Graft dysfunction in chronic antibody-mediated rejection correlates with B-cell-dependent indirect antidonor alloresponses and autocrine regulation of interferon-γ production by Th1 cells

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• 作者：Kin Yee Shiu¹ ; ³ ; Laura McLaughlin¹ ; Irene Rebollo-Mesa¹ ; ⁴ ; Jingyue Zhao¹ ; Hannah Burton¹ ; Harriet Douthwaite¹ ; Hannah Wilkinson¹ ; Vikki Semik¹ ; Philippa C. Dodd¹ ; Paul Brookes² ; Robert I. Lechler¹ ; Maria P. Hernandez-Fuentes¹ ; Claudia Kemper¹ ; Anthony Dorling¹ ; ^{anthony.dorling@kcl.ac.uk}
• 关键词：B lymphocyte ; chronic allograft nephropathy ; ELISPOT ; indirect alloresponses ; interferon-γ
• 刊名：Kidney International
• 出版年：2017
• 出版时间：February 2017
• 年：2017
• 卷：91
• 期：2
• 页码：477-492
• 全文大小：1276 K
• 卷排序：91

文摘

Chronic antibody-mediated rejection, a common cause of renal transplant failure, has a variable clinical phenotype. Understanding why some with chronic antibody-mediated rejection progress slowly may help develop more effective therapies. B lymphocytes act as antigen-presenting cells for in vitro indirect antidonor interferon-γ production in chronic antibody-mediated rejection, but many patients retain the ability to regulate these responses. Here we test whether particular patterns of T and B cell antidonor response associate with the variability of graft dysfunction in chronic antibody-mediated rejection. Our results confirm that dynamic changes in indirect antidonor CD4+ T-cell responses correlate with changes in estimated glomerular filtration rates, independent of other factors. Graft dysfunction progressed rapidly in patients who developed unregulated B-cell–driven interferon-γ production. However, conversion to a regulated or nonreactive pattern, which could be achieved by optimization of immunosuppression, associated with stabilization of graft function. Functional regulation by B cells appeared to activate an interleukin-10 autocrine pathway in CD4+ T cells that, in turn, impacted on antigen-specific responses. Thus, our data significantly enhance the understanding of graft dysfunction associated with chronic antibody-mediated rejection and provide the foundation for strategies to prolong renal allograft survival, based on regulation of interferon-γ production.