Dr Ben Guan:
University of Alabama
University of South Carolina
Ph.D. Hunan Medical University, China
Office: (803) 216-3411
My research currently focuses on study of the role of CD44 in development of immune response, regulation of immunity and the role in endothelial injury related to cancer immunotherapy and autoimmune disease.
CD44 is a widely distributed cell surface glycoprotein expressed by a variety of lymphoid and non-lymphoid cells. The CD44 family consists of a standard form and group of isoforms with molecular weights ranging from 85 kDa to more than 200 kDa. Hyaluronic acid has been shown to be a primary ligand for CD44. The CD44 molecule has been demonstrated to participate in cell adhesion and migration, lymphocyte homing, activation and proliferation, lytic activity of T cells and NK cells, and tumor metastasis. It is known as an activation marker and a property of long-lived memory T cells. Although it was once believed to function primarily in tethering cells to extracellular ligands, it is now recognized as having broader functions in cellular signaling cascades. The CD44 transmembrane glycoprotein family adds new aspects to these roles by participating in signal-transduction processes not only by establishing specific transmembrane complexes, but also by organizing signaling cascades through association with its partner proteins, which monitor changes in the extracellular matrix that influence cell growth, survival and differentiation.
- Role of CD44 in effector T cell differentiation, including Th1, Th2 and Th17.
In this study, we use mouse model of targeted deletion of CD44 and explore in vivo and in vitro lineage differentiation of effector T cells including Th1, Th2 and Th17 in response to sheep red blood cell and chicken ovalbumin. We observed that deletion of CD44 tended to inhibit Th1 and Th17 while promoting Th2 differentiation. The regulation by CD44 occurred at the transcription level leading to up-regulated GATA3 and down-regulated T-bet expression in activated CD4 T cells. We also noticed that CD44-deletion could modify the state of dendritic cells to induce a Th2-biased development in correlation with the characteristic DC subsets. We are currently investigating the involved signal pathway.
- Role of CD44 in immune surveillance of experimental autoimmune encephalomyelitis (EAE).
We have demonstrated that CD44 plays a critical role in the development of autoimmune encephalomyelitis. Knockout of CD44 dramatically ameliorated the symptoms and delayed the onset of the disease. Deletion of CD44 tamed T cells so that the suppressive T cells overplayed encephalogenic T cells. It correlates with the immune phenotype shift from encephalogenic Th1/Th17 to suppressive Th2/ Treg differentiation. In this study, we are trying to depict a full profile of CD44 isoforms and the variant-specific regulation on the disease progress. We have found that CD44 variant V7 plays a critical suppressive role in the development of EAE. Knockout CD44V7 dramatically deteriorated the disease and created a new form of the disease progress. Currently, we are investigating how CD44v7 monitors and controls the balance of the immune surveillance.
- Role of CD44 variant-specific regulation for the function, homing, migration and homeostasis of the regulatory T cells (Treg).
In this study, we are testing hypothesis that CD44 specific variants regulate the suppressive activity of Treg and their influence on homeostasis of Treg pool. This study is also investigating how CD44 modulates the homing of Treg into compartmental reservoirs and the migrating of Treg to effect sites.
- Role of CD44 in endothelial cell (EC) injury and antitumor immunity.
In this study, we are investigating the role of CD44 in IL-2-induced endothelial cell injury and correspondent antitumor immunity. We observed that CD44 plays a critical role in the EC damage caused by cytotoxic lymphocytes. Blockade of its ligand with a specific peptide, Pep-1, could prevent EC damage and increase the efficacy of IL-2 therapy against cancer. Currently, we are trying to dissect and identify unique CD44 isoforms involved in EC injury and developing novel therapeutic modalities to prevent the injury while increase the efficacy of IL-2 therapy against cancer
- Role of resveratrol and thymic stromal lymphopoietin (TSLP) in endothelial cell (EC) injury and antitumor immunity.
The vascular leak syndrom (VLS) is the lethal toxicity of high-dose IL-2 treatment in melanoma patients. In this study, we are investigating resveratrol and TSLP in protection from EC injury by IL-2. we have found that resveratrol totally inhibited development of VLS and maintained effectiveness of IL-2 in melanoma model. We also found that resveratrol regulates the development, proliferation and function of myeloid-derived suppressive cells (MDSC) and Treg in VLS. We observed that resveratrol-educated MDSC revealed differential suppressive function on cytotoxicity of killer T cells to endothelial cell and melanoma. The differential suppressive activity of MDSC could result from the conditional functionality of TSLP induced by resveratrol. The precise mechanisms are under exploring.
Search Pubmed for publications by Dr. H Guan
- Guan, H., Nagarkatti, P. S., Nagarkatti, M. 2007. Blockade of hyaluronan inhibits IL-2-induced vascular leak syndrome and maintains effectiveness of IL-2 treatment for metastatic melanoma. Journal of Immunology. 179: 3715-3723.
- Guan, H., Moretto, M.,Bzik, D. J.,Gigley, J.,Khan, I. A. 2007. NK cells enhance dendritic cell response against parasite antigens via NKG2D pathway. Journal of Immunology. 179: 590-596.
- Kim, H. K.,Guan, H., Zu, G.,Li, H.,Wu, L.,Feng, X.,Elmets, C.,Fu, Y.,Xu, H. 2006. High-level expression of B7-H1 molecules by dendritic cells suppresses the function of activated T cells and desensitizes allergen-primed animals. J Leukoc Biol. 79: 686-695.
- Melencio, L.,McKallip, R. J., Guan, H., Ramakrishnan, R.,Jain, R., Nagarkatti, P.,S., Nagarkatti, M. 2006. Role of CD4(+)CD25(+) T regulatory cells in IL-2-induced vascular leak. Int Immunol. 18: 1461-1471.
- Guan, H., Zu, G., Xie, Y., Tang, H., Johnson, M., Xu, X., Kevil, C., Xiong, W.-C., Elmets, C., Rao, Y., Wu, J.Y., and Xu, H. 2003. Neuronal repellent Slit2 inhibits dendritic cell migration and the development of immune response. Journal of Immunology. 171(12): 6519-6526.
- Guan, H., Zu, G., Slater, M., Elmets, C. and Xu, H. 2002. Gamma delta T Cells regulate the development of hapten-specific CD8+ effector T cells in contact hypersensitivity responses. J Invest Dermatol. 119 (1): 137-142.
- Hui Xu, H., Guan, H., Zu, G., Bullard, D., et al. 2001. The role of ICAM-1 molecule in the migration of Langerhans cells in the skin and regional lymph node. Eur J Immunol 31:3085-3093.