Long‐term administration of IgG2a anti‐NK1.1 monoclonal antibody ameliorates lupus‐like disease in NZB/W mice in spite of an early worsening induced by an IgG2a‐dependent BAFF/BLyS production

Abstract

Summary The role of natural killer (NK) T cells in the development of lupus‐like disease in mice is still controversial. We treated NZB/W mice with anti‐NK1.1 monoclonal antibodies (mAbs) and our results revealed that administration of either an irrelevant immunoglobulin G2a (IgG2a) mAb or an IgG2a anti‐NK1.1 mAb increased the production of anti‐dsDNA antibodies in young NZB/W mice. However, the continuous administration of an anti‐NK1.1 mAb protected aged NZB/W mice from glomerular injury, leading to prolonged survival and stabilization of the proteinuria. Conversely, the administration of the control IgG2a mAb led to an aggravation of the lupus‐like disease. Augmented titres of anti‐dsDNA in NZB/W mice, upon IgG2a administration, correlated with the production of BAFF/BLyS by dendritic, B and T cells. Treatment with an anti‐NK1.1 mAb reduced the levels of interleukin‐16, produced by T cells, in spleen cell culture supernatants from aged NZB/W. Adoptive transfer of NK T cells from aged to young NZB/W accelerated the production of anti‐dsDNA in recipient NZB/W mice, suggesting that NK T cells from aged NZB/W are endowed with a B‐cell helper activity. In vitro studies, using purified NK T cells from aged NZB/W, showed that these cells provided helper B‐cell activity for the production of anti‐dsDNA. We concluded that NK T cells are involved in the progression of lupus‐like disease in mature NZB/W mice and that immunoglobulin of the IgG2a isotype has an enhancing effect on antibody synthesis due to the induction of BAFF/BLyS, and therefore have a deleterious effect in the NZB/W mouse physiology.

Recent findings on the role of natural killer cells in the pathogenesis of systemic lupus erythematosus

“…NK cells from liver and lungs of diseased MRL/MpJ lpr mice have enhanced natural cytotoxicity compared with healthy controls [79,80]. Long-term NK cell depletion delays glomerulonephritis onset in NZBxNZW(F1) mice [81], which suggests a local role for these cells. NK cells from diseased MRL/MpJ lpr were also phenotypically more active than those from healthy mice, with increased CD69 expression, granzyme B and perforin production, and IFNg secretion [42].…”

Invariant natural killer T cells in rheumatic disease: a joint dilemma

“…92,93 The development of lupus in NZB x NZw F1 mice was associated with expansion and activation of iNKT cells, and transfer of iNKT cells from diseased mice to healthy recipients induced signs of lupus nephritis. 94 Thus, depending on the disease model, an environment can be created that favors the immune-potentiating rather than suppressive function of iNKT cells. This potentiation might involve IFN-γ secretion and promotion of pathogenic IgG2a anti-DNA antibodies.…”

Administration of a nondepleting anti-CD25 monoclonal antibody reduces disease severity in mice infected withTrypanosoma cruzi

“…Staining was done as previously described [23]. The fl uorochrome-conjugated monoclonal antibodies used were anti-CD4, anti-CD8, anti-CD44, anti-CD62L, anti-CD25 (clone PC61), anti-foxp3, anti-IL2, anti-IL10, anti-IFN-γ, and anti-TNF-α, and were purchased from eBioscience or CALTAG.…”

“…Biotin-conjugated antibodies were revealed by streptavidin-PE-Cy5.5 from CALTAG. Intracellular staining for IL-2, IL-10, IFN-γ, and TNF-α were performed as described previously [23]. After surface staining, the cells were fi xed with 1% para-formaldehyde in PBS and analyzed using a FACScan (Becton and Dickinson).…”