BACKGROUND: The BTB domain of B-cell lymphoma 6 (BCL6) protein was identified as a therapeutic target for B-cell lymphoma. This study compared the pharmacokinetics (PK) of the BCL6 BTB inhibitor (FX1) between mice and macaques, as well as evaluating its lymphoid suppressive effect in uninfected macaques with lymphoid hyperplasia. MATERIALS AND METHODS: Eight uninfected adult Indian rhesus macaques (Macaca mulatta) were used in the study, four animals carrying lymphoid tissue hyperplasia. Plasma FX1 levels were measured by HPLC-MS/MS. Lymph node biopsies were used for H&E and immunohistochemistry staining, as well as mononuclear cell isolation for flow cytometry analysis. RESULTS: Inhibition of the BCL6 BTB domain with FX1 led to a reduction in the frequency of GC, Tfh CD4+ , and Tfh precursor cells, as well as resolving lymphoid hyperplasia, in rhesus macaques. CONCLUSIONS: B-cell lymphoma 6 inhibition may represent a novel strategy to reduce hyperplastic lymphoid B-cell follicles and decrease Tfh cells.
BACKGROUND: The BTB domain of B-cell lymphoma 6 (BCL6) protein was identified as a therapeutic target for B-cell lymphoma. This study compared the pharmacokinetics (PK) of the BCL6BTB inhibitor (FX1) between mice and macaques, as well as evaluating its lymphoid suppressive effect in uninfected macaques with lymphoid hyperplasia. MATERIALS AND METHODS: Eight uninfected adult Indian rhesus macaques (Macaca mulatta) were used in the study, four animals carrying lymphoid tissue hyperplasia. Plasma FX1 levels were measured by HPLC-MS/MS. Lymph node biopsies were used for H&E and immunohistochemistry staining, as well as mononuclear cell isolation for flow cytometry analysis. RESULTS: Inhibition of the BCL6BTB domain with FX1 led to a reduction in the frequency of GC, Tfh CD4+ , and Tfh precursor cells, as well as resolving lymphoid hyperplasia, in rhesus macaques. CONCLUSIONS:B-cell lymphoma 6 inhibition may represent a novel strategy to reduce hyperplastic lymphoid B-cell follicles and decrease Tfh cells.
Authors: Courtney V Fletcher; Kathryn Staskus; Stephen W Wietgrefe; Meghan Rothenberger; Cavan Reilly; Jeffrey G Chipman; Greg J Beilman; Alexander Khoruts; Ann Thorkelson; Thomas E Schmidt; Jodi Anderson; Katherine Perkey; Mario Stevenson; Alan S Perelson; Daniel C Douek; Ashley T Haase; Timothy W Schacker Journal: Proc Natl Acad Sci U S A Date: 2014-01-27 Impact factor: 11.205
Authors: Mariano G Cardenas; Wenbo Yu; Wendy Beguelin; Matthew R Teater; Huimin Geng; Rebecca L Goldstein; Erin Oswald; Katerina Hatzi; Shao-Ning Yang; Joanna Cohen; Rita Shaknovich; Kenno Vanommeslaeghe; Huimin Cheng; Dongdong Liang; Hyo Je Cho; Joshua Abbott; Wayne Tam; Wei Du; John P Leonard; Olivier Elemento; Leandro Cerchietti; Tomasz Cierpicki; Fengtian Xue; Alexander D MacKerell; Ari M Melnick Journal: J Clin Invest Date: 2016-08-02 Impact factor: 14.808
Authors: Atsuhiko Hasegawa; Huining Liu; Binhua Ling; Juan T Borda; Xavier Alvarez; Chie Sugimoto; Heather Vinet-Oliphant; Woong-Ki Kim; Kenneth C Williams; Ruy M Ribeiro; Andrew A Lackner; Ronald S Veazey; Marcelo J Kuroda Journal: Blood Date: 2009-04-21 Impact factor: 22.113
Authors: Ramon Lorenzo-Redondo; Helen R Fryer; Trevor Bedford; Eun-Young Kim; John Archer; Sergei L Kosakovsky Pond; Yoon-Seok Chung; Sudhir Penugonda; Jeffrey Chipman; Courtney V Fletcher; Timothy W Schacker; Michael H Malim; Andrew Rambaut; Ashley T Haase; Angela R McLean; Steven M Wolinsky Journal: Nature Date: 2016-01-27 Impact factor: 49.962
Authors: Nicolas Huot; Steven E Bosinger; Mirko Paiardini; R Keith Reeves; Michaela Müller-Trutwin Journal: Front Immunol Date: 2018-04-19 Impact factor: 7.561
Authors: Yanhui Cai; Adi Narayana Reddy Poli; Surya Vadrevu; Kwasi Gyampoh; Colin Hart; Brian Ross; Matt Fair; Fengtian Xue; Joseph M Salvino; Luis J Montaner Journal: Eur J Immunol Date: 2021-09-16 Impact factor: 5.532
Authors: Rajkumar Venkatadri; Vikram Sabapathy; Murat Dogan; Saleh Mohammad; Scott E Harvey; Sean R Simpson; Jason M Grayson; Nan Yan; Fred W Perrino; Rahul Sharma Journal: Eur J Immunol Date: 2022-02-15 Impact factor: 6.688