Evidence for functional inter-relationships between FOXP3, leukaemia inhibitory factor, and axotrophin/MARCH-7 in transplantation tolerance

作     者：Muthukumarana, Poorni A. D. S. Lyons, Gary E. Miura, Yuji Thompson, Lorraine H. Watson, Tracy Green, Colin J. Shurey, Sandra Hess, Allan D. Rosengard, Bruce R. Metcalfe, Su M. 

作者机构：Univ Cambridge Dept Surg Addenbrookes Hosp Cambridge CB2 2QQ England Univ Wisconsin Sch Med Dept Anat Madison WI 53706 USA Johns Hopkins Univ Sidney Kimmel Comprehens Canc Ctr Baltimore MD 21231 USA Northwick Pk Inst Med Res Surg Res Unit London HA1 3UJ England 

出 版 物：《INTERNATIONAL IMMUNOPHARMACOLOGY》 (国际免疫药理学)

年 卷 期：2006年第6卷第13-14期

页      面：1993-2001页

核心收录：

学科分类：1007[医学-药学(可授医学、理学学位)] 1001[医学-基础医学(可授医学、理学学位)] 10[医学] 

基　　金：NCI NIH HHS [CA15396] Funding Source: Medline NHLBI NIH HHS [P01 HL47053] Funding Source: Medline NICHD NIH HHS [R29 HD29471] Funding Source: Medline PHS HHS [5-RO1-A1-047257-03] Funding Source: Medline 

主　　题：Foxp3 LIF axotrophin in immune tolerance 

摘      要：In an ex vivo mouse model, regulatory transplantation tolerance is not only linked to Foxp3, but also to release of leukaemia inhibitory factor (LIF) and to expression of axotrophin (also known as MARCH-7), a putative ubiquitin E3 ligase associated with feedback control of T cell activation and of T cell-derived LIF. Given this coordinate correlation with tolerance, we now ask if Foxp3 expression is influenced by LIF or by axotrophin. In spleen cells from allo-rejected mice we found that exogenous LIF reduced interferon gamma release in response to donor antigen by 50%, but LIF had no direct effect on levels of Foxp3 protein in allo-primed cells that were either tolerant, or aggressive, for donor antigen. However, we did find an effect of axotrophin on Foxp3: in the axotrophin null mouse, thymic Foxp3 transcripts were reduced compared to axotrophin wildtype littermates. To test whether these findings in the mouse were of potential significance in man we measured transcript levels of axotrophin and LIE in peripheral blood cell samples collected for a recently published clinical study concerning haematopoietic stem cell recipients. In controls, human peripheral blood CD4+CD25+cells contained significantly more FOXP3 and axotrophin than CD4+CD25-cells. In bone marrow autograft recipients, where peripheral blood cell samples directly represent both the grafted tissue and the immune response, both FOXP3 and axotrophin negatively con-elated with graft versus host disease (GVHD). These data suggest that (i) thymic Foxp3+T cell development is influenced by axotrophin;and (ii) clinical auto-GVHD inversely correlates with axotrophin transcript expression as has been previously reported for FOXP3. (c) 2006 Elsevier B.V. All rights reserved.