Session Information
Session Type: Abstract Submissions (ACR)
Background/Purpose:
Apoptosis is both a conserved and highly regulated process that is essential for normal development and tissue homeostasis. This process, also known as programmed cell death, is tightly regulated by the BCL-2 family proteins. Dysregulation of these proteins has been linked to survival of autoreactive lymphocytes and to Systemic Lupus Erythematosus (SLE). Inhibition of BCL-2 proteins may therefore ameliorate autoimmunity.
This study evaluated the effects of inhibition of BCL-2 survival proteins in a murine model of lupus nephritis, as well as the effect on human leukocytes ex vivo.
Methods:
We have established previously that adenovirus vector-mediated delivery of murine IFN-α in lupus-prone (NZB × NZW)F1 mice induces a rapid and severe disease with many characteristics of SLE, including death due to severe glomerulonephritis. These mice were treated daily with vehicle or 3, 10, 30 mg/kg of navitoclax, a BH3 mimetic that binds with high affinity to BCL-2, BCL-XL, and BCL-W. Mycophenolate (100 mg/kg) was used as a clinical benchmark and positive treatment control. Proteinuria and survival data were presented as Kaplan-Meyer survival curves using Prism. For ex vivo human lymphocyte studies, B and T cells from healthy donors were cultured and treated with navitoclax overnight, prior to flow cytometric analysis. Some cultures were incubated with anti-CD40L/IgM or anti-CD3/CD28 to stimulate B or T cells, respectively. IC50 calculations were performed using GraphPad. Results were considered significant at the level of p < 0.05.
Results:
BCL-2 family inhibition by navitoclax in the IFNĄ-induced (NZB x NZW) F1 lupus model significantly reduced both the incidence of severe proteinuria (> 300mg/dL) and mortality as compared to vehicle controls (p < 0.05). In addition, chronic administration of navitoclax at 30 mg/kg demonstrated 95% survival rate and 50% of animals without proteinuria as compared to 80% and 20%, respectively, in mycophenolate-treated animals. Consistent with its mechanism of action, navitoclax caused a dose-dependent reduction in murine lymphocyte counts, which correlated with long-term efficacy. In ex vivo human cell cultures, navitoclax treatment led to a rapid reduction in the numbers of both stimulated and unstimulated human lymphocytes, with B cells showing a higher sensitivity to navitoclax compared to T cells.
Conclusion:
Treatment of lupus nephritis-prone mice with the BCL-2 family inhibitor navitoclax resulted in preservation of renal function and overall survival. Furthermore, BCL-2 inhibition in ex vivo human lymphocyte cultures led to a rapid and selective reduction of B and T cells via apoptosis. Taken together, these data support a role for BCL-2 inhibition in the treatment of autoimmune diseases such as SLE.
Disclosure:
L. C. Wang,
AbbVie,
3;
S. Perper,
AbbVie,
3;
D. Perron,
AbbVie,
3;
E. Tarcsa,
AbbVie,
3;
P. Bardwell,
AbbVie,
3;
N. Mozaffarian,
AbbVie,
9;
A. Souers,
AbbVie,
3,
AbbVie,
1;
S. Elmore,
AbbVie,
3;
T. Ghayur,
AbbVie,
3;
L. Olson,
AbbVie,
3.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/therapeutic-inhibition-of-anti-apoptotic-bcl-2-family-proteins-in-a-murine-model-of-lupus-nephritis/