Immunology
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Donald A. Harn, Jr.

Department of Medicine
Dept. of Immunology and Infectious Diseases
Harvard School of Public Health
Building I, Room 805
665 Huntington Avenue
Boston, MA 02115
Tel: 617-432-1257
Fax: 617-432-2082
e-mail:dharn@hsph.harvard.edu
3 Postdoctoral Fellows, 3 Graduate Students

  

Numerous studies have examined innate activation of dendritic cells (DCs) by Th1-type PAMPs such as LPS, however, few studies have examined how Th2-driving DCs are generated. Our lab described the first Th2 PAMP, a glycan found on parasitic helminths. Interestingly, this glycan activates immature DCs in a TLR4 dependent mechanism but signals in an MyD88 independent manner. There is also differential activation of MAP kinases and NF-kB as compared with LPS activated cells. Recently, another group confirmed these observations on glycan activation of DCs via TLR4. We are interested in examining how TLR4 can be involved in driving both pro-inflammatory and anti-inflammatory responses and are currently examining events upstream and downstream of TLR4. Upstream studies are focused on a proteomic comparison of lipid raft signalosomes from glycan versus LPS activated cells. Downstream we are focused on the TIR adaptor molecules the glycan activates as well as signaling molecules that regulate alternative NF-kB activation following glycan activation. The helminth glycan also expands "suppressor" macrophages in vivo. Suppressor macrophages expand when tumors are present and also during viremia. Interestingly, this glycan is on certain tumors as well as on virus such as HIV-1. In contrast to activation of DCs, activation of "suppressor" macrophages is not TLR4 dependent and we are currently dissecting the mechanism of suppressor macrophage action on T cells as well as identifying they macrophage receptor for this glycan. Because this glycan drives anti-inflammatory responses we have evaluated the therapeutic potential for Type 1 autoimmune diseases and have found that treatment with this glycan prevents development of colitis or psoriasis in murine models of these diseases.

Among our research interests is defining the protective mechanisms that these sugars induce in vivo.

 

Papers & Publications:

  1. Okano M, Satoskar A, Brombacher F, and Harn DA. Lacto-N-fucopentaose III found on Schistosoma mansoni egg antigens functions as adjuvant for proteins by inducing Th2-type responses induces polyclonal IgE production in vivo. J Immunology. 2001.167:442-450.
  2. Atochina O, Daly-Engel T, McGuire E, Piskorska D, and Harn DA. Lewisx expands Gr1+ macrophages that suppress naðve CD4+ cells via a nitric oxide dependent mechanism. A pattern recognition model of suppression. J Immunol. 2001 Oct 15;167(8):4293-302.
  3. Terrazas LI, Walsh KL, Piskorsk D, McGuire E, Harn DA Jr. The schistosome oligosaccharide lacto-N-neotetraose expands Gr1(+) cells that secrete anti-inflammatory cytokines and inhibit proliferation of naive CD4(+) cells: a potential mechanism for immune polarization in helminth infections. J Immunol. 2001 Nov 1;167(9):5294-303.
  4. Thomas PG, Carter M, Atochina O, Da'Dara A, Piskorska D, McGuire E, and Harn DA. Maturation of dendritic cell 2 phenotype by a helminth glycan uses a Toll-like Receptor 4-dependent mechanism.ÊJ. Immunology. 2003. 171:5837-5841.
  5. Thomas PG, Harn DA Jr. Immune biasing by helminth glycans. Cell Microbio. 2004. 6:13-22.