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Articles by C Detre
Total Records ( 2 ) for C Detre
  G Liao , S Nayak , J. R Regueiro , S. B Berger , C Detre , X Romero , R de Waal Malefyt , T. A Chatila , R. W Herzog and C. Terhorst
 

Naturally occurring regulatory T cells (Treg) express high levels of glucocorticoid-induced tumour necrosis factor receptor (GITR). However, studies of the role of GITR in Treg biology has been complicated by the observation that upon activation effector CD4+ T (Teff) cells also express the receptor. Here, we dissect the contribution of GITR-induced signaling networks in the expansion and function of FoxP3+ Treg. We demonstrate that a high-affinity soluble Fc-GITR-L dimer, in conjugation with CD3, specifically enhances in vitro proliferation of Treg, which retain their phenotypic markers (CD25 and FoxP3) and their suppressor function, while minimally affecting Teff cells. Furthermore, Fc-GITR-L does not impair Teff susceptibility to suppression, as judged by cocultures employing GITR-deficient and GITR-sufficient CD4+ T-cell subsets. Notably, this expansion of Treg could also be seen in vivo, by injecting FoxP3-IRES-GFP mice with Fc-GITR-L even in the absence of antigenic stimulation. In order to test the efficacy of these findings therapeutically, we made use of a C3H/HeJ hemophilia B-prone mouse model. The use of liver-targeted human coagulation factor IX (hF.IX) gene therapy in this model has been shown to induce liver toxicity and the subsequent failure of hF.IX expression. Interestingly, injection of Fc-GITR-L into the hemophilia-prone mice that were undergoing liver-targeted hF.IX gene therapy increased the expression of F.IX and reduced the anticoagulation factors. We conclude that GITR engagement enhances Treg proliferation both in vitro and in vivo and that Fc-GITR-L may be a useful tool for in vivo tolerance induction.

  J. E Walter , F Rucci , L Patrizi , M Recher , S Regenass , T Paganini , M Keszei , I Pessach , P. A Lang , P. L Poliani , S Giliani , W Al Herz , M. J Cowan , J. M Puck , J Bleesing , T Niehues , C Schuetz , H Malech , S. S DeRavin , F Facchetti , A. R Gennery , E Andersson , N. R Kamani , J Sekiguchi , H. M Alenezi , J Chinen , G Dbaibo , G ElGhazali , A Fontana , S Pasic , C Detre , C Terhorst , F. W Alt and L. D. Notarangelo
 

The contribution of B cells to the pathology of Omenn syndrome and leaky severe combined immunodeficiency (SCID) has not been previously investigated. We have studied a mut/mut mouse model of leaky SCID with a homozygous Rag1 S723C mutation that impairs, but does not abrogate, V(D)J recombination activity. In spite of a severe block at the pro–B cell stage and profound B cell lymphopenia, significant serum levels of immunoglobulin (Ig) G, IgM, IgA, and IgE and a high proportion of Ig-secreting cells were detected in mut/mut mice. Antibody responses to trinitrophenyl (TNP)-Ficoll and production of high-affinity antibodies to TNP–keyhole limpet hemocyanin were severely impaired, even after adoptive transfer of wild-type CD4+ T cells. Mut/mut mice produced high amounts of low-affinity self-reactive antibodies and showed significant lymphocytic infiltrates in peripheral tissues. Autoantibody production was associated with impaired receptor editing and increased serum B cell–activating factor (BAFF) concentrations. Autoantibodies and elevated BAFF levels were also identified in patients with Omenn syndrome and leaky SCID as a result of hypomorphic RAG mutations. These data indicate that the stochastic generation of an autoreactive B cell repertoire, which is associated with defects in central and peripheral checkpoints of B cell tolerance, is an important, previously unrecognized, aspect of immunodeficiencies associated with hypomorphic RAG mutations.

 
 
 
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