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Allo-Specific Memory B Cell Recall Responses Are Dependent on B Cell Autophagy.

J. Leventhal,1 M. Fribourg,2 J. Ni,1 P. Heeger.1

1Medicine, Icahn School of Medicine at Mount Sinai, NY, NY
2Neurology, Icahn School of Medicine at Mount Sinai, NY, NY.

Meeting: 2016 American Transplant Congress

Abstract number: 468

Keywords: Alloantibodies, Allorecognition, Rejection, Sensitization

Session Information

Session Name: Concurrent Session: B cells and Antibody-Mediated Rejection: Animal Models

Session Type: Concurrent Session

Date: Tuesday, June 14, 2016

Session Time: 4:30pm-6:00pm

 Presentation Time: 4:30pm-4:42pm

Location: Room 309

B cells, and in particular, memory B cells (Bmem) are sources of donor specific antibodies (DSA) that cause allograft injury. Understanding requirements for Bmem function/survival could guide novel developing therapies aimed at preventing/treating DSA-mediated allograft injury. Expanding upon published work in anti-viral immunity, we tested the hypothesis that autophagy is required for function/survival of donor-reactive Bmem. We observed 4-25 fold higher levels of autophagy genes (p<0.05) and more autophagosome+ cells (62.4% vs 35.1% p<0.05) in IgG+ vs IgG- B cells. To specifically analyze autophagy in memory B cells we sensitized mice expressing a tamoxifen inducible YFP reporter under the Activation-Induced Cytidine Deaminase (AID) promoter (AID-CreERT2; Rosa-YFP transgenic mice), and analyzed YFP+ B cells 5 mo later. Imaging flow analysis showed more autophagosomes in YFP+ Bmem vs YFP- B cells (p<0.05). Compared with WT B cells, B cells from conditional KO mice deficient in autophagy protein 7 (CD19-Cre ATG7KO) contained less activated autophagy protein LC3 and showed impaired processing of autophagy substrate p62, confirming that absent ATG7 impairs autophagy in the B cells. Primary alloantibody responses were similar in ATG7KO and control mice 2 weeks after immunization with BALB/c splenocytes and fell equally over time. To assess secondary Bmem dependent responses we then challenged sensitized animals 4-5 mo post-sensitization with heart transplant from BALB/c donors and 7 days later measured serum alloantibodies and quantified donor specific splenic B cells by ELISpot. Whereas DSA at all titers increased significantly (2.46 to 5.07 fold) in sensitized control animals, titers in ATG7KO mice were minimally increased (1.18 to 1.47 fold p<0.05 vs controls, n=6/group). Frequencies of donor reactive B cells were 4-fold lower in the ATG7KO vs control heart recipients (21 vs 86/2.5X106 splenocytes), supporting the hypothesis that B cell autophagy is required for Bmem survival/function. Similar results were observed in control animals treated with the pharmacological autophagy inhibitor 3-methyladenine vs vehicle (n=5/grp). Together the data show for the first time that alloreactive Bmem require autophagy for function/survival and demonstrate feasibility for therapeutically targeting autophagy to inhibit alloreactive B cells and thereby prevent/remove DSA.

CITATION INFORMATION: Leventhal J, Fribourg M, Ni J, Heeger P. Allo-Specific Memory B Cell Recall Responses Are Dependent on B Cell Autophagy. Am J Transplant. 2016;16 (suppl 3).

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To cite this abstract in AMA style:

Leventhal J, Fribourg M, Ni J, Heeger P. Allo-Specific Memory B Cell Recall Responses Are Dependent on B Cell Autophagy. [abstract]. Am J Transplant. 2016; 16 (suppl 3). https://atcmeetingabstracts.com/abstract/allo-specific-memory-b-cell-recall-responses-are-dependent-on-b-cell-autophagy/. Accessed June 3, 2025.

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