Annual Report of Activities CNC 2008 - Center for Neuroscience and ...

Cellular Immunology and Oncobiology | Head: Maria Celeste LopesObjectivesThe researchers of the cellular immunology andoncobiology group share common interests inidentifying the cellular mechanisms that regulate thefunction of normal human cells and inunderstanding how disruption of these processesleads to disease, namely to allergic contactdermatitis, osteoarthritis, autoimmunity and cancer.One of the strengths of this group is the variety ofapproaches, ranging from in vitro studies inhuman primary cell cultures and established celllines, to in vivo experiments with animal modelsand analysis of clinical samples made in closecollaboration with hospital clinical units, namelywith the: i) Dermatology Department of theUniversity Hospital of Coimbra (HUC); ii)Orthopaedic and Bone Bank Departments of HUC;iii) Clinical Hematology Department of HUC; iv)Portuguese Oncology Institute of Coimbra; v)Neuropathology Laboratory and NeurosurgeryService of HUC and vi) Center for Cancer Researchof the Salamanca University, Spain.Research on cellular immunology focused in:i) how different maturation stimuli, namely contactsensitizers, irritants, an endotoxin and the parasiteLeismania infantum, modulate the expression ofdendritic cell (DC) surface molecules (chemokine andcytokine receptors), cytokine production and transcriptionfactors activation; ii) identifying defective processesinvolved in chondrocyte susceptibility to highglucose‐induced cell damage, thus contributing tothe development and/or progression of OA; iii) therole of the CD38 on the regulation of immuneresponses, namely infection and autoimmunity.Research on oncobiology focused in:i) molecular changes relevant to the thyroid, breastand cervical carcinogenesis; ii) the involvement ofoxidative stress and cell signalling in haematologicalneoplasias and chemoresistance and its implicationson the therapeutic approach; iii) chromosomal andgenetic abnormalities of human gliomas and cellsignalling pathways involved in tumour progressionand migration.Main AchievementsCellular Immunology:Effects of maturation stimuli on dendritic cell (DC)protein expression: LPS increases the expression of costimulatoryproteins and cytokines/chemokines inDC. Th2 cytokine production induced by LPS isdependent on NF‐kB and ERK activation, beingnegatively modulated by p38 MAPK. The contact ofvirulent L. infantum parasites with DC activates AKTand ERK1/2, but was unable to fully activate DCs, asdemonstrated by low expression of cell surface costimulatorymarkers and MHC molecules.Modulation of chondrocyte functions by metabolicstimuli: unlike normal counterparts, OA humanchondrocytes under hyperglycemia are unable toadjust glucose transport and undergo oxidativestress. OA chondrocytes express functional insulinreceptors, while showing IGFR resistance.Role of CD38 in immune function: using CD38KOmice, we found that CD38 is required for effectivemacrophage activation by T cells, NO production,chemotaxis and chemokine secretion duringimmune responses against mycobacteria; and forthe control of systemic autoimmunity.Oncobiology:Pathways involved in thyroid and cervical cancer:we unravelled a new pathway involved in nonmedullarythyroid cancer involving LRP1B andWnt; identified and characterized a new probablehighrisk HPV (HPV108); and identified changes indefensins associated with increased susceptibilityto HPV infection and cervical cancer.Cell signalling pathways involved in cancer andchemoresistance: we found a decrease in antioxidantdefences and an increase in peroxides formation,which decreases at relapse. In cells resistant toazaguanine, occurs a decrease in the expression ofpro‐apoptotic proteins.Genomic and phenotypic abnormalities of humangliomas: The results show genetic heterogeneity amonghuman gliomas and support the existence of differentcytogenetic pathways of intratumoral evolution in highversus low grade tumours, which could explain theirdifferent histopathological behaviour.79