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Lawlor K.E.,Reid Rheumatology Laboratory | Lawlor K.E.,University of Melbourne | Smith S.D.,Reid Rheumatology Laboratory | van Nieuwenhuijze A.,Reid Rheumatology Laboratory | And 5 more authors.
Journal of Leukocyte Biology

Therapeutic manipulation of cellular apoptosis holds great promise for malignant and potentially nonmalignant diseases. A relative resistance to apoptosis in RA synovium is associated with increased expression of prosurvival Bcl-2 family members. In this study, we demonstrate that treatment of DBA/1 mice, prior to the onset of CIA with ABT-737, a BH3 mimetic targeting Bcl-2, Bcl-w, and Bcl-x L, ameliorated disease development. In contrast, treatment of mice with ABT-737 in established CIA did not alter the course of disease. ABT-737 induced lymphopenia, however pathogenic lymphoid populations in CIA mice were less affected, as shown by relatively normal T and B cell responses to CII. Naïve lymphocytes were highly sensitive to apoptosis after culture with ABT-737, but synovial macrophages and neutrophils were not. Mcl-1 was detected in synovial monocyte/macrophages and neutrophils and strikingly, its expression, rather than Bcl-2 and Bclx L, increased in the affected paws and lymphoid organs of mice with CIA. These observations implicate Mcl-1, which is not targeted by ABT-737, in the survival of inflammatory cells in established CIA and suggest that antagonism of Mcl-1 may be more effective in diseases such as RA. © Society for Leukocyte Biology. Source

Lawlor K.E.,Reid Rheumatology Laboratory | Lawlor K.E.,University of Melbourne | Lawlor K.E.,Walter and Eliza Hall Institute of Medical Research | van Nieuwenhuijze A.,Reid Rheumatology Laboratory | And 12 more authors.
Journal of Leukocyte Biology

RA is a chronic autoimmune disease characterized by accumulation of inflammatory cells within synovial joints. RA is associated with a failure of apoptosis of infiltrating leukocytes, thought to be a result of overexpression of prosurvival Bcl-2 proteins. Overexpression of Bcl-2 in hematopoietic cells can result in spontaneous autoimmunity. We therefore hypothesized that increased Bcl-2 in the hematopoietic compartment would reduce apoptosis and thereby, exacerbate inflammatory arthritis. Paradoxically, we found that overexpression of Bcl-2 in mice (vav-bcl-2) markedly reduced pathology in antibody-dependent models of RA (CIA and K/BxN serum transfer arthritis). No such protection was observed in a model of CD4+ T cell-dependent, B cell-independent arthritis (mBSA/IL-1-induced arthritis). In CIA, vav-bcl-2 Tg mice had lower antibody production to CII, which might explain reduced disease. However, Bcl-2 overexpression also reduced passive K/BxN serum transfer arthritis. Overexpression of Bcl-2 caused a monocytosis, with preferential expansion of Ly6Clo monocytes and increased expression of the inhibitory receptor for IgG, FcγRIIb, on leukocytes. Skewing of the myeloid cell population, increases in FcγRIIb, and reduced arthritis were independent of the hypergammaglobulinemia found in vav-bcl-2 Tg mice. These data reveal selective effects of the Bcl-2-regulated apoptotic pathway on monocyte differentiation and the expression of FcRs critical for regulation of antibody/immune complex-mediated disease. © Society for Leukocyte Biology. Source

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