C17 Prevents Inflammatory Arthritis and Associated Joint Destruction in Mice

C17 was first described about ten years ago as a gene expressed in CD34+ cells. A more recent study has suggested a role for C17 in chondrogenesis and development of cartilage. However, based on sequence analysis, we believe that C17 has homology to IL-2 and hence we present the hypothesis that C17 is a cytokine possessing immune-regulatory properties. We provide evidence that C17 is a secreted protein preferentially expressed in chondrocytes, hence in cartilage-rich tissues. Systemic expression of C17 in vivo reduces disease in a collagen antibody-induced arthritis model in mice (CAIA). Joint protection is evident by delayed disease onset, minimal edema, bone protection and absence of diverse histological features of disease. Expression of genes typically associated with acute joint inflammation and erosion of cartilage or bone is blunted in the presence of C17. Consistent with the observed reduction in bone erosion, we demonstrate reduced levels of RANKL in the paws and sera of mice over-expressing C17. Administration of C17 at the peak of disease, however, had no effect on disease progression, indicating that C17's immune-regulatory activity must be most prominent prior to or at the onset of severe joint inflammation. Based on this data we propose C17 as a cytokine that s contributes to immune homeostasis systemically or in a tissue-specific manner in the joint

Circulating and gut-resident human Th17 cells express CD161 and promote intestinal inflammation

The C-type lectin-like receptor CD161, which has recently been described to promote T cell expansion, is expressed on a discrete subset of human CD4 T cells. The function of such cells, however, has remained elusive. We now demonstrate that CD161+ CD4 T cells comprise a circulating and gut-resident T helper 17 (Th17) cell population. During Crohn's disease (CD), these CD161+ cells display an activated Th17 phenotype, as indicated by increased expression of interleukin (IL)-17, IL-22, and IL-23 receptor. CD161+ CD4 T cells from CD patients readily produce IL-17 and interferon γ upon stimulation with IL-23, whereas, in healthy subjects, priming by additional inflammatory stimuli such as IL-1β was required to enable IL-23–induced cytokine release. Circulating CD161+ Th17 cells are imprinted for gut homing, as indicated by high levels of CC chemokine receptor 6 and integrin β7 expression. Supporting their colitogenic phenotype, CD161+ Th17 cells were found in increased numbers in the inflammatory infiltrate of CD lesions and induced expression of inflammatory mediators by intestinal cells. Our data identify CD161+ CD4 T cells as a resting Th17 pool that can be activated by IL-23 and mediate destructive tissue inflammation

Effects of soluble guanylate cyclase stimulator on renal function in ZSF-1 model of diabetic nephropathy

Background Diabetic nephropathy is associated with endothelial dysfunction and oxidative stress, in which the nitric oxide-soluble guanylate cyclase-cyclic guanosine monophosphate (NO-sGC-cGMP) signaling pathway is impaired. We hypothesize that sGC stimulator Compound 1 can enhance NO signaling, reduce proteinuria in a diabetic nephropathy preclinical model with diminished NO bioavailability and increased oxidized sGC. Therefore, we evaluated the effect of sGC stimulator Compound 1 on the renal effect in obese ZSF1 (ZSF1 OB) rats. Materials and methods The sGC stimulator Compound 1, the standard of care agent Enalapril, and a combination of Compound 1 and Enalapril were administered chronically to obese ZSF1 rats for 6 months. Mean arterial pressure, heart rate, creatinine clearance for glomerular filtration rate (eGFR), urinary protein excretion to creatinine ratio (UPCR), and urinary albumin excretion ratio (UACR) were determined during the study. The histopathology of glomerular and interstitial lesions was assessed at the completion of the study. Results While both Compound 1 and Enalapril significantly reduced blood pressure, the combination of Compound 1 and Enalapril normalized blood pressure levels. Compound 1 improved eGFR and reduced UPCR and UACR. A combination of Enalapril and Compound 1 resulted in a marked reduction in UPCR and UACR and improved GFR. Conclusion The sGC stimulator Compound 1 as a monotherapy slowed renal disease progression, and a combination of the sGC stimulator with Enalapril provided greater renal protection in a rodent model of diabetic nephropathy. </jats:sec

