AI-10 A mimetic peptide of suppressor of cytokine signalling-1 ameliorates lupus pathology in a spontaneous mouse model

Background Although aberrant antibody production is a lupus disease hallmark, abundant evidence implicates a dysregulated peripheral T lymphocyte repertoire in the onset and progression of lupus. Notably, the intracellular protein suppressor of cytokine signalling-1 (SOCS1) has been shown to regulate T lymphocyte effector functions and modulate lupus-like pathlogies in rodent models. Significantly, it has been previously shown that a peptide (SOCS1-KIR), capable of mimicking SOCS1, was effective in mitigating T lymphocyte effector functions associated with lupus disease progression. The peptide has been shown to function through the inhibition of the janus kinases Jak2 and Tyk2. We first test the hypothesis that administration of SOCS1-KIR would partially restore SOCS1 function in animals genetically deficient in SOCS1. We next test the hypothesis that SOCS1-KIR administration will have efficacy in modulating lupus disease pathologies in the MRL lpr/lpr spontaneous model of lupus, whose disease is mediated by a genetic defect in Fas mediated apoptosis of (auto)immune cells. We also assess peptide mediated changes in T lymphocyte effector functions. Materials and methods SOCS1 heterozygous mating pairs were obtained from St. Jude and used to generate SOCS1-/- mice. SOCS1-KIR (10 micrograms/gram) was administered daily at birth. 3–4 month old female MRL lpr/lpr mice were purchased from Jackson labs and received 10 micrograms/gram of peptide 3 x week. SOCS1-KIR mediated changes in the survival SOCS1-/- mice and onset of skin pathologies in MRL lpr/lpr mice were assessed by Kaplan Meier curves. SOCS1-KIR mediated changes in lymphadenopathy and splenomegaly were assessed by calliper readings and immune organ weighing at death. The capacity of SOCS1-KIR to modulate T lymphocyte effector functions was accomplished through flow cytometic analysis of peripheral blood and immune organ analysis both directly ex-vivo and subsequent to culture. Results SOCS1 deficient mice (SOCS1-/-) die of a systemic auto-inflammatory disease within 21 days after birth. The administration of SOCS1-KIR significantly prolonged the survival of SOCS1-/- mice. The enhanced survival of SOCS1-/- mice was correlated to enhanced peripheral Foxp3+ cells. The administration of SOCS1-KIR to MRL lpr/lpr mice significantly inhibited spontaneous skin lesion formation and lymphadenopathy. The amelioration of lupus pathology in MRL lpr/lpr mice was correlated to decreased frequencies of interferon gamma producing memory T lymphocytes and increased levels of PD1, which promotes apoptosis. Conclusions Together these results suggest that a peptide mimic of SOCS1 may have value as a therapeutic for lupus. Acknowledgements We thank Dr. Howard M. Johnson for a generous gift of SOCS1 and SOCS3 antibodies. We also thank Dr. Laurence Morel for critical review of this manuscript and Dr. Tenisha Wilson for technical support. The study was supported by a grant from the Lupus Research Institute, a BD Biosciences Research Grant, the NIH/NCATS Clinical and Translational Science Awards to the University of Florida TL1 TR000066 and UL1TR000064, a sub-award from NIH/NIAID/U01AI101990, and the University of Florida.