Neutralization of (NK-cell-derived) B-cell activating factor by Belimumab restores sensitivity of chronic lymphoid leukemia cells to direct and Rituximab-induced NK lysis.

Natural killer (NK) cells are cytotoxic lymphocytes that substantially contribute to the therapeutic benefit of antitumor antibodies like Rituximab, a crucial component in the treatment of B-cell malignancies. In chronic lymphocytic leukemia (CLL), the ability of NK cells to lyse the malignant cells and to mediate antibody-dependent cellular cytotoxicity upon Fc receptor stimulation is compromised, but the underlying mechanisms are largely unclear. We report here that NK-cells activation-dependently produce the tumor necrosis factor family member 'B-cell activating factor' (BAFF) in soluble form with no detectable surface expression, also in response to Fc receptor triggering by therapeutic CD20-antibodies. BAFF in turn enhanced the metabolic activity of primary CLL cells and impaired direct and Rituximab-induced lysis of CLL cells without affecting NK reactivity per se. The neutralizing BAFF antibody Belimumab, which is approved for treatment of systemic lupus erythematosus, prevented the effects of BAFF on the metabolism of CLL cells and restored their susceptibility to direct and Rituximab-induced NK-cell killing in allogeneic and autologous experimental systems. Our findings unravel the involvement of BAFF in the resistance of CLL cells to NK-cell antitumor immunity and Rituximab treatment and point to a benefit of combinatory approaches employing BAFF-neutralizing drugs in B-cell malignancies

T-cells and B-cells in systemic sclerosis

Systemic sclerosis (SSc) is characterized by activation of fibroblasts with extensive deposition of collagen, by small vessel vasculopathy with fibrointimal proliferation, and activation of the immune system, with hyper-γ- globulinaemia and autoantibodies. Twin studies have shown that genetic factors play a minor role in SSc development. Serum autoantibodies and skin lymphocytic infiltrates and small vessel damage occur very early before the appearance of skin fibrosis. T cells can cause fibrosis and vasculopathy through cell-cell contact and cytokines. They produce TH2 cytokines (IL-4, IL13) and TH17 cytokines (IL-17), which are profibrotic. TH2 cells in experimental models also induce pulmonary arterial hypertension. Genetically engineered TGFβ expression in pig arteries causes fibrointimal proliferation. T cells in skin lesions exhibit oligoclonality that persists over time, which indicates an antigen-driven T cell activation, but the antigen(s) responsible are not known. There are known environmental factors that can elicit an immune response and cause a SSc-like disease. T cells also provide help for B cells. B cells can contribute to fibrosis and vasculopathy through cytokines and autoantibodies. Autoantibodies can activate endothelial cells and fibroblasts to a profibrotic phenotype. Finally, treatments directed against T cells and B cells show promising effects in SSc. © 2010 Bentham Science Publishers Ltd

Systemic sclerosis: From pathogenesis towards targeted immunotherapies

Systemic sclerosis (SSc), a chronic disease with widespread collagen deposition, has three pathogenetic facets: immune activation, microvasculopathy and fibroblast activation. Immune activation and microvasculopathy occur very early in the disease process, and inflammatory infiltrates in the skin are restricted in early-phase disease. There is good evidence that fibroblast activation with collagen production may be triggered by the immune system. In early-phase disease, we slowly move from general immunosuppression to therapeutically targeting specific molecules involved in immune activation, such as T cell-directed targets, B cell-directed targets, cytokine targets, and tyrosine kinases targets. © 2012 Bentham Science Publishers