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The UNC FAI lab team conducts research in several areas aiming to better understand food allergy and develop approaches for its treatment.

Scientist doing experimentsCurrently, our group is working with the NIH-funded Consortium of Food Allergy Research (CoFAR) as the Central Biomarker Facility. Through this work, we coordinate biomarker assays, including basophil activation testing and serologic studies, from 10 sites throughout the US conducting cutting-edge clinical trials. We are actively working with samples from our own investigator-initiated trials at UNC, including oral and sublingual immunotherapy for peanut allergy. These research studies aim to determine the predictive value of IgE, IgG4, basophil activation, T cell phenotypes, salivary IgA, and metabolomics in response to therapies. Moreover, our team is investigating novel therapeutic strategies in mouse models through work funded by the DoD and NIH. Some of these studies include depletion of allergen-specific B cells, induction of protective IgG antibodies using virus-like particles (VLPs) and mRNA-based vaccines, and adjuvanted sublingual immunotherapy. Finally, we use mouse models to gain insight into how food allergy develops and potential targets for prevention.

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Affiliated Labs

 

Research Projects

Exploiting inhibitory Siglecs to combat food allergy

Inhibitory Siglecs are present on key immunologic cells in food allergy, for example Siglec 2 (CD22) on B cells, and Siglec 3 (CD33) on mast cells and basophils. Our research aims are to target these Siglecs to delete peanut allergen-specific B cells and inhibit degranulation of mast cells and basophils via STALs (Siglec-engaging Tolerance-inducing Antigenic Liposomes). Specifically, we have demonstrated that Ara h 2 CD22-STALs prevent the production of Ara h 2-specific IgE in a mouse model of peanut allergy. More recently, we have generated data indicating tolerance of memory B cells following STALs treatment. Ongoing studies aim to build on promising preliminary data demonstrating the utility of Ara h 2 CD33-STALs to prevent basophil degranulation.

diagram with title "exploiting inhabitory siglecs to combat food allergy"
Figure 1. Preventing immune responses to peanut allergen by targeting Siglecs. (A) Part A shows Siglec-engaging tolerance-inducing antigenic liposomes (STALs) with Ah2 and a high affinity CD22 ligand induce apoptosis of Ah2-specific B cells. (B) Part B shows STALs formulated with Ah2 and a high affinity CD33 ligand temporarily inhibit basophil and mast cell degranulation. (C) Structures of high-affinity Siglec ligands for mouse and human CD22 and human CD33.

 

Publications:

  1. Exploiting CD22 on antigen-specific B cells to prevent allergy to the major peanut allergen Ara h 2 [Kelly A. Orgel, Wesley Burks, Mike Kulis | Journal of Allergy and Clinical Immunology | January 2017]
  2. Antigenic Liposomes for Generation of Disease-specific Antibodies [LaKeya Hardy, Johanna Smeekens, Mike Kulis | Journal of Visualized Experiments | October 2018]

Collaborator: Matthew Macauley, PhD – University of Alberta

Funding: DoD

Sensitization to peanut through the airway

Mechanisms underlying sensitization to foods are not well understood. Recently, the dual allergen exposure hypothesis has posited that non-oral routes of exposure, prior to oral exposure, lead to the development of food allergy. Cutaneous exposure has been the focus of many studies, but we are interested in the airway as a route of exposure. Specifically, we have developed a mouse model demonstrating sensitization to peanuts can occur through the airway using house dust extract as an adjuvant.

Diagram showing the dual allergen exposure hypothesis, which posits that non-oral routes of exposure to an allergen, prior to oral exposure, can lead to the development of food allergy. The illustrations show that airway and cutaneous exposure lead to the release of IgE in the body; whereas GI tract exposure leads to oral tolerance.Publications:

  1. Indoor dust acts as an adjuvant to promote sensitization to peanuts through the airway [Johanna Smeekens, Mike Kulis, Tim Moran | Clinical & Experimental Allergy | August 2019]
  2. House dust promotes sensitization to peanuts through the airway [Johanna Smeekens, Mike Kulis, Tim Moran | Journal of Allergy and Clinical Immunology | February 2019]

Collaborator: Timothy Moran, MD, PhD – University of North Carolina

Funding: CEHS

A genetically-susceptible mouse model of peanut allergy

Over the past five years, we have tested several strains of mice from the UNC collection of Collaborative Cross mouse strains and identified one in particular, CC027/GeniUnc, that is susceptible to developing peanut allergy. Importantly, these mice can be orally sensitized to peanut, in the absence of a Th2-skewing adjuvant, and react upon oral challenge to peanut. We have identified differences in immunologic responses between CC027/GeniUnc and other strains of mice, including increased number of mast cells in the gut, decreased Tregs, and lower levels of fecal IgA. Furthermore, there are distinct gut microbiome differences associated with the development of peanut allergy, including lower levels of Akkermansia.

