TGF-[beta] upregulation drives tertiary lymphoid organ formation and kidney dysfunction in calcineurin A-[alpha] heterozygous mice

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 [alpha] 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[[alpha].sup.+/-]) mice. In addition to renal dysfunction and inflammation, we find that CnA[[alpha].sup.+/-] 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)-[beta] is significantly increased in CnA[[alpha].sup.+/-] mice. Neutralization of TGF-[beta] attenuated TLO formation and improved kidney function. In conclusion, we report that haploinsufficiency of CnA[alpha] causes uregulation of TGF-[beta] 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-[beta] may be a novel therapeutic target. calcineurin inhibition; nephrotoxicity; posttransplant lymphoproliferative disorder