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This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: 296/3/F512    most recent 90629.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Kelly, F. M. Articles by Gooch, J. L. Search for Related Content PubMed PubMed Citation Articles by Kelly, F. M. Articles by Gooch, J. L.

TGF-β upregulation drives tertiary lymphoid organ formation and kidney dysfunction in calcineurin A- heterozygous mice

¹Department of Medicine/Division of Nephrology, ²Emory Transplant Center, ³Department of Digestive Diseases, Emory University School of Medicine, and ⁴Atlanta Veterans Administration Medical Center, Atlanta, Georgia

Submitted 23 October 2008 ; accepted in final form 5 January 2009

Calcineurin is an important intracellular signaling molecule which can be inhibited by cyclosporin resulting in immune suppression and nephrotoxicity. Previously, we reported that homozygous loss of the isoform of calcineurin impairs kidney development and function and mimics many features of cyclosporin nephrotoxicity. However, early lethality of null mice prevented further study of renal changes. Alternatively, we examined aged heterozygous (CnA^+/–) mice. In addition to renal dysfunction and inflammation, we find that CnA^+/– mice spontaneously develop tertiary lymphoid aggregates in the kidney, small intestine, liver, and lung. Lymphoid aggregates contain both T cells and B cells and exhibited organization suggestive of tertiary lymphoid organs (TLOs). Kidney function and TLO formation were highly correlated suggesting that this process may contribute to nephrotoxicity. Consistent with previous findings, transforming growth factor (TGF)-β is significantly increased in CnA^+/– mice. Neutralization of TGF-β attenuated TLO formation and improved kidney function. In conclusion, we report that haploinsufficiency of CnA causes uregulation of TGF-β which contributes to chronic inflammation and formation of TLOs. While the process that leads to TLOs formation in transplant allografts is unknown, TLOs are associated with poor clinical prognosis. This study suggests that calcineurin inhibition itself may lead to TLO formation and that TGF-β may be a novel therapeutic target.

calcineurin inhibition; nephrotoxicity; posttransplant lymphoproliferative disorder