ACR Meeting Abstracts

ACR Meeting Abstracts

  • Meetings
    • ACR Convergence 2024
    • ACR Convergence 2023
    • 2023 ACR/ARP PRSYM
    • ACR Convergence 2022
    • ACR Convergence 2021
    • ACR Convergence 2020
    • 2020 ACR/ARP PRSYM
    • 2019 ACR/ARP Annual Meeting
    • 2018-2009 Meetings
    • Download Abstracts
  • Keyword Index
  • Advanced Search
  • Your Favorites
    • Favorites
    • Login
    • View and print all favorites
    • Clear all your favorites
  • ACR Meetings

Abstract Number: 2678

Novel Nuclear Export Inhibitors Deplete Autoreactive Plasma Cells and Protect Mice with Lupus-Like Disease From Nephritis

Teresa Owen1, Wensheng Wang1, Dilara McCauley2, Laura Strojny1, Jennifer Hossler1, Javier Rangel-Moreno3, Michael Kauffman2, Sharon Shacham4 and Jennifer H. Anolik5, 1Medicine- Allergy, Immunology, and Rheumatology, University of Rochester Medical Center, Rochester, NY, 2Karyopharm, Therapeutics Inc., Natick, MA, 3Medicine- Allergy, Immunology, and Rheumatology, University of Rochester, Rochester, NY, 4Karyopharm Therapeutics Inc., Natick, MA, 5Medicine- Allergy, Immunology and Rheumatology, University of Rochester Medical Center, Rochester, NY

Meeting: 2012 ACR/ARHP Annual Meeting

Keywords: Nephritis, plasma cells, proteinuria and systemic lupus erythematosus (SLE)

  • Tweet
  • Click to email a link to a friend (Opens in new window) Email
  • Click to print (Opens in new window) Print
Session Information

Title: Systemic Lupus Erythematosus - Animal Models

Session Type: Abstract Submissions (ACR)

Background/Purpose:  Most therapies currently used to treat systemic lupus erythematosus (SLE) and B cell targeted therapies under development do not effectively target plasma cells and autoantibodies.  We postulated that selective inhibition of nuclear export (SINE) with novel small molecule CRM1 antagonists, which have demonstrated potent activity for hematologic malignancies, may be useful in the treatment of SLE by targeting plasma cells and other immune cells critical to disease pathogenesis.

Methods: Nephritic NZB/W F1 lupus-prone female mice, with elevated serum anti-dsDNA antibodies and established proteinuria, were treated with the SINE KPT-251 (injections 5/7 days for 5 weeks) (initially 75 mg/kg x 3 weeks and then 50 mg/kg for 2 additional weeks) or vehicle control subcutaneously (n=10 per group).  Spleen and bone marrow (BM) lymphocytes were harvested, stained with antibodies, and analyzed by flow cytometry. Plasma cells (PC) were identified with antibodies against intracellular kappa light chain. We monitored nephritis severity by measuring proteinuria (Uristix) and analyzing pathological changes in kidney histology.  Serum auto-antibody levels (anti-dsDNA) were measured by ELISA. ELISpot was used to enumerate IgG- and dsDNA antibody secreting cells (ASC). 

Results:  KPT-251 SINE treatment of NZB/W F1 mice prevented nephritis progression with a statistically significant reduction in urine protein levels in the treated group (p<0.05 beginning at 3 weeks) and notably reduced the number of mice with significant proteinuria (77% of treated mice had low urine protein concentrations <100 mg/dL compared to only 10% of controls at 5 weeks) (p=0.003). Importantly, serum anti-dsDNA IgG levels were significantly reduced after KPT-251 treatment (>6-fold reduction, p=0.0017) with profound effects on antibody secreting plasma cells. We found a significant reduction in splenic plasmablasts (2.18-fold reduction, p=0.001), BM PCs (2-fold reduction, p=0.02) and plasmablasts (MHCII high) (2.24-fold reduction, p=0.003).  Moreover, ASC numbers were notably decreased with nuclear transport inhibition.  Total IgG and anti-dsDNA IgG ASC numbers in the spleen were drastically reduced after treatment  (70% reduction, p=0.002).  In bone marrow, there was a pronounced decline in IgG ASC numbers (81%), with a more dramatic effect on anti-dsDNA IgG ASCs (96% reduction, p=0.002). 

Conclusion: These results suggest that nuclear transport inhibition preferentially affects auto-reactive PC and prevents SLE-associated nephritis. Therefore, these data support the further development of SINE drugs as a novel therapeutic approach for SLE.


Disclosure:

T. Owen,
None;

W. Wang,
None;

D. McCauley,

Karyopharm Therapeutics Inc.,

3;

L. Strojny,
None;

J. Hossler,
None;

J. Rangel-Moreno,
None;

M. Kauffman,

Karyopharm Therapeutics Inc.,

3;

S. Shacham,

Karyopharm Therapeutics Inc.,

3;

J. H. Anolik,

Karyopharm,

2.

  • Tweet
  • Click to email a link to a friend (Opens in new window) Email
  • Click to print (Opens in new window) Print

« Back to 2012 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/novel-nuclear-export-inhibitors-deplete-autoreactive-plasma-cells-and-protect-mice-with-lupus-like-disease-from-nephritis/

Advanced Search

Your Favorites

You can save and print a list of your favorite abstracts during your browser session by clicking the “Favorite” button at the bottom of any abstract. View your favorites »

All abstracts accepted to ACR Convergence are under media embargo once the ACR has notified presenters of their abstract’s acceptance. They may be presented at other meetings or published as manuscripts after this time but should not be discussed in non-scholarly venues or outlets. The following embargo policies are strictly enforced by the ACR.

Accepted abstracts are made available to the public online in advance of the meeting and are published in a special online supplement of our scientific journal, Arthritis & Rheumatology. Information contained in those abstracts may not be released until the abstracts appear online. In an exception to the media embargo, academic institutions, private organizations, and companies with products whose value may be influenced by information contained in an abstract may issue a press release to coincide with the availability of an ACR abstract on the ACR website. However, the ACR continues to require that information that goes beyond that contained in the abstract (e.g., discussion of the abstract done as part of editorial news coverage) is under media embargo until 10:00 AM ET on November 14, 2024. Journalists with access to embargoed information cannot release articles or editorial news coverage before this time. Editorial news coverage is considered original articles/videos developed by employed journalists to report facts, commentary, and subject matter expert quotes in a narrative form using a variety of sources (e.g., research, announcements, press releases, events, etc.).

Violation of this policy may result in the abstract being withdrawn from the meeting and other measures deemed appropriate. Authors are responsible for notifying colleagues, institutions, communications firms, and all other stakeholders related to the development or promotion of the abstract about this policy. If you have questions about the ACR abstract embargo policy, please contact ACR abstracts staff at [email protected].

Wiley

  • Online Journal
  • Privacy Policy
  • Permissions Policies
  • Cookie Preferences

© Copyright 2025 American College of Rheumatology