Complete B Cell Deficiency Reduces Allograft Inflammation and Intragraft Macrophages a Rat Kidney Transplant Model

ABSTRACT Background Increasingly it is being appreciated that B cells have broad roles beyond the humoral response, and are able to contribute to and regulate inflammation. The specific role of B cells in the pathogenesis of early allograft inflammation remains unclear. Methods To address this question, we generated B cell deficient Lewis rats via CRISPR technology. In a full mismatch transplant model, kidneys from Brown Norway donors were transplanted into B cell deficient Lewis recipients (B-/-) or wild type Lewis recipients. T cell mediated rejection was attenuated with cyclosporine. Results Renal inflammation was reduced at 1 week after transplant (Banff scores for interstitial inflammation, microvascular inflammation, glomerulitis, and C4d) in allografts from B-/- recipients. The reduction in interstitial inflammation was predominantly due to a decline in graft infiltrating macrophages. Intragraft T cell numbers remained unchanged. In addition, B cell deficiency was associated with increased T regulatory cells and reduced splenic T follicular helper cells at baseline; and significantly increased intragraft and splenic IL-10 mRNA levels after transplant. In vitro, B-/- and wild type splenic T cells produced similar levels of IFN-γ in response to T cell specific activation. Conclusions B cell deficiency in this model produced an anti-inflammatory phenotype with a shift towards regulatory T cell populations, production of anti-inflammatory cytokines (IL-10), and a reduction in allograft inflammation. These findings define a role for B cells to influence the cell populations and mediators involved in the pathogenesis of early allograft inflammation. Corresponding author: Sarah E. Panzer, MD, Division of Nephrology, Department of Medicine, 1685 Highland Avenue, Madison, WI 53705, sepanzer@medicine.wisc.edu Authorship statement: Sarah E. Panzer: concept, study design, performance of research, data analysis, writing of paper Nancy A. Wilson: performance of research, data analysis, writing of paper Bret M. Verhoven: performance of research, data analysis, writing of paper Ding Xiang: performance of research, review of manuscript C. Dustin Rubinstein: performance of research, data analysis, writing of paper Robert R. Redfield: data analysis, review of manuscript Weixiong Zhong: performance of research, review of manuscript Shannon R. Reese: study design, performance of research, data analysis, writing of paper Disclosure: The authors declare no conflict of interest. Funding: This project was supported by the Clinical and Translational Science Award (CTSA) program, through the NIH National Center for Advancing Translational Sciences (NCATS), grant UL1TR000427, and the KL2 training Award (KL2TR000428). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.

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