The current projects in my laboratory study the cellular and cytokine regulation of local immune responses in the lung and in the eye. It is known that while adaptive immune cells, like T lymphocytes, respond to antigen-specific signals by differentiating into effector cells, innate immune cells, like macrophages, NK and NKT cells, respond immediately by producing cytokines that bias the kind of adaptive immune response that follows. Our particular interest is the role of NKT cells [identified by surface expression of both natural killer (NK) cell markers and T cell receptors] and macrophages called “antigen presenting cells” (APC) in their ability to deviate the differentiation of T lymphocytes from effector cells toward regulatory cells. We study this mechanism in a model of ocular tolerance called “Anterior Chamber Associated Immune Deviation” (ACAID) and a model of gut tolerance called low dose oral tolerance.
Based on the observation that NKT-deficient mice are unable to develop the CD8+ regulator (Tr) cells in both models, we showed that NKT cells secrete critical cytokines that both recruit and influence other cells needed to gather together in the spleen to induce the Tr cell. Moreover, characterization of the eye-derived APC in ACAID shows that the macrophages are highly specialized for the induction of the differentiation of Tr cells.
We are also exploring the potential of adapting ACAID mechanisms for immunotherapy of immune inflammatory diseases. Our mouse lung model for pulmonary fibrosis demonstrates that Th1 cell immune mechanism involved in allergic contact dermatitis contribute to lung disease. A model of airway hyperreactivity in mice exhibits some aspects of human asthma that is mediated by Th2 immune responses. Our studies show that the adoptive transfer of in vitro-generated ACAID-like tolerogenic APC downregulates both Th1 and Th2 responses (fibrosis and airway hyperreactivity, respectively) not only in naïve, but also primed mice. Potentially, mechanisms used by the eye may be the basis of novel therapy that will alter the immunologic state in patients and promote healing of autoimmune disease and other immune inflammatory disorders in the eye and other tissues.