New Treatments: Blocking MCP-1

In November of 2009, a study was conducted by researchers Tominaga, Miyazaki, Sasaki, Mihara, Komatsu, Yakura and Inoue from the Division of Ophthalmology & Visual Science at Tottori University in Japan and published in Investigative Ophthalmology & Visual Science. The study focused on the effects of monocyte chemoattractant protein-1 (MCP 1) in the inflammatory response associated with allergic conjunctivitis. Before delving into the study, let's go into a little more detail regarding allergic reactions.

Allergic reactions can be divided into two categories: Type I immediate-type hypersensitivity or Type 4 delayed-type hypersensitivity (DTH). We are already familiar with Type I, which involves IgE antibodies on mast cells. If you remember, the process of Type I is as follows:

- Allergen enters the body and binds to receptors on a type of white blood cell called a B cell

- B cells digest the allergen and present it to a type of white blood cell called a CD4+ TH2 helper cell

- TH2 cells secrete some mediators that attract other types of white blood cells and other mediators called cytokines IL-4 and IL-5

- IL-4 and IL-5 induce B cells to differentiate into another type of white blood cell called a plasma cell, which then secretes the IgE antibody

- IgE antibodies bind to mast cells

- IgE antibodies are now ready to bind allergen, activating the mast cell to release histamine and other inflammatory mediators

Type 4 or DTH gets its name from the fact that it takes longer (about 1 - 2 days) for this type of allergic reaction to take place, whereas Type I is acute or immediate. DTH involves a type of white blood cell called a macrophage, which basically eats things. In DTH, the macrophage eats the allergen. The process is as follows:

- Attractive mediators secreted by TH2 cells in Type I hypersensitivity recruit other white blood cells, such as macrophages, to the site of the allergen exposure

- Allergen is recognized as foreign by the macrophage, which engulfs it and breaks it up inside

- Macrophage brings those tiny pieces of the allergen to its cell surface and presents it to another type of white blood cell, called a CD4+ TH1 helper cell

- TH1 cells secrete mediators or cytokines called IL2 and IFN γ

- IFN γ stimulates the macrophage to produce a substance called nitric oxide, which produces vasodilation or opening of blood vessels that leads to eye swelling and redness

- IL2 activates another type of white blood cell called a CD8+ cytotoxic T cell (CTL) which essentially kills other cells that have bound the allergen, resulting in eye tissue damage and pain

With all of the different types of white blood cells and cytokines it can get a little confusing, but the take-home message is that an allergic reaction begins with Type I immediate-type hypersensitivity. The longer the allergen stays in the body, the more activated Type I hypersensitivity TH2 cells are and the more likely macrophages will be attracted to the site of the allergen, increasing the chances of a Type 4 DTH.

In the study, the researchers found that injecting mice subjects with MCP-1 caused an allergic reaction, while blocking MCP-1 prevented the allergic reaction. Therefore, MCP-1 must play a key role in causing an allergic reaction. Through further analysis, researchers determined that MCP-1 did not affect IgE antibodies on mast cells at all, which suggests that MCP-1 is necessary for mast cell activation even if IgE binds an allergen. Therefore, blocking MCP-1 may be a new route of therapy for patients with allergic conjunctivitis. Also, blocking MCP-1 prevented Type 4 DTH from occurring after Type I hypersensitivity set in.

The results are interesting and goes to show that we don't know the whole picture for something that seems as simple as allergies. The more things we find are involved with allergic reactions, the more options the pharmaceutical industry has for designing drugs. Maybe the next new drug for allergic conjunctivitis will involve blocking of MCP-1. The fact that more and more mediators are being discovered only gives hope that one day a drug target may be discovered, in which the medication to alter it has an even larger safety profile than what is available today.

New Treatments: Cyclosporine A (CyA)

In March of 2010, a study was conducted by researchers Shii, Nakagawa, Yoshimi, Katsuta, Oda and Nakamura from the Research & Development Center of Santen Pharmaceutical Company in Nara, Japan and published in the Biological & Pharmaceutical Bulletin. This study focused on the use of Cyclosporine A (CyA) to treat allergic conjunctivitis. Cyclosporine is an immunosuppressant medication commonly used to treat patients who have received organ transplants. Cyclosporine eye drops have been used to treat pets, such as dogs and cats, with allergies. However, the use of cyclosporine to treat allergic conjunctivitis in humans hasn't been widely studied. Restasis is a cyclosporine product that has been used in humans, but its indication has been for dry eyes. The researchers in this study sought to study CyA specifically for allergic conjunctivitis.

In the study, researchers injected guinea pigs with a mixture of ovalbumin (OVA) and Freund's complete adjuvant (FCA), which are just chemicals that induce an allergic reaction. The guinea pigs expressed swelling and discharge from the eyes, suggesting the allergic response had taken hold. After six hours, the researchers used the CyA eye drops on the guinea pigs, which produced a decrease in discharge from the eye. However, CyA did not significantly decrease the swelling.

CyA did inhibit infiltration of white blood cells and fluid in the later stage of the allergic reaction. The researchers have concluded that CyA is effective in decrease late-stage symptoms, but does not alleviate symptoms related to the early-phase of the reaction. With the other medications out there, like anti-histamines and mast cell stabilizers, that work in both the early and late-stage phases of the inflammatory response, it may be better to just skip this one.

