The loss of immune tolerance characterizes the airway inflammation seen in asthma and allergy. This immune dysregulation has been attributed to reduced numbers and function of regulatory T-cells, including FoxP3+ regulatory T-cells (Treg) and IL-10 producing TR1. Strategies to promote their numbers and function would have great therapeutic benefit. Both Treg and TR1 require signaling through the IL-2R and the TCR for their induction and maintenance. However, the availability of IL-2 is tightly regulated and exposure to cognate antigens is often intermittent. Mechanisms that support regulatory T-cells in settings of low IL-2 and low cognate antigen are therefore crucial to immune homeostasis. The PI has identified roles for the extracellular matrix molecule hyaluronan (HA) and its receptor CD44 in promoting the number and function of regulatory T-cells. CD44 crosslinking in the setting of low-dose antigen promotes the function and maintenance of Foxp3+ Treg. The same cues also promote the induction of TR1 from conventional T-cell precursors. Building on this finding, intra-nasal delivery of low dose antigen and HMW- HA was used to induce antigen-specific TR1 in vivo. These responses are mediated through synergistic effects on IL-2R and TCR signaling. Because high molecular weight HA (HMW-HA) but not low molecular weight HA (LMW-HA) is capable of crosslinking CD44, tissue integrity plays a decisive role in these effects.
In Aims 1 and 2 the PI proposes to investigate the natural role of HMW-HA in Treg homeostasis.
In Aim 3 the PI will evaluate whether TR1 induced using intra-nasal vaccination with a HMW-HA adjuvant can prevent inflammation in an antigen-specific mouse model of airway hypersensitivity. This is a novel and highly innovative approach to immune modulation with great potential for the prevention of asthma and allergy.

Public Health Relevance

This work has the potential to greatly advance our understanding of the mechanisms that promote immune homeostasis in peripheral tissues. Moreover, the ability to induce antigen-specific TR1 in situ would be a boon for the treatment of diseases associated with airway inflammation, including asthma and allergy.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL113294-01A1
Application #
8399338
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Noel, Patricia
Project Start
2012-08-15
Project End
2012-12-31
Budget Start
2012-08-15
Budget End
2012-12-31
Support Year
1
Fiscal Year
2012
Total Cost
$426,750
Indirect Cost
$176,750
Name
Benaroya Research Institute at Virginia Mason
Department
Type
DUNS #
076647908
City
Seattle
State
WA
Country
United States
Zip Code
98101
Gebe, John A; Yadava, Koshika; Ruppert, Shannon M et al. (2016) Modified High Molecular Weight Hyaluronan Promotes Allergen-Specific Immune Tolerance. Am J Respir Cell Mol Biol :
Kuipers, Hedwich F; Rieck, Mary; Gurevich, Irina et al. (2016) Hyaluronan synthesis is necessary for autoreactive T-cell trafficking, activation, and Th1 polarization. Proc Natl Acad Sci U S A 113:1339-44
Kuipers, H F; Nagy, N; Ruppert, S M et al. (2016) The pharmacokinetics and dosing of oral 4-methylumbelliferone for inhibition of hyaluronan synthesis in mice. Clin Exp Immunol 185:372-81
Yadava, Koshika; Bollyky, Paul; Lawson, Melissa A (2016) The formation and function of tertiary lymphoid follicles in chronic pulmonary inflammation. Immunology 149:262-269
Balaji, Swathi; King, Alice; Marsh, Emily et al. (2015) The role of interleukin-10 and hyaluronan in murine fetal fibroblast function in vitro: implications for recapitulating fetal regenerative wound healing. PLoS One 10:e0124302
Nagy, Nadine; Kaber, Gernot; Johnson, Pamela Y et al. (2015) Inhibition of hyaluronan synthesis restores immune tolerance during autoimmune insulitis. J Clin Invest 125:3928-40
Ruppert, Shannon M; Falk, Ben A; Long, S Alice et al. (2015) Regulatory T Cells Resist Cyclosporine-Induced Cell Death via CD44-Mediated Signaling Pathways. Int J Cell Biol 2015:614297
Secor, Patrick R; Sweere, Johanna M; Michaels, Lia A et al. (2015) Filamentous Bacteriophage Promote Biofilm Assembly and Function. Cell Host Microbe 18:549-59
Nagy, Nadine; Kuipers, Hedwich F; Frymoyer, Adam R et al. (2015) 4-methylumbelliferone treatment and hyaluronan inhibition as a therapeutic strategy in inflammation, autoimmunity, and cancer. Front Immunol 6:123
Ruppert, S M; Hawn, T R; Arrigoni, A et al. (2014) Tissue integrity signals communicated by high-molecular weight hyaluronan and the resolution of inflammation. Immunol Res 58:186-92

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