University of California, Riverside

Division of Biomedical Sciences



Biomedical Sciences Faculty


David Lo

Distinguished Professor of Biomedical Sciences
Senior Associate Dean, Research

 David Lo

University of California, Riverside
Riverside, CA 92521

Tel: (951) 827-4553
Fax: (951) 827-5504
E-mail: david.lo@ucr.edu
Office: 2140 Webber Hall

Education and Training

  • Ph.D., University of Pennsylvania, Philadelphia, Pennsylvania
  • M.D., University of Pennsylvania, Philadelphia, Pennsylvania
  • Postdoctorate, University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania

Biography

Dr. David D. Lo, M.D., Ph.D., is the senior associate dean for research at the University of California, Riverside School of Medicine and a distinguished professor in the Division of Biomedical Sciences.

Prior to joining UCR in 2006, Lo had worked at the La Jolla Institute for Allergy and Immunology, the Scripps Research Institute and the biotech company Digital Gene Technologies.

Lo is affiliated with the UCR Center for Disease Vector Research and the UC Global Health Institute.

He is a fellow of the American Association for the Advancement of Sciences and a recipient of the Grand Challenges in Global Health award from the Bill and Melinda Gates Foundation and the Foundation for the National Institutes of Health.

Research Summary

M cells and Mucosal Immune Surveillance

Mucosal surfaces in the lung and intestine are exposed to environmental antigens and allergens and, in the case of the intestine, abundant food antigens. They are also exposed to a variety of infectious organisms such as viruses (influenza, polio, SARS, HIV), bacteria (staphylococcus, streptococcus, anthrax), and parasites (Toxoplasma). The mucosal immune system must be able to identify pathogenic infectious agents and respond to them without reacting to beneficial commensal bacteria, or developing allergic responses to food or environmental antigens.

At mucosal surfaces, epithelial cells provide a tight barrier to entry into the body, but the immune system also induces the development of specialized epithelial cells called M cells to detect the presence of infectious organisms. These M cells are selective gatekeepers that capture particles such as viruses and bacteria for delivery to cells of the immune system waiting below the epithelial layer. Our laboratory has been studying the development of M cells, and the mechanisms used by M cells in their selective uptake of particles. We are also using the information we have learned about M cell function to engineer novel technologies for needle-free vaccine delivery that we hope to use against influenza and other infectious organisms. Several related projects are ongoing in our lab:

M Cell Differentiation

We have developed a cell culture model of M cell development using cytokine induction of an intestinal epithelial cell line. From gene expression profiling of this induction, we have identified genes associated with M cell function and differentiation, and signaling pathways associated with differentiation. In a gene knockout mouse model, we have also identified a signaling pathway (CD137-CD137L) necessary for the differentiation of M cells in vivo. In addition, we have developed a novel transgene fluorescent reporter system for following M cell development in vivo. With this transgene we have been able to identify distinct lineages and phenotypes among M cells, and more recently, we have shown that intestinal inflammatory diseases also induce development of a novel M cell type in the colonic epithelium.

Mucosal Epithelial Barrier and Selective Particle Uptake

Using a variety of cytokine induced cell lines, we have modeled the uptake of bacteria by intestinal epithelium and M cells. The selective binding and uptake of bacterial particles by intestinal epithelium suggests that innate immune receptors specific for bacterial components are involved.

Interestingly, particles are also taken up by M cells using mechanisms that are not dependent on specific ligands. Interactions between particles and mucosal epithelium are also affected by long range electrostatic forces, and M cells may take advantage of these forces in the uptake of microbes. In collaboration with Sharon Walker (UCR Chemical and Environmental Engineering), we showed that electrostatic forces play a major role in M cell particle capture.

Transcytosis Machinery

We have been using confocal microscopy approaches to identifying the cellular machinery used in the endocytosis and transport of bacterial particles by intestinal epithelial cells and M cells. Interestingly, M cells may use multiple mechanisms for transporting particles across the epithelial barrier. Our studies have already identified an unusual involvement of tight junction proteins such as Claudin 4 in one important pathway of bacterial particle uptake. We also showed that M cells produce cytoplasmic microvesicles that are delivered to underlying dendritic cells, providing a novel route for delivery of intracellular antigens.

Needle-free Vaccines: M Cell-targeted Vaccine Delivery

We have identified a number of receptors used by M cells in the capture and transport of bacterial particles across the epithelial barrier. From these discoveries, we are using a variety of protein engineering approaches to develop molecular “hooks” that may be used to target the delivery of vaccine antigens to M cells; technology based on these targeting strategies has been awarded a US patent. Recombinant proteins are presently being tested as needle-free mucosal vaccine formulations that may soon have application in clinical settings. We are also designing polymer nanoparticles and biopolymer formulations as delivery vehicles for these vaccine antigens.

