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ARS Home » Northeast Area » Beltsville, Maryland (BARC) » Beltsville Agricultural Research Center » Animal Parasitic Diseases Laboratory » Research » Publications at this Location » Publication #341241

Title: Helminth-induced production of TGFß and suppression of graft-versus-host disease is dependent on Interleukin 4 production by host cells

item LI, YUE - University Of Iowa
item LIU, WEIREN - University Of Iowa
item GUAN, XIAOQUN - University Of Iowa
item CHEN, HUNG-LIN - University Of Iowa
item ZAVAZAVA, NICHOLAS - University Of Iowa
item BLUMBERG, RICHARD - Brigham & Women'S Hospital
item WEINER, GEORGE - University Of Iowa
item Urban, Joseph
item ELLIOTT, DAVID - University Of Iowa
item INCE, NEDIM - University Of Iowa
item TRUSCOTT, JAMIE - University Of Iowa
item KARAKAY, BAHRI - University Of Iowa

Submitted to: Journal of Immunology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/5/2018
Publication Date: 11/15/2018
Citation: Li, Y., Liu, W., Guan, X., Chen, H., Zavazava, N., Blumberg, R.S., Weiner, G.J., Urban Jr, J.F., Elliott, D.E., Ince, N.M., Truscott, J., Karakay, B. 2018. Helminth-induced production of TGFß and suppression of graft-versus-host disease is dependent on Interleukin 4 production by host cells. Journal of Immunology. 201(10):2910-2922.

Interpretive Summary: Allogeneic bone marrow transplantation and hematopoietic stem cell transplantation are curative approaches for the treatment of some malignant and lethal nonmalignant disorders. The beneficial outcome of transplantation is limited by donor immune cell-mediated reactivity against the host tissues resulting in severe graft-versus-host disease (GVHD). Treatment options for GVHD are limited to immune-suppressive medications, such as steroids, that can have limited benefits and cause severe toxicity. An alternative approach is to regulate lethal GVHD using regulatory T cells (Tregs) that suppress inflammation, but obtaining adequate numbers of these cells is difficult. Intestinal worm parasites, notably, have immune modulating properties that expand Tregs, and also suppress aberrant immune reactivity through the products that they secrete. A factor called T-cell growth factor beta (TGFß) appears to be a central player in worm-induced immune suppression critical to the expansion of Tregs and suppression of GVHD. Scientists at the University of Iowa and USDA/ARS in Beltsville showed that worm-induced suppression of GVHD depends on production of a host protein called IL4 that is critical for the production of TGFß and TGFß-dependent expansion of Tregs that modulate suppression of GVHD. This information is important to scientists interested in the modulating effects of worm parasites on the host, and to clinicians interested in using these pathways to regulate inflammation and reduce disease.

Technical Abstract: Helminths stimulate the secretion of T helper 2 (Th2) cytokines, such as interleukin 4 (IL-4) and suppress lethal graft-versus-host disease (GVHD) after bone marrow transplantation (BMT). This suppression - in a Th2 polarized environment - depends on the production of immune-modulating TGF and is associated with TGF-dependent expansion of Foxp3+ regulatory T cells (Treg). Th2 and the TGF pathways counter-regulate each other in different inflammatory conditions; and it is unknown how Th2 and TGF pathways remain active during helminth infection. Here we show that helminth-induced secretion of the Th2 cytokine IL4 is critical to the induction and maintenance of TGFß secretion, the TGFß-dependent expansion of Foxp3+ donor Tregs, and the suppression of GVHD. We also found that IL4-dependent suppression of GVHD by helminth colonization does not require invariant NKT (iNKT) cells of the host - a cell type known to stimulate Th2 pathway and suppress GVHD in different models. Thus, TGF generation - in a manner dependent on IL4 - constitutes a critical effector arm of helminthic immune modulation that promotes the expansion of Tregs and that suppresses GVHD.