Is there B cell involvement in a rat model of spontaneous idiopathic nephrotic syndrome treated with LF15-0195?

• Published in: Journal of nephrology Vol. 27; no. 3; pp. 265 - 273
• Main Authors: Le Berre, Ludmilla, Tilly, Gaëlle, Dantal, Jacques
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.06.2014; Italian Society of Nephrology/Springer
• Subjects: Adoptive Transfer; Animals; B-Lymphocytes - drug effects; B-Lymphocytes - immunology; B-Lymphocytes - metabolism; B-Lymphocytes - transplantation; Disease Models, Animal; Gene Expression Regulation; Guanidines - pharmacology; Human health and pathology; Kidney - drug effects; Kidney - immunology; Kidney - metabolism; Life Sciences; Medicine; Medicine & Public Health; Mitoxantrone - pharmacology; Nephrology; Nephrotic Syndrome - drug therapy; Nephrotic Syndrome - genetics; Nephrotic Syndrome - immunology; Nephrotic Syndrome - metabolism; Original Article; Phenotype; Proteinuria - drug therapy; Proteinuria - immunology; Rats; Rats, Inbred BUF; RNA, Messenger - metabolism; Time Factors; Urology; FSGS; Animal model; LF15-0195; Buffalo/Mna rats; Idiopathic nephrotic syndrome; Proteinuria
• ISSN: 1121-8428; 1724-6059
• DOI: 10.1007/s40620-014-0081-0

Background The Buffalo/Mna (Buff/Mna) rat spontaneously develops idiopathic nephrotic syndrome (INS), and its nephropathy recurs after the renal transplantation of a healthy graft. Only LF15-0195 is able to cause regression of the Buff/Mna nephropathy and to induce regulatory T cells, which decrease proteinuria when transferred into proteinuric Buff/Mna rats. Based on previous research on B cells in human INS, we evaluated the involvement of B cells in our model and the impact of LF15-0195. Methods We studied the effect of LF15-0195 on peripheral B cells by flow cytometry and quantitative reverse transcription-polymerase chain reaction. B cells were purified from LF15-0195-treated Buff/Mna rats in remission, and transferred into proteinuric Buff/Mna rats. We treated the Buff/Mna rats with mitoxantrone and measured the depletion of B/T cells in parallel with proteinuria. Results LF15-0195 changed the phenotype of B cells: the number of naïve mature B cells increased significantly, while the number of switched, transitional 1, and transitional 2 B cells decreased. There were no changes in the amount of memory, activated or regulatory B cells. We observed a significant increase of immunoglobulin (Ig)M mRNA transcripts in the LF15-0195-treated Buff/Mna B cells compared to controls, but no difference in the level of IgG. This profile is consistent with a block in B cell maturation at the IgM to IgG switch. The transfer of B cells from LF15-0195-treated rats into proteinuric Buff/Mna rats did not have an effect on proteinuria. Mitoxantrone, despite causing a significant depletion of B cells, did not reduce proteinuria. Conclusion Despite LF15-0195 acting on B cells, the beneficial effects of this drug on nephrotic syndrome did not involve the induction of regulatory B cells. Moreover, the B cell depletion was not effective in reducing proteinuria, indicating that B cells are not a therapeutic target.