Our Science – Chen Website
Xin Chen, M.D., Ph.D.
Modulation of immune response: targeting tumor and autoimmunity - studies of the effects of pharmacological agents, derived from alternative medicine system (traditional Chinese medicine) and conventional biomedical system (natural products), on the function of chemokine receptors, CD4+FoxP3+ regulatory T cells and dendritic cells as a means of modifying immune responses.
Identification of novel chemokine receptor antagonists in traditional Chinese medicines. Chemokine receptors comprise a family of seven transmembrane domain G protein-coupled receptors, which orchestrate immune response by directing migration of leukocytes. Recently, chemokine receptors have been shown to play an important role in the pathogenesis of some major human diseases, including HIV, cancer and inflammation. Dr. Chen has studied traditional Chinese medicine as a source of inhibitors of chemokine receptors. Starting with multiple component Chinese herbal medicines, Dr. Chen has successfully identified a number of chemically defined chemokine receptor antagonists, such as deoxycholic acid, chenodeoxycholic acid, tannic acid, and shikonin. One of Dr. Chen's on-going projects is to study anti-tumor activity of these compounds in animal models.
Dr. Chen has also studied pharmacological manipulation of dendritic antigen presenting cells (DC) using component from traditional Chinese medicine. He found that triptolide, an immunosuppressive agent from Chinese herbal medicine with anti-rheumatoid activity, potently inhibited DC maturation and trafficking. One of his on-going projects is the study of another immunosuppressive compound derived from an anti-rheumatoid Chinese herb on the generation of a tolerogenic feedback loop between tolerogenic DC and Tregs.
Immunobiology and pharmacological manipulation of CD4+FoxP3+ regulatory T cell (Treg) function - Tregs, which constitute ~10% of peripheral CD4+ T cells, play a crucial role in the maintenance of peripheral tolerance and suppression of immune responses to alloantigens and autoantigens, including tumor antigens. Inhibition of Treg function can boost anti-tumor immune response, while up-regulation of Treg activity has been shown to inhibit autoimmunity, allergy, transplantation rejection and GVHD. Dr. Chen has reported that BALB/c mice have more Tregs and consequently showed greater susceptibility to suppression of their CD4+CD25- responder T cells than C57BL/6 mice. He observed that Tregs were relatively resistant to glucocorticoid-induced cell death and that IL-2 selectively, greatly protected Tregs from spontaneous and induced cell death. Based on this observation, he developed a combination therapy of glucocorticoid and IL-2 and found that this combination treatment markedly expanded Tregs in vivo. Treatment with glucocorticoids and IL-2 inhibited development of mouse model of an autoimmune disease, experimental autoimmune encephalomyelitis (EAE). Dr. Chen also found that mice induced to develop EAE were deficient in functional Treg cells in the spleen. These studies by Dr. Chen led to the discovery that pertussis toxin (PTx), an adjuvant component of the immunogen used to induce EAE, was responsible for inhibiting suppressive Treg activity. PTx blocked the differentiation of Tregs, while promoting the generation of Th17 cells in an IL-6-dependent manner. Conversely, Dr. Chen found that rapamycin blocked Th17 responses while promoting Treg activity. In mice deficient in IL-6, in vivo administration of PTx resulted in the expansion of Tregs. This observation led to the unexpected finding by Dr. Chen that TNF had the capacity to activate and expand Tregs through TNFR2, one of the TNF receptors preferentially expressed by 30~40% of mouse peripheral Tregs. Furthermore, Dr. Chen found that the expression of TNFR2 actually identified the maximally suppressive subset of mouse Tregs, and by combining with CD25, TNFR2 expression identifies the more of the functional human Tregs than CD25high criterion. Although TNFR2 was also expressed by activated Teffs which had enhanced resistance to Treg-mediated inhibition, however, Dr. Chen found that activated Tregs present in the tumor environment expressed markedly higher levels of TNFR2 on per cell basis, and potently inhibited activated Teffs and therefore dominated the immunosuppressive microenvironment of the tumor. Dr. Chen's ongoing research aims to elucidate the mechanism and molecular pathways of TNF-TNFR2 interaction in the activation of Tregs, and to devise more effective cancer immunotherapy by targeting this pathway.
This page was last updated on 9/13/2013.