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Daniel R. Saban, Sharmila Masli, Payal Khandelwal, Hyun S. Lee, Simona Schelereth, Tomas Blanco; Deletion of Thrombospondin (TSP)-1 in Dendritic Cells (DC) of the Conjunctiva Exacerbates Allergic Conjunctivitis (AC). Invest. Ophthalmol. Vis. Sci. 2012;53(14):1241.
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It is known that DCs contribute to an allergic reaction via activation of secondary T cell responses, though the molecular factors that regulate DCs in this process are poorly understood. TSP-1 is an extracellular matrix protein that modulates immunity and is abundantly expressed throughout the ocular surface, but its role in allergy is unknown. We assessed whether TSP-1 influences the contribution of DCs to allergic immunity in experimental AC.
Wildtype (WT) vs. TSP1-/- mice were immunized with ovalbumin (OVA; 100µg)/ pertussis toxin (300ng)/ alum (1mg), and 14 d later mice were challenged with topical OVA eye drops (250 ug daily, 10 d consecutively). In other experiments, WT vs. TSP1-/- mice were adoptively transferred with primed WT T cells (10^6), and then challenged. In a final experiment, TSP1-/- mice were adoptively transferred with WT T cells, subconjunctivally (subconj) engrafted with WT vs. TSP1-/- null bone marrow-derived (BM) DC (10^5), and then challenged. Masked clinical scoring was performed 20 min post challenge. Cytokines profiles from in vitro recall assays were evaluated by ELISA, FACS enumeration of conj eosinophils (CD45+ Siglec F+), and serum OVA specific IgE were also assessed. Experiments (n>3 mice per group) were repeated at least twice.
Either in response to immunization or to adoptive transfer of WT T cells, peak clinical scores were significantly (p<0.05) elevated (by ≥40%) in TSP1-/- mice relative to scores in WT controls. However, in TSP1-/- mice in response to adoptively transferred WT T cells, such an increase in clinical scores as reversed by subconj engraftment of WT but not TSP1-/- BMDCs. Likewise, this reversal was associated with a decrease in eosinophil recruitment (by 130%), a decrease (p<0.05) in IL-4 (by 2.3-fold), IL-5 (by 2.2-fold), and IL-13 (by 1.2-fold), and a decrease (p<0.05) in OVA specific IgE levels (by 30%).
AC is exaggerated by deletion of TSP-1 in immunized mice. This effect is important during activation of secondary T cell responses, as exaggeration in TSP1-/- mice was observed even though WT T cells were adoptively transferred into these mice. Interestingly, however, subconj engraftment of WT DCs completely reverses this exaggerated effect in TSP1-/- mice. Taken together, our data suggest that TSP-1 expression by DCs regulates their capacity to mediate allergic immune responses in AC.
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