The main thrust of research in the Molecular Immunology Section is to understand molecular and cellular mechanisms that regulate host immunity, with particular emphasis on: (i) mechanisms that regulate lymphocyte development and cell-fate decisions; (ii) identifying and characterizing autoreactive memory T cell subsets that mediate remitting and recurrent central nervous system (CNS) autoimmune diseases; (iii) Developing Biologics for treating CNS inflammatory diseases, such as uveitis, multiple sclerosis and Age-related Macular Degeneration (AMD).
Major Areas of Investigation and Findings:
(i) Cellular and molecular mechanisms that mediate human and mouse autoimmune uveitis
Ocular inflammatory diseases are a major cause of severe visual handicap in the USA and include sight-threatening idiopathic inflammatory ocular disease such as scleritis and uveitis, and T cells are currently thought to be the etiologic agents. We found that blood of patients with uveitis or scleritis contain more Th17 cells than that of healthy individuals and expansion of the Th17 was driven by IL-2 but inhibited by IL-27 and IL-35. The Th17 cells mediate ocular pathology by inducing the production of tumor-necrosis factor alpha (TNF-α) in the eye and we can treat mouse uveitis by administering IL-17-specific antibodies. A great deal of effort is now devoted to studies aimed at understanding factors that promote Th17-mediated uveitis and mechanisms by which IL-27 and IL-35 inhibit uveitis and mitigate ocular pathology.
(ii) Investigate where autoreactive memory T cells that mediate uveitis reside in-between cycles of remitting and relapsing disease.
Organ-specific autoimmune diseases such as multiple sclerosis and uveitis are characterized by repeated cycles of remission and recurrent inflammation. Pertinent to the development of effective treatment for autoimmune diseases is the age-old question of where autoreactive memory lymphocytes reside in-between episodes of recurrent-inflammation and how they can be deprived of their survival-niche. We have developed sensitive assays that now allow us to track autoreactive lymphocytes that mediate blinding uveitis over a seven months period. We discovered that the autoreactive memory T cells preferentially reside in the bone marrow and have characterized molecular mechanisms that promote their recruitment into the bone marrow. We are now exploiting the use of bone marrow ablation to deplete pathogenic memory lymphocytes as viable alternative to conventional therapy for recalcitrant uveitis, multiple sclerosis, and other autoimmune diseases.
(iii) Genetic engineering and development a new class of therapeutic cytokines.
IL-12 family cytokines have emerged as important players in the development of CNS autoimmune diseases. Each member is comprised of an alpha and beta chain and 4 heterodimeric IL-12 cytokines have been described, with some members (IL-12, IL-23) promoting autoimmune pathology while others (IL-27, IL-35) suppress inflammation and limit tissue injury. A major goal of our drug discovery program is to genetically engineer each α and β IL-12 subunit protein and novel combinations of these subunits for use as potential therapeutic cytokines. To this end, we have genetically engineered: (i) Recombinant (r) IL-35 (human & mouse); (ii) rIL-27 (human & mouse); (iii) Novel rIL27p28/IL12p40 cytokine (p28/p40); (iv) rIL12p35, rIL12p40; rIL27p28; and rEbi3 single chain proteins. We have shown that the rIL-35, rIL-27, or rIL27p28/IL12p40 inhibits experimental autoimmune uveitis while rIL12p35 and Ebi3 suppresses lymphocyte proliferation. These proof-of-concept studies suggest that cytokines comprising of unique IL-12 α and β subunits pairing may constitute a new class of therapeutic cytokines.
Dr Charles E. Egwuagu is an epidemiologist/immunologist and Chief of the Molecular Immunology Section, National Eye Institute. He received his Ph.D and M.Phil. from Yale University and an M.P.H. from the Yale School of Medicine, New Haven, Connecticut. Dr Egwuagu then served as a Commissioned Officer of the USA Public Health Service for ten years, attaining the rank of Captain (06). The major research focus in the Egwuagu laboratory is on autoreactive lymphocytes that mediate CNS auto-inflammatory diseases like uveitis and multiple sclerosis. Particular interest is on cytokine signaling and epigenetic mechanisms that regulate lymphocyte development and cell-fate decisions. The ultimate goal is to develop cytokine-based therapy for autoimmune and neurodegenerative diseases.