For more information about the history of CyA Click Here

For more information about Atopica, an ophthalmic CyA for animals Click Here

For more information about Restasis Click Here

New Treatments: Beta-escin

Horse-chestnut Tree Seed

In May of 2010, a study was conducted by researchers Lindner, Meier, Url, Unger, Grassauer, Prieschl-Grassauer and Doerfler from Marinomed Biotechnologie GmbH in Vienna, Austria and published in BMC immunology. The study focused on the use of beta-escin to treat Type I hypersensitivity or allergic reaction. Beta-escin is the major active ingredient in Aesculus hippocastanum or Horse-chestnut tree seed extracts. Due to its anti-inflammatory properties, it has been used for many conditions, such as hemorrhoids or swollen veins in the rectum. However, there have been no prior experiments to test the use of beta-escin in subjects with allergies.

In the study, researchers divided the mice subjects into three categories: pre-treated with beta-escin, dexamethasone or sodium chloride. Dexamethasone is a corticosteroid that will reduce inflammation, so it can be used to prevent allergic reactions. Sodium chloride has no effect and simply serves as a control. After pre-treatment with a designated compound, an allergic reaction was induced in the mice at varying times. The researchers found that beta-escin was comparable to and sometimes more effective than dexamethasone. Earlier pre-treatment with beta-escin produced protective effects for at least six hours, preventing allergen-IgE-mediated mast cell activation. Later pre-treatment with beta-escin reduced the inflammatory response already started by mast cell activation. Beta-escin also inhibited the release of cytokines from TH2 helper cells, decreasing later activation of mast cells.

As promising as these results appear, this study focused on the use of oral beta-escin to treat allergy-associated inflammation of the airways. Experiments on the eyes were not conducted, so we don't really know the safety profile of beta-escin when used in eye drop form. However, the fact that the compound countered the allergic reaction, gives hope that it can effectively reduce inflammation of the conjunctiva.

The benefit of beta-escin, is that it is a natural and relatively safe product. Long-term use of anti-histamines and corticosteroids, like dexamethasone, have unfavorable side effects and serious complications that make them less safe. Beta-escin has a much better safety profile, so it could be an alternative for patients wanting to the avoid the side effects of other medications. Of course beta-escin must be tested further and long-term clinical trials must be conducted to determine if it has long-term safety, but the results look promising. It will be interesting to see how this compound develops over the next couple of years.

New Treatments: Targeting TSLP

In June of 2010, a study was conducted by researchers Zheng, Ma, de Paiva, Cunningham, Hwang, Pflugfelder and Li from the Department of Ophthalmology at Baylor College of Medicine and published in Investigative Ophthalmology & Visual Science. The study focuses on targeting the mediator, thymic stromal lymphopoietin (TSLP), to reduce the inflammatory response associated with an allergic reaction. Before delving into the study, let's take a look at the role of TSLP in an inflammatory response:

- Allergen enters the body and binds to receptors on a type of white blood cell called a B cell

- B cells digest the allergen and present it to a type of white blood cell called a CD4+ TH2 helper cell

- TH2 cells secrete mediators called cytokines IL-4 and IL-5

- IL-4 and IL-5 induce B cells to differentiate into another type of white blood cell called a plasma cell, which then secretes the IgE antibody

- IgE antibodies bind to mast cells

If you remember, the IgE antibodies on the mast cells are ready to bind allergen, activating the mast cell to release histamine and other inflammatory mediators, such as arachadonic acid. In this general scheme of the allergic response, TSLP's role is activation of TH2 cells:

- Allergen stimulates epithelial cells, like the conjunctiva, to release TSLP

- TSLP activates a type of white blood cell called a dendritic cell (DC)

- DCs release mediators that activate TH2 cells, which release IL-4 and IL-5

- IL-4 and IL-5 increase B cell differentiation into plasma cells and release of IgE

- IgE antibodies bind to mast cells

So you can see that TSLP also plays a role in the inflammatory response. The effect of TSLP is comparable to an antigen-bound B cell because both are involved in activating the TH2 cells to release IL-4 and IL-5. With all the different types of white blood cells and the mediators they release, it can get a little confusing.

The take-home message is that the immediate effects of TSLP produce the end-result of IgE antibodies binding to mast cells, which can now bind allergens and produce the inflammatory response. The function of TSLP has been shown in the lungs, gut and skin, but not the eyes...

This study was used to identify the presence of TSLP in allergic conjunctivitis because it hasn't been proven to be involved in the inflammatory process of the eye. An allergic reaction was induced in the experimental group of mice multiple times, using pollen extract. Another group of mice did not receive the pollen extract, serving as the control. After the last allergic reaction, the conjunctiva was harvested from both the experimental and control groups, and the genetic sequences analyzed for expression of the TSLP mediator.

The researchers found a significantly increased expression of TSLP genes in the experimental group compared to the control group. Although the results are promising, much of the study is theoretical and more experiments must be conducted to determine if TSLP really plays a key role in the inflammatory response. If TSLP is determined to play a causative role in the inflammatory response, it serves as a new target for drugs aimed at preventing allergic conjunctivitis.

For information about TSLP Click Here

To view another TSLP study from Clinical & Molecular Allergy Click Here

New Treatments: Cooling Sheets

In July of 2010, a study was conducted by researchers Hirakawa, Yanoshita, Yoshii and Yano from Kobayashi Pharmaceutical Company in Tokyo and published in the Journal of the Pharmaceutