UBC Faculty Research and Publications

CD34 function in intracellular signaling and mucosal inflammatory disease development Gold, Matthew; Blanchet, Marie-Renee; Samayawardhena, Lionel A; Bennett, Jami; Maltby, Steven; Pallen, Catherine J; McNagny, Kelly M Nov 26, 2010

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POSTER PRESENTATION Open AccessCD34 function in intracellular signaling andmucosal inflammatory disease developmentMatthew Gold1*, Marie-Renee Blanchet1, Lionel A Samayawardhena2, Jami Bennett1, Steven Maltby1,Catherine J Pallen2, Kelly M McNagny1From AllerGen NCE Inc.’s Fifth Annual Research Conference: Innovation from Cell to SocietyQuébec City, QC, Canada. 7-9 February 2010Objective/purposeCD34 is a cell surface sialomucin that has been the sub-ject of extensive interest, largely based on its use as amarker for hematopoietic stem cells (HSCs) and vascu-lar endothelia. Despite the almost ubiquitous use ofCD34 as a HSC marker, little is known about its cellularfunction. Our lab was the first to show that CD34 isalso highly expressed on mature murine mast cells, andwe and other groups have found it to be expressed oneosinophils and dendritic cells. We found that mast cellsderived from Cd34-/- mice exhibit a marked increase incell-cell aggregation. Moreover, when Cd34-/- mice werechallenged in a mouse model of asthma, immune cellaccumulation in the lung was drastically reduced, whilethe number of immune cells in the lung at baseline wassimilar to that of their wild-type counterparts. We havesince found that deletion of the Cd34 gene in mice ren-ders these animals resistant to a wide range of othermucosal inflammatory diseases, including hypersensitiv-ity pneumonitis (HP), ulcerative colitis, salmonella infec-tion and intestinal tumor development. Our objectivesare to examine the specific role of CD34 in cellularfunction and to see whether or not CD34 is a viabletherapeutic target to treat mucosal inflammatorydiseases.MethodsBone marrow mast cells were derived from wild-typeand Cd34-/- mice after four week culture in media con-taining IL-3. Changes in migration, polarization, degra-nulation and cytokine production were measured afterc-kit and/or FceRI stimulation. For in vivo studies, wedeveloped transgenic mice that lack the mouse Cd34gene and instead express, in all the appropriate tissues,the human Cd34 gene. These mice were put through astandard Ovalbumin (OVA) induced asthma model. Air-way inflammation severity was assessed by analysis ofthe broncho-alveolar lavage (BAL) content, histologicalscoring of H&E stained lung sections and cytokine pro-duction of isolated lung inflammatory cells in responseto OVA.FindingsPreliminary experiments have suggested that CD34 playsan important role in c-kit signaling events and FceRIinduced degranulation. Initial testing of our hCd34tgmice has shown that expression of the human Cd34gene in CD34-deficient mice is sufficient to regain sus-ceptibility to both allergic asthma and HP in mouseCD34-deficient animals. These findings suggest thathuman CD34 serves a similar function to mouse CD34in both animal disease models.Deliverables and relevanceWe show that in mast cells, CD34 plays an importantrole in regulating cellular signaling through both the c-kit and FceRI pathways. In addition, we have demon-strated that expression of human CD34 serves a similarfunction to mouse CD34 in both asthma and HP, pro-viding a proof-of-concept to assess therapeutics target-ing human CD34 in hCd34tg mice as a humanizedmouse model to treat these diseases. Allergic asthmaaffects more than 10% of all North Americans and is amajor cause of hospitalization of children. Current ther-apeutics are largely ineffective for chronic asthma andthe most potent therapies can carry a number of sideeffects. CD34 could represent a new therapeutic target,and since we have shown that CD34 plays a role in the* Correspondence: mgold@brc.ubc.ca1The Biomedical Research Centre, University of British Columbia, Vancouver,B.C., CanadaFull list of author information is available at the end of the articleGold et al. Allergy, Asthma & Clinical Immunology 2010, 6(Suppl 3):P15http://www.aacijournal.com/content/6/S3/P15 ALLERGY, ASTHMA & CLINICAL IMMUNOLOGY© 2010 Gold et al; licensee BioMed Central Ltd.susceptibility to a wide range of mucosal inflammatorydiseases, it is likely that it could serve as a viable treat-ment for a number of diseases.Author details1The Biomedical Research Centre, University of British Columbia, Vancouver,B.C., Canada. 2The Child & Family Research Institute, University of BritishColumbia, Vancouver, B.C., Canada.Published: 26 November 2010doi:10.1186/1710-1492-6-S3-P15Cite this article as: Gold et al.: CD34 function in intracellular signalingand mucosal inflammatory disease development. Allergy, Asthma &Clinical Immunology 2010 6(Suppl 3):P15.Submit your next manuscript to BioMed Centraland take full advantage of: • Convenient online submission• Thorough peer review• No space constraints or color figure charges• Immediate publication on acceptance• Inclusion in PubMed, CAS, Scopus and Google Scholar• Research which is freely available for redistributionSubmit your manuscript at www.biomedcentral.com/submitGold et al. Allergy, Asthma & Clinical Immunology 2010, 6(Suppl 3):P15http://www.aacijournal.com/content/6/S3/P15Page 2 of 2

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