Anaphylaxis in peanut-sensitized mice after oral peanut challenge. (Left to Right) Body temperatures after oral challenge with peanut extract in C3H/HeJ, BALB/cJ, and CC027/GeniUnc mice sensitized with PBS, peanut extract once per week (PN 1X), peanut extract plus cholera toxin once per week (PN+CT), or peanut extract 3 times per week (PN 3X). The findings are described in the image caption.
After oral challenge with peanut, all groups of C3H/HeJ and BALB/cJ mice did not experience decreased body temperatures. However, CC027/GeniUnc mice sensitized with peanut alone, 1 or 3 times per week, experienced, on average, a greater than 3°C and 4°C decrease, respectively, that is comparable with that seen in mice sensitized with peanut plus cholera toxin.

 

Total fecal IgA (CC027/GeniUnc: n = 39; C3H/HeJ: n = 32). The vast majority of CC027/GeniUnc mice (34 of 39 mice) had <15 ng/ml of IgA, while IgA quantities in C3H/HeJ mice average 127 ng/ml (range: 18–509 ng/ml). The findings are described in the caption.
CC027/GeniUnc mice had significantly lower total fecal IgA quantities compared to C3H/HeJ mice.
Relative abundances based on order. Orders are: Bacillales, YS2, Coriobacteriales, Enterobacteriales, RF32, Verrucomicrobiales, Erysipelotrichales, RF39, Anaeroplacmatales, Lactobacillales, Burkholderiales, CW040, Clostridiales, Bacteroidales. This diagram shows that the gut microbiome composition differs between the two mice lines CC027 and C3H. The findings are described in the caption.
This shows marked visual differences in the average gut microbiome composition of CC027/GeniUnc and C3H/HeJ mice.
Principal coordinate analysis plot of gut microbiome between CC027/GeniUnc (blue) and C3H/HeJ (red) mice. The findings are described in the caption.
Compositional data analysis revealed the gut microbiome composition was significantly different between strains at baseline, using a combination of machine learning and beta diversity analysis.

Publications:

  1. Genetic diversity between mouse strains allows identification of the CC027/GeniUnc strain as an orally reactive model of peanut allergy [Kelly Orgel, Johanna Smeekens, Ping Ye, Rishu Guo, Wesley Burks, Mike Kulis | Journal of Allergy and Clinical Immunology | October 2018]
  2. Fecal IgA, Antigen Absorption, and Gut Microbiome Composition Are Associated With Food Antigen Sensitization in Genetically Susceptible Mice [Johanna Smeekens, Andrew Hinton, Tim Moran, Janelle Kesselring, Erin Steinbach, Kelly Orgel, Wesley Burks, Mike Kulis | Frontiers in Immunology | January 2021]
  3. Model of Walnut Allergy in CC027/GeniUnc Mice Recapitulates Key Features of Human Disease [Johanna Smeekens, Kelly Orgel, Janelle Kesselring, Mike Kulis | Yale Journal of Biology and Medicine | December 2020]

Collaborators: Martin Ferris, PhD – University of North Carolina | Fernando Pardo-Manuel de Villena, PhD – University of North Carolina

Previous funding: NC TraCS TTSA award

CoFAR Central Biomarker Facility

The UNC FAI is home to the NIH-sponsored Consortium of Food Allergy Research (CoFAR) Central Biomarker Facility. In this role, we perform two major functions: conducting biomarker assays and acting as a repository for biological specimens generated from clinical trials. In particular, we are performing basophil activation tests (BATs) and serological measurements of food-specific antibodies for the ongoing OUTMATCH study. Within the repository, UNC houses serum, plasma, PBMCs, saliva, stool, and urine. We will also play a key role in the SUNBEAM birth cohort study quantifying food-specific antibodies and storing biological samples.

Current funding: CoFAR Biomarker