Approaches to Prevention of Antibody Rebound after HLA Sensitization in a Mouse Model
Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, CA.
Meeting: 2018 American Transplant Congress
Abstract number: 161
Keywords: Alloantibodies, B cells, HLA antibodies, Immunosuppression
Session Information
Session Name: Concurrent Session: Novel Therapeutics
Session Type: Concurrent Session
Date: Sunday, June 3, 2018
Session Time: 4:30pm-6:00pm
Presentation Time: 4:54pm-5:06pm
Location: Room 602/603/604
Purpose: Control of donor specific antibodies (DSA) is critical for prevention of antibody mediated rejection (ABMR). Removal of DSAs with PLEX often results in significant rebound of DSAs with attendant ABMR. Here, we report a proof of concept study to use combined therapies to suppress DSA rebound by targeting multiple pathways in B-cells and plasma cells post-sensitization.
Methods: A mouse model of HLA.A2 sensitization/re-sensitization was utilized to investigate the effects of CD28 costimulatory blockade using CTLA4Ig (abatacept), IL-6 receptor signaling interruption by anti-IL6 receptor (mMR16-1), Bruton's tyrosine kinase (BTK) inhibition by ibrutinib, B cell deletion by anti-CD20 and JAK-3 inhibition by tofacitinib on de novo and recall DSA responses.
Results: All the individual treatments (including abatacept, mMR16-1, ibrutinib, anti-CD20 and tofacitinib) significantly suppressed de novo DSA IgM levels compared to controls (p<0.01, respectively), De novo DSA IgG suppression was also observed in all the treatment groups, with the strongest suppression by abatacept (26.15+16.39 MFI, p=9.2E-9 vs. control 426+61 MFI). In re-sensitized recipients, recall DSA IgG responses were suppressed by abatacept (p=0.033 vs. control), mMR16-1 (p=0.0195), anti-CD20 (p=0.015) and ibrutinib (p=0.03), but not by Tofacitinib (p>0.05). Looking at combined therapies, we found therapy with abatacept, mMR16-1, and anti-CD20 resulted in a strongest suppression (73.15+31.8MFI, p=0.012 vs. control 433.7+139.3MFI) in which DSA IgG was reduced to base line levels observed on sera at Day -1 (92.2+12.9MFI). DSA suppression was associated with reduction of CD138+ plasma cells in the spleens (2.5+0.22% vs. control,3.83+0.21%, p<0.01) demonstrated by multi-perimeter FACS .
Conclusion: Our data demonstrate that a maximal suppression can be achieved by combined therapies targeting multiple pathways critical to B/plasma cell activation and antibody production. This work could have relevance to desensitization strategies for human HLA incompatible organ transplantation.
CITATION INFORMATION: Kim I., Wu G., Chai N-.N., Klein A., Jordan S. Approaches to Prevention of Antibody Rebound after HLA Sensitization in a Mouse Model Am J Transplant. 2017;17 (suppl 3).
To cite this abstract in AMA style:
Kim I, Wu G, Chai N-N, Klein A, Jordan S. Approaches to Prevention of Antibody Rebound after HLA Sensitization in a Mouse Model [abstract]. https://atcmeetingabstracts.com/abstract/approaches-to-prevention-of-antibody-rebound-after-hla-sensitization-in-a-mouse-model/. Accessed May 9, 2025.« Back to 2018 American Transplant Congress