmunity) is required. Clinical application to lupus must be based on their safety profile, adverse effects, risks, and advantages. Likewise, in this analysis we offer specific recommendations, based on evidence, for the best, is Th1/TH2 balance shift in vivo by using IL-4 gene therapy.