Trick or Treat: Trick your Immune System and Turn off your Peanut Allergy

“We think we’ve found a way to safely and rapidly turn off the allergic response to food allergies,” 

says Paul Bryce, an assistant professor at Northwester University

Anaphylaxis is the body’s severe, allergic reaction to an allergen. It occurs after the initial exposure to a foreign substance such as a peanut or bee sting venom causes a body to become sensitized to that substance.  On a second exposure to this foreign substance, the body recognizes it as an allergen triggering an adverse reaction, which can result in anaphylaxis. Typically within 15 to 30 minutes of exposure, the body undergoes a severe reaction.  Some of the symptoms include throat swelling, an itchy rash, low blood pressure and/or shock which can eventually lead to loss of consciousness and death.  During anaphylaxis, tissues from different parts of the body release histamine and other cytokines that can cause the airways to tighten the throat to close.  According to the National Institutes of Health (NIH), approximately 15,000 to 30,000 episodes of anaphylaxis and 100 to 200 related deaths occur each year within the United States.

            From an immunological perspective, anaphylaxis is classified as a type 1 hypersensitivity. In type 1 hypersensitivity, an antigen producing cell (APC) presents an antigen to a CD4+ Th2 cell which stimulates B cell proliferation, differentiation and production of IgE antibodies specific to the antigen.  The IgE antibodies bind to Fc receptors on the surface of mast cells and basophils.  These coated cells are termed “sensitized” by the IgE. When the body is exposed to the same allergen another time, the bound IgE on these sensitized cells cross-link. This interaction signals the release of active mediators of inflammations such as histamine, leukotriene, and prostaglandin to the surrounding tissues which leads to anaphylaxis.

 All of this research raises the question of why do some people develop hypersensitivity while others do not? The exact mechanism as to why some individuals are more prone to type-I hypersensitivity is not fully understood. However, previous research has shown that individuals with this form of sensitivity produce more TH2 cells that secrete IL-4, IL-5 and IL-13 which promote isotype switching to the IgE production observed in this allergic response.

            For highly allergic individuals, even the smallest amount of allergen can provoke anaphylaxis. Currently avoidance and symptom control are the most widely used means to cope with most allergies. Therefore in his study titled Antigen-Fixed Leukocytes Tolerize Th2 Responses in Mouse Models of Allergy, Smarr and his team of researchers attempted to find a more pragmatic cure for allergies.  In previous research projects, Smarr’s team has demonstrated that intravenous administration of peptides attached to the surface of syngeneic splenic leukocytes termed Ag-coupled splenocytes (Ag-SPs) with the chemical crosslinking agent 1-ethyl-3-(39-dimethylaminopropyl)-carbodimide (ECDI) safely and efficiently induced Ag-specific immune tolerance.  This enabled the team to attach an antigen the hypersensitive person would normally recognize as foreign and attack, such as antigens from peanuts, to white blood cells called leukocytes.  When these modified white blood cells were reintroduced into the individual the individual would not experience the life-threatening allergic reaction because their immune system now recognizes the antigen as safe. Their previous success with this model in autoimmune studies with TH1/Th17 mediated models encouraged them to extend their work with this model to study Th2 models associated with food allergies.

            In this study, Smarr et al 2011 pretreated mice with ECDI-fixed Ag-coupled splenocytes in two murine models: a food allergy model to whole peanut extract (WPE) and an Ovalbumin-induced (OVA-induced) allergic asthma airway inflammation model to examine the effectiveness of Ag-SP–induced tolerance to control allergic reactions. These models therefore mimicked an allergic asthma and an allergic peanut food allergy response in mice respectively. 

In the allergic airway inflammation model, they administered OVA-coupled splenocytes (OVA-SP) into pre-sensitized mice before two exposures with OVA in alum adjuvant. They compared the effect of the OVA-SP to Sham-SP (MBP-SP) on local allergic responses induced by the inhaled allergen, aerosolized OVA. After examining the Bronchoalveolar lavage (BAL) fluid, they determined that the OVA-SP treated mice had significantly reduced lung esinophilia as well as reduced Th2-associated cytokines IL-4 and IL-5.  Furthermore, the allergic response was inhibited which was indicated by the reduced concentrations of blood eosinophils as well as reduced OVA-specific IgE levels. 

In the food allergy model (WPE), the researchers constructed Ag-SPs by attaching peanut proteins onto white blood cells called leukocytes. They reintroduced these modified leukocytes into the mice prior to sensitization.  After two treatments, the mice were fed a peanut extract. Fifteen minutes after digestion, the mice tolerized with WPE showed significantly reduced symptom scores compared to the control Sham-SP tolerized mice. Tolerization occurs when allergens rendered nonimmunogenic are used to stimulate formation of allergen-specific suppressor T lymphocytes that will suppress IgE synthesis.  The core body temperature was also measured because anaphylaxis is known to lead to vascular leaks and hypothermia because of hypotension which can lead to decreases in body temperature. They found that the WPE-Sps significantly prevented core temperature decreases. Peripheral blood esopsinophil numbers were also reduced.  Furthermore WPE-specific IgE was undetectable whereas the WPE-specific IgG1 was unaffected. The results suggested that WPE treated mice prevented the Ag-specific Th2 associated allergic response. The treated mice also showed extremely reduced or absent levels of anaphylaxis, which led Smarr’s team to conclude that the mice’s immune system now recognized the protein as safe and therefore restrained from mounting an immune response.        

The authors’ work shows that the Ag-SP method efficiently, quickly and safely prevented allergic disease responses in mice.  Ag-SP in both models decreased Th2 responses, eosophilia and Ag-Specific IgE.  The success of the project has led the authors to want to extend their work in the future to perhaps attaching more than one protein to the surface of white blood cells to see if they can target multiple allergies at once.  They also have extended this model to other fields of concern in immunology such as autoimmune diseases like rheumatoid arthritis and type I diabetes.  Other researchers at Northwestern University are currently using a similar technique to study the progression of multiple sclerosis. Hopefully this model that appears to be successful in murine models will be equally successful in humans. Maybe one day peanut allergies and asthma will be a thing of the past. 

Source

Smarr CB, Hsu CL, Byrne AJ, Miller SD, Bryce PJ. (2011). Antigen-Fixed Leukocytes     Tolerize Th2 Responses in Mouse Models of Allergy. J Immunol.

Other Sources

Anaphylaxis . NIH (2010). Retrieved on October 16, 2011 from http://www.ncbi.nlm.nih.gov/pubmedhealt/PMH0001847/

Ghaffar, Abdul. IMMUNOLOGY - CHAPTER   SEVENTEEN HYPERSENSITIVITY            REACTIONS. Retrieved on October 16^th 2011 from http://pathmicro.med.sc.edu/ghaffar/hyper00.htm.