Development of a Humanized 3D Tumor Spheroid Models and Discovery of Effective Immunotherapy Strategies Against Resistant Microsatellite Stable Colorectal Cancers

Abstract Despite the current success of immunotherapies, only microsatellite instable (MSI) Colorectal Cancer (CRC) typically respond to T cell-driven immunotherapies while microsatellite stable (MSS) CRC displays poor response. Our goal is to identify resistance mechanisms in MSS-CRC to uncover novel therapeutic targets. Current syngeneic CRC models are largely immunogenic and lack complex structure. Therefore, we developed novel 3D humanized CRC mouse models which form complex human-like tumors which are typically absent in syngeneic systems. We investigated molecular profiles of human MSI-versus MSS-CRC tumor xenografts following Keytruda immunotherapy and identified an immunosuppressive profile in MSS models that was not observed in MSI-CRC. We evaluated the therapeutic potential of blocking inflammation in combination with other immuno-modulatory therapies in both cold and hot CRC models and identified a significant regression of tumor burden in MSS-CRC mice. Our studies provide a novel CRC in vivo model and a unique opportunity to better define how immune cells interact in human MSS- and MSI-CRC microenvironments, to enable clinical therapeutic implementation.</jats:p

Antitumor efficacy of combined CTLA4/PD-1 blockade without intestinal inflammation is achieved by elimination of FcγR interactions

Background Programmed cell death protein 1 (PD-1) and CTLA4 combination blockade enhances clinical efficacy in melanoma compared with targeting either checkpoint alone; however, clinical response improvement is coupled with increased risk of developing immune-related adverse events (irAE). Delineating the mechanisms of checkpoint blockade-mediated irAE has been hampered by the lack of animal models that replicate these clinical events.Methods We have developed a mouse model of checkpoint blockade-mediated enterocolitis via prolonged administration of an Fc-competent anti-CTLA4 antibody.Results Sustained treatment with Fc-effector, but not Fc-mutant or Fc-null, anti-CTLA4 antagonist for 7 weeks resulted in enterocolitis. Moreover, combining Fc-null or Fc-mutant CTLA4 antagonists with PD-1 blockade results in potent antitumor combination efficacy indicating that Fc-effector function is not required for combination benefit.Conclusion These data suggest that using CTLA4 antagonists with no Fc-effector function can mitigate gut inflammation associated with anti-CTLA4 antibody therapy yet retain potent antitumor activity in combination with PD-1 blockade

Significantly enriched pathways.

(A) Top 15 significant pathways of both KEGG and IPA from Enalapril vs Vehicle. (B) Top 15 significant pathways of both KEGG and IPA from Enalapril and Compound 1 vs Vehicle. (C) Significant (P adj P adj P adj <0.05) from Enalapril and Compound 1 vs Vehicle and Compound 1 vs Vehicle.</p

Antitumor efficacy of combined CTLA4/PD-1 blockade without intestinal inflammation is achieved by elimination of FcγR interactions

BackgroundProgrammed cell death protein 1 (PD-1) and CTLA4 combination blockade enhances clinical efficacy in melanoma compared with targeting either checkpoint alone; however, clinical response improvement is coupled with increased risk of developing immune-related adverse events (irAE). Delineating the mechanisms of checkpoint blockade-mediated irAE has been hampered by the lack of animal models that replicate these clinical events.MethodsWe have developed a mouse model of checkpoint blockade-mediated enterocolitis via prolonged administration of an Fc-competent anti-CTLA4 antibody.ResultsSustained treatment with Fc-effector, but not Fc-mutant or Fc-null, anti-CTLA4 antagonist for 7 weeks resulted in enterocolitis. Moreover, combining Fc-null or Fc-mutant CTLA4 antagonists with PD-1 blockade results in potent antitumor combination efficacy indicating that Fc-effector function is not required for combination benefit.ConclusionThese data suggest that using CTLA4 antagonists with no Fc-effector function can mitigate gut inflammation associated with anti-CTLA4 antibody therapy yet retain potent antitumor activity in combination with PD-1 blockade.</jats:sec