1404 A peptide mimetic of the kinase inhibitory region of suppressor of cytokine signaling-1 attenuates lymphocyte activation and lupus progression in MRL/Lpr lupus model

BackgroundLupus progression is driven by the aberrant activation of T and B lymphocytes which promote a dysregulated cytokine milieu and produce pathogenic antibodies. Many cytokines, including interferon gamma (IFN-γ), utilize the janus kinase/signal transduction and activation of transcription (JAK/STAT) pathway for signal propagation. Suppressor of Cytokine Signaling-1 (SOCS-1) is an inducible, intracellular protein which regulates the JAK/STAT pathway and IFNγ signaling. We have previously shown that a peptide mimicking the kinase inhibitory region of SOCS1 (SOCS1-KIR) inhibited IFN-γ signaling and inflammation-mediated disease progression.Using MRL/lpr mice, which spontaneously develop SLE-like disease, we test the hypothesis that SOCS1-KIR administration inhibits T and B lymphocyte activation leading to an amelioration in lupus pathology.MethodsFemale MRL/lpr mice received intraperitoneal injections of SOCS1-KIR peptide, or PBS carrier, 3 times per week and were monitored for lupus-like disease progression. Disease progression was based on the presence of skin lesions, lymphadenopathy, overall body score, and proteinuria. Peripheral blood, lymph nodes, and spleen was evaluated for peptide-mediated changes in lymphocyte populations by flow cytometry and qPCR. ELISA and western blot analysis were also employed to assess changes in lymphocyte activation. Finally, peptide mediated changes in renal pathology were analyzed.ResultsWe show that intraperitoneal administration of SOCS1-KIR reduced the frequency, activation, and cytokine production of memory CD8+ and CD4+ T lymphocytes within the peripheral blood, spleen, and lymph nodes of treated mice. In addition, administration of SOCS1-KIR mimetic peptide treatment reduced lymphadenopathy, delayed the development and severity of skin lesions, reduced autoantibody production, and lupus associated kidney destruction. On a cellular level, SOCS1-KIR administration enhanced Foxp3 expression in both total splenic Tregs and follicular Tregs (figure 1). In addition, SOCS1-KIR treatment reduced the frequency of GL7+ germinal center enriched B cells and CD80+ leukocytes, which may potentially activate T lymphocytes.Abstract 1404 Figure 1Graphical representation of the study design and resultsConclusionTogether, these data show that SOCS1-KIR treatment was effective in reducing auto-reactive lymphocyte effector functions and suggest that therapeutic targeting of the SOCS1 pathway through peptide administration may ha