IFNα kinoid vaccine-induced neutralizing antibodies prevent clinical manifestations in a lupus flare murine model

Abstract

A major involvement of IFN␣ in the etiopathogenesis of systemic lupus erythematosus has been suggested by clinical observations, including the increase of serum levels of this cytokine in patients with active disease. Supporting this hypothesis, we have shown that expression of IFN␣ from a recombinant adenovirus (IFN␣ Adv) precipitates lupus manifestations in genetically susceptible New Zealand Black (NZB) ؋ New Zealand White (NZW)F 1 mice (NZB/W) but not in BALB/c mice. In the present investigation, we have prepared an IFN␣ immunogen, termed IFN␣ kinoid, which, appropriately adjuvanted, induces transient neutralizing antibodies (Abs) but no cellular immune response to the cytokine and without apparent side effects. Using this preparation, we also showed that, in kinoid-vaccinated NZB/W mice, lupus manifestations, including proteinuria, histological renal lesions, and death triggered by IFN␣ Adv challenge were delayed/prevented as long as an effective threshold of anti-IFN␣ inhibitory capacity was present in the serum.anti-IFN␣ immunization ͉ anti-SLE immune therapy ͉ systemic lupus erythematosous S ystemic lupus erythematosus (SLE) is a frequent and lifethreatening chronic autoimmune disease characterized by a break of tolerance to nuclear components and profound alterations of the immune system (1). Dysregulated activation of many cells of the immune system involving several cytokines has been studied extensively in both human and murine lupus. Recently, type I IFNs (IFN␣ and ␤) have gained considerable interest as candidates in the etiopathogenic process of lupus (2-4). Involvement of IFN␣ in SLE has initially been suggested by clinicians as early as 1979 based on the findings of (i) elevated levels of this cytokine in the serum of SLE patients (5-7); (ii) IFN␣ treatment of cancer or hepatitis C induced in some patients' autoantibodies (autoAbs), including anti-nucleus Abs and anti-native DNA, and more rarely SLE (Ͻ1%) (8, 9); (iii) gene expression characteristic of an IFN␣ signature in blood cells of SLE patients, revealed by microarray assays (10, 11); (iv) animal experiments in which type I IFN receptor deficiency significantly reduced the expression of the lupus hallmarks in lupus-prone mice (12). More recently, we (13) developed an SLE-like murine flare model in which IFN␣5 supplied by recombinant adenovirus-expressing IFN␣5 (IFN␣ Adv) drives the early expression of lupus manifestations, including autoAbs, glomerulonephritis, and death.SLE patients are currently treated with the antimalarial agents chloroquine and hydroxychloroquine, steroids, and/or immunosuppressive drugs (14). More recently, biological therapies targeting immune cells involved in lupus pathogenesis have been developed, such as CD20 monoclonal antibodies (mAbs) (rituximab) that inhibit B cell activation (15). Monoclonal Abs have also been produced to counteract pathogenic effects of cytokines in SLE. Given the key role of IFN␣ in the SLE pathogenesis (3), anti-BDCA2/4 mAbs blocking IFN␣ production by plasmacytoid dendritic cells were p...

IFN-α and CD46 stimulation are associated with active lupus and skew natural T regulatory cell differentiation to type 1 regulatory T (Tr1) cells

“…This provides a rationale for therapeutically targeting IFN-α to prevent lupus activity (13). As a proof of concept, we have demonstrated in an IFN-α-dependent lupus model (New Zealand Black × New Zealand White F1 mice), that Ab-induced IFN-α neutralization prevented occurrence of SLE symptoms and death (32). Finally, considering the context-dependent nTreg functional plasticity therapeutic trials based on adoptive nTregs or cytokines interfering with nTreg physiology, such as IL-2, should be carefully managed to avoid undesirable outcomes as those observed in a recent phase 3 trial in AIDS patients receiving IL-2 (33).…”

Amine-reactive OVA multimers for auto-vaccination against cytokines and other mediators: perspectives illustrated for GCP-2 inL. majorinfection

“…The proposed rationale underlying this reaction is that the self-reactive B cell, which has captured the complex or fusion protein, will present foreign peptides on its MHC class II membrane proteins and thus, attract help from T cells reactive with the nonself structure [5]. Examples of successful application of this approach include TNF-␣ [3], IL-1␣ and IL-1␤ [6], IL-5 [7], IL-9 [8], IL-12 [9], IL-17A [10], VEGF [11], and IFN-␣ [12].…”

Humoral markers of active Epstein–Barr virus infection associate with anti-extractable nuclear antigen autoantibodies and plasma galectin-3 binding protein in systemic lupus erythematosus

“…27 Promising therapies that target IFN-a are currently emerging. [44][45][46] Nevertheless, if EBV is the main trigger of an overactive type I IFN system in a subgroup of patients with SLE, highly specific treatments might be developed to control the disease more efficiently with fewer potential adverse effects. Previous case reports describe a temporal collision of primary/reactivated EBV infection with the development/exacerbation of SLE.…”