Mucosal Vaccines: Dengue

In collaboration with Sujan Shresta (La Jolla Institute for Allergy and Immunology) we are testing whether a mucosal vaccine and induced mucosal IgA responses can be protective in a mouse model of Dengue infection. We engineered a novel hybrid vaccine in which a bacterial component and Dengue envelop protein are able to polymerize and induce both T helper dependent and T helper-independent antibody responses. This novel engineered protein scaffold has many potential applications for multivalent vaccines as well as in immunodeficiency settings.

CD4 T Cell Homeostatic Proliferation
In the face of T cell deficits, the residual T cells proliferate in what appears to be an attempt to restore the normal lymphocyte population. Yet in animals and patients with a deficit in T lymphocytes, there is a paradoxical predisposition for autoimmune diseases such as Type 1 diabetes and inflammatory bowel disease. We have identified cytokines, especially CCL21, that appear to drive this proliferation among CD4 T cells. In collaboration with Monica Carson (UCR Biomedical Sciences) and Emma Wilson (UCR Biomedical Sciences), we are studying the role of these cytokines in driving the development of T cells that may drive autoimmune disease and neuroinflammation. In collaboration with Dimitri Morikis (UCR Bioengineering) we are examining the structural basis of the chemokine interactions with their receptor (CCR7) on lymphocytes.

