The role of T-cell co-stimulatory molecules in murine models of allergic asthma

Summary The role of T-cell co-stimulatory molecules in murine models of allergic asthma.  Allergen-specific T helper type 2 (Th2) cells play a pivotal role in the pathogenesis and progression of allergic asthma by orchestrating the inflammatory response. For optimal activation, T-cells require nonspecific co-stimulatory signals in addition to the antigen-specific signal conferred by the T-cell receptor. In this thesis, the role and therapeutic potential of blockade of T-cell co-stimulation in ovalbumin (OVA)-induced murine models of allergic asthma were investigated. The main co-stimulatory receptor on T-cells is CD28. Two ligands are available for this receptor: B7-1 and B7-2. The second receptor for the B7 ligands, CTLA4, is expressed on activated T-cells and delivers an inhibitory signal to terminate the immune response. The existence of a third B7-1/B7-2 receptor was postulated in a recent study using a novel mouse strain lacking both CD28 and CTLA4 (CD28/CTLA4? /? ). However, no manifestations of allergic asthma could be induced by OVA in both CD28/CTLA4? /? and B7-1/B7-2? /? mice. So, whereas T-cell co-stimulation via the putative B7-1/B7-2 receptor appears to play no role in the development of asthma manifestations in this murine model, CD28 signaling is critical. However, asthma patients start therapy after the development of airway symptoms while exposure to environmental allergen mostly continues. Therefore, it was investigated if blockade of CD28 can reverse established manifestations of allergic asthma in mice after the development of these manifestations while OVA exposures are continued (ongoing murine model of allergic asthma) (chapter 3). Blockade of CD28 substantially inhibited the established antigen-induced airway manifestations in mice. In a more severe ongoing model induced by a different OVA sensitization- and challenge protocol, the effects of CD28 blockade on established asthma manifestations were less pronounced. The recently discovered, CD28-family member, inducible T-cell co-stimulator (ICOS) has been suggested to play a more prominent role in the effector phase rather than in the initiation of the Th2-dominated allergic inflammatory response. However, blockade of ICOS appeared to have no effect on any of the established manifestations in the ongoing murine model of allergic asthma whereas blockade during the development of these manifestations was much less effective compared with blockade of CD28 (chapter 4). Blockade of T-cell co-stimulation has been shown not only to result in the immediate suppression of the immune response but to induce in some disease models long-term antigen-specific unresponsiveness (tolerance) as well. Short-lived treatment that induces selective tolerance to the inhalant allergen would be a very attractive therapeutic approach for allergic asthma. Therefore, it was investigated if blockade of T-cell co-stimulation during the development of asthma manifestations also had an effect after serum clearance when mice were re-challenged with OVA (chapter 5). Blockade of the CD28:B7 pathway -but not of the CD40 ligand:CD40 pathway (another well-known pathway of T-cell co-stimulation)- could induce tolerance for some asthma manifestations re-induced by OVA re-challenge. So, these pre-clinical studies indicate that blockade of T-cell co-stimulation, especially the CD28:B7 interaction, may be an alternative therapy for both asthma patients in clinical remission and those with ongoing disease. The latter group possibly requiring additional therapy.