title: Local administration of soluble CD40:Fc to the salivary glands of non-obese diabetic mice does not ameliorate autoimmune inflammation.
abstract: OBJECTIVE
  CD40-CD154 (CD40 ligand) interaction in the co-stimulatory pathway is involved in many (auto)immune processes and both molecules are upregulated in salivary glands of Sjögren's syndrome (SS) patients. Interference within the CD40 pathway has ameliorated (auto)inflammation in a number of disease models. To test the potential role of the CD40 pathway in loss of gland function and inflammation in SS, an inhibitor of CD40-CD154 interaction was overexpressed in the salivary glands (SGs) of a spontaneous murine model of SS; the Non-Obese Diabetic (NOD) mouse.
  
  
  METHODS
  At different disease stages an adeno associated viral vector encoding CD40 coupled to a human Fc domain (CD40:Fc) was injected locally into the SGs of NOD mice. Delivery was confirmed by PCR. The overall effect on local inflammation was determined by assessment of the focus score (FS), quantification of infiltrating cell types, immunoglobulin levels, and microarray analysis. The effect on SG function was determined by measuring stimulated salivary flow.
  
  
  RESULTS
  CD40:Fc was stably expressed in the SG of NOD mice, and the protein was secreted into the blood stream. Microarray analysis revealed that expression of CD40:Fc affected the expression of many genes involved in regulation of the immune response. However, FS, infiltrating cell types, immunoglobulin levels, and salivary gland output were similar for treated and control mice.
  
  
  CONCLUSIONS
  Although endogenous CD40 is expressed in SG inflammatory foci in the SG of NOD mice, the expression of soluble CD40:Fc did not lead to reduced overall inflammation and/or improved salivary gland function. These data indicate possible redundancy of the CD40 pathway in the SG and suggests that targeting CD40 alone may not be sufficient to alter the disease phenotype.
authors.affiliation: Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Nienke
authors.initials: N
authors.lastname: Roescher
authors.forename: Jelle L
authors.initials: JL
authors.lastname: Vosters
authors.forename: Zhenan
authors.initials: Z
authors.lastname: Lai
authors.forename: Toshimitsu
authors.initials: T
authors.lastname: Uede
authors.forename: Paul P
authors.initials: PP
authors.lastname: Tak
authors.forename: John A
authors.initials: JA
authors.lastname: Chiorini
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D023201:CD40 Ligand / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000235:genetics; D007249:Inflammation / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D016688:Mice, Inbred NOD; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D011961:Receptors, Fc / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012469:Salivary Glands / Q000276:immunology / Q000378:metabolism*; D012859:Sjogren's Syndrome / Q000209:etiology / Q000378:metabolism / Q000473:pathology*
chemical_list: D015415:Biomarkers; D016207:Cytokines; D012333:RNA, Messenger; D011961:Receptors, Fc; D023201:CD40 Ligand