The role of co-stimulation in airway inflammation

There is considerable evidence to support an important role for co-stimulat ory molecules in regulating the proliferation and activation of T cells in the immune response. Of particular relevance is the interaction between CD2 8 on T cells and B7 expressed on the surface of antigen presenting cells (A PCs). CTLA-4, another molecule present on activated T cells may downregulat e T cell activity, but its role remains uncertain. CTLA4-Ig, a fusion prote in consisting of the extracellular domain of CTLA4 and the Fc portion of hu man immunoglobulin G1 (IgG(1)), has been useful for studying the role of CD 28/B7 interactions in immune responses. A number of studies have shown that CTLA4-Ig can switch off T cell activation. In an ovalbumin sensitive murin e model of asthma, CTLA4-Ig treatment suppressed the response to inhaled al lergen (increased airway hyperresponsiveness [AHR]. IgE production, recruit ment of eosinophils into the lungs, production of IL-4, IL-5, and IL-10 and increased IFN gamma production from CD3-TCR-activated T cells). Anti B7-2 treatment has similar effects suggesting that interaction of B7-2 with CD28 is important in the development of a Th-2 type inflammatory response in mi ce. Recent observations have been of relevance to human allergic disease. I n vitro studies have shown that CTLA4-Ig or anti-B7-2 antibody can inhibit allergen-induced proliferation and cytokine production by peripheral blood mononuclear cells from atopic subjects. The role of co-stimulation has been studied in a human bronchial explant model of asthma. CTLA4-Ig fusion prot ein effectively blocked allergen-induced production of IL-5 and IL-13 in br onchial explants from atopic asthmatics. These studies confirm the requirem ent for interaction between costimulatory molecules in cytokine production and allergic inflammation, and point to the CD28-B7 pathway as being import ant to the allergen-induced inflammation in asthma. Studies of organ transp lantation in primates suggest that CTLA4-Ig is extremely effective in preve nting organ rejection. While phase 1 clinical trials have shown CTLA-4-Ig t reatment of patients with psoriasis vulgaris to be well tolerated and to re sult in clinical improvement, its role in asthma management merits further investigation.