Differential Suppressive Effects of Costimulatory Blockade (CD28/B7), Anti-IL6R, Bruton's Tyrosine Kinase and Janus Kinase Inhibition on De Novo vs. Recall Alloantibody Responses: Are Combined Drug Therapy Approaches Desirable?
Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, CA
Meeting: 2017 American Transplant Congress
Abstract number: C15
Keywords: Alloantibodies, B cells, Immunosuppression, Mice
Session Information
Session Name: Poster Session C: Antibody and B Cell
Session Type: Poster Session
Date: Monday, May 1, 2017
Session Time: 6:00pm-7:00pm
Presentation Time: 6:00pm-7:00pm
Location: Hall D1
Purpose: Preformed and de novo donor specific antibodies (DSA) contribute significantly to demise of allograft functions. There is no approved therapies for prevention or treatment of DSA+ patients. We investigate the effect and immunosuppressive mechanisms of CD28-costimulatory blockage (abatacept), IL-6 receptor signaling interruption (anti-IL6r), BTK inhibitor (ibrutinib)and JAK-3 inhibitor (tofacitinib) on DSA responses in a mouse model of allosensitization.
Methods: Mice were primarily sensitized with skin grafts from HLA.A2+ transgenic mice and recall responses elicited by repeat skin grafting. Kinetic of anti-HLA.A2 IgM and IgG productions were studied using a cytometric antibody binding assay. Splenic and bone marrow T-, B- and plasma cells analyzed in multiparameter FACS. B and plasma cells isolated from the bone marrows and the spleens were studied in IgG ELISpot assay.
Results: All the treatments significantly suppressed de novo DSA IgM levels when compared to controls (22.9+5 MFI), including abatacept (9.3+3 MFI, p<0.01), anti-IL6r (12.7+2.3MFI, p<0.01), ibrutinib (13.7+2.3MFI, p=0.004) and Tofacitinib (10.01±5.58 MFI, p<0.05). De novo DSA IgG suppression was also observed in all the treatments, with the strongest IgG suppression by abatacept (26.15+16.39 MFI, p=9.2E-9 vs. control 426+61 MFI), followed by mMR16-1 (99.41 +35.31 MFI, p=0.0006), ibrutinib (241+86 MFI, p=0.003) and tofacitinib (207.56±48.06, p<0.05). Recall DSA IgG responses were significantly suppressed by abatacept (88+46 MFI, p=0.033 vs. control 575+175 MFI), mMR16-1 (212.7+167.9, p=0.0195), and ibrutinib (258+116 MFI, p=0.03). Tofacitinib has no effect on recall DSA IgG levels (350+42 MFI, p>0.05). Combination of abetacept and anti-IL6r exhibit the most potent DSA IgG suppression (71+25 MFI, p=0.03 vs. control).Both abatacept and ibrutinib treated spleens exhibited a reduction of plasma cells (CD138+) in immunofluorescent microscopy.
Conclusion: Abetacept has significant suppressive effects on de novo and memory DSA responses compared to anti-IL-6R alone. BTK inhibitor reduced B-cells and plasma cells in the spleens. The combination of abetacept + anti-IL6R gave the most potent inhibition in de novo and memory responses, suggesting a possible synergistic effect that could have clinical applications.
CITATION INFORMATION: Kim I, Wu G, Chai N.-N, Klein A, Jordan S. Differential Suppressive Effects of Costimulatory Blockade (CD28/B7), Anti-IL6R, Bruton's Tyrosine Kinase and Janus Kinase Inhibition on De Novo vs. Recall Alloantibody Responses: Are Combined Drug Therapy Approaches Desirable? 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. Differential Suppressive Effects of Costimulatory Blockade (CD28/B7), Anti-IL6R, Bruton's Tyrosine Kinase and Janus Kinase Inhibition on De Novo vs. Recall Alloantibody Responses: Are Combined Drug Therapy Approaches Desirable? [abstract]. Am J Transplant. 2017; 17 (suppl 3). https://atcmeetingabstracts.com/abstract/differential-suppressive-effects-of-costimulatory-blockade-cd28b7-anti-il6r-brutons-tyrosine-kinase-and-janus-kinase-inhibition-on-de-novo-vs-recall-alloantibody-responses-are-combined-dr/. Accessed May 18, 2025.« Back to 2017 American Transplant Congress