Selected Publications

  • Bennett, K.M., Parnell, E.A., Sanscartier, C., Parks, S., Chen, G., Nair, M.G., and Lo, D.D., Induction of colonic M cells during intestinal inflammation. Am. J. Pathol. In press, 2016.
  • Bennett, K.M., Gorham, R.D., Gusti, V., Trinh, L., Morikis, D., and Lo, D.D., Hybrid flagellin as a T cell independent vaccine scaffold. BMC Biotechnology, 15:71, 2015 (PMID 26265529).
  • Sakhon, O.S., Ross, B., Gusti, V., Pham, A.J., Vu, K., and Lo, D.D., M cell-derived vesicles suggest a unique pathway for trans-epithelial antigen delivery. Tissue Barriers 3:1-2 (e1004975), 2015.
  • Gusti, V., Bennett, K.M., and Lo, D.D., CD137 signaling enhances tight junction resistance in intestinal epithelial cells. Physiological Reports 2: e12090, 2014 (PMID 25096552).
  • Bennett, K.M., Walker, S.L., and Lo, D.D., Epithelial microvilli establish an electrostatic barrier to microbial adhesion. Infect. Immun. 82: 2860-2871, 2014. (PMID: 24778113) Highlighted in “IAI Spotlight”.
  • Sakhon, O.S., and Lo, D.D., Therapeutic implications of immune surveillance at the intestinal epithelial barrier. Curr. Drug Therapy 9:2-8, 2014.
  • Lo, D.D., Mucosal Vaccine Delivery: Is M cell targeted delivery effective in the mucosal lumen?. Expert Opinion on Drug Delivery, 10:157-61, 2013 (PMID:23252467).
  • Vandrangi, P., Lo, D.D., Kozaka, R., Ozaki, N., Carvajal, N., and Rodgers, V.G., Electrostatic properties of confluent Caco-2 cell layer correlates to their microvilli growth and determines underlying transcellular flow. Biotechnol. Bioeng. 110:2742-8, 2013.
  • Lo, D.D., Ling, J., Hamer, M.M., and Rajapaksa, T., Claudin-4 binding peptides, compositions and methods of use. U.S. Patent 8,258,257. Issued September 4, 2012.
  • Vandrangi, P., Jreij, P., Rajapaksa, T., Bansal, N., Lo, D., and Rodgers, V., Novel in-situ normal streaming potential device for characterizing electrostatic properties of confluent cells. Rev. Scientific Instruments, 83:074302, 2012. (PMID:22852705)
  • Hsieh, E.-H., and Lo, D.D., Jagged1 and Notch1 help edit M cell patterning in Peyer's patch follicle epithelium. Dev. Comp. Immunol. 37:306-12, 2012. (PMCID: PMC3374009)
  • Lo, D.D., Ling, J., and Eckelhoefer, H.A., M cell targeting by a claudin 4 targeting peptide can enhance mucosal IgA responses. BMC Biotechnology. 12:7, 2012. (PMCID:3337280)
  • Woodward, K., Bennett, K., and Lo, D.D., Mucosal vaccine design and delivery. Annu. Rev. Biomed. Engr. 14:17-46, 2012.
  • Wang, J., Gusti, V., Saraswati, A., and Lo, D. D., Convergent and divergent development among M cell lineages in mouse mucosal epithelium. J. Immunol. 187:5277-85, 2011. (PMCID: 3208058)
  • Lopez de Victoria, A., Gorham, R.D., Bellows, M.L., Ling, J., Lo, D.D., Floudas, C.A., and Morikis, D., A new generation of potent complement inhibitors of the Compstatin family. Chemical Biology and Drug Design, 77:431-40, 2011. (PMCID: PMC3095715)
  • Eckelhoefer, H.A., Rajapaksa, T.E., Wang, J., Stover-Hamer, M., Appleby, N.C., Ling, J., Lo, D.D., Claudin-4: Functional studies beyond the tight junction. Methods Mol. Biol. 762: 115-128, 2011. (PMID: 21717353)
  • Ploix, C.C., Noor, S., Crane, J., Masek, K., Carter, W., Lo, D.D., Wilson, E.H., and Carson, M.J., CNS-derived CCL21 is both sufficient to drive homeostatic T cell proliferation and necessary for efficient T cell migration into the CNS parenchyma following Toxoplasma gondii infection. Brain, Behavior, and Immunity 25:883-96, 2011. (PMCID: PMC3032828)
  • Rajapaksa, T.E., Bennett, K., Hamer, M , Lytle, C., Rodgers, V.G.J., and Lo, D.D., Intranasal M cell uptake of nanoparticles is independently influenced by targeting ligands and solvent ionic strength. J. Biol Chem. 285:23739-46, 2010. (PMCID: PMC2911333)
  • Hsieh, E.H., Fernandez, X., Wang, J., Stover-Hamer, M., Calvillo, S., Croft, M., Kwon, B.S., and Lo, D.D., CD137 is required for M cell functional maturation. Am. J. Pathol. 177: 666-676, 2010. (PMCID: PMC2913358)
  • Rajapaksa, T.E., Stover-Hamer, M., Fernandez, X., Eckelhoefer, H., and Lo, D.D., Claudin-4-targeted protein incorporated into PLGA nanoparticles can mediate M cell targeted delivery. J. Controlled Release 142: 196-205, 2010. (PMCID: PMC2823968)
  • Rajapaksa, T.E., and Lo, D.D., Microencapsulation of vaccine antigens and adjuvants for mucosal targeting. Current Immunology Reviews, 6:29-37, 2010.
  • Wang, J., Lopez-Fraga M., Rynko, A., Lo, D.D. TNFR and LTbetaR agonists induce Follicle-Associated Epithelium and M cell specific genes in rat and human intestinal epithelial cells. Cytokine 47:69-76, 2009. (PMCID: PMC2756805)
  • Ploix, C., Zuberi, R.I., Liu, F.-T., Carson, M.J., Lo, D.D. Induction and effector phase of allergic lung inflammation is independent of CCL21/CCL19 and LT-beta. Intl. J. Med. Sci. 6:85-92, 2009. (PMCID: PMC2653789)
  • Schmid, C., Melchior, B., Masek, K., Puntambekar, S., Danielson, P., Lo, D., Sutcliffe, J., and Carson, M., Differential gene expression in LPS/IFNg activated microglia and macrophages: in vitro versus in vivo. J. Neurochemistry 109:117-125, 2009. (PMCID: PMC2766614)
  • Clark, R.T., Hope, A., Lopez-Fraga, M., Schiller, N., and Lo, D.D., Bacterial particle endocytosis by epithelial cells is selective and enhanced by tumor necrosis factor-receptor ligands. Clin. Vacc. Immunol., 16:397-407, 2009. (PMCID: PMC2650861)
  • Ling, J., Liao, H., Clark, R., Wong, M.S.M., and Lo, D.D., Structural constraints for the binding of short peptides to Claudin-4 revealed by Surface Plasmon Resonance. J. Biol Chem., 283:30585-95, 2008. (PMCID: PMC2576538)
  • Li, C.R, Santoso, S., and Lo, D., Quantitative analysis of T cell homeostatic proliferation. Cell. Immunol., 250: 40-54, 2007. (PMCID: PMC2430158)
  • Carson, M.J., and Lo, D., Perspective is everything: an irreverent discussion of CNS-immune system interactions as viewed from different scientific traditions. Brain, Behavior, and Immunity, 21:367-73, 2006. (PMCID: PMC2626194)
  • Lo, D., Tynan, W., Dickerson, J., Scharf, M., Cooper, J., Byrne, D., Brayden, D., Higgins, L., Evans, C., and O'Mahony, D.J., Cell culture modeling of specialized tissue: Identification of genes expressed specifically by Follicle Associated Epithelium of Peyer's Patch by expression profiling of Caco-2/Raji co-cultures. Intl. Immunol. 16:91-99, 2004. (PMID: 14688064)
  • Lo, D., Tynan, W., Dickerson, J., Mendy, J., Chang, H.-W., Scharf, M., Byrne, D., Brayden, D., Higgins, L., Evans, C., O'Mahony, D.J., Peptidoglycan recognition protein expression in mouse Peyer's patch Follicle Associated Epithelium suggests functional specialization. Cell. Immunol. 224:8-16, 2003. (PMID: 14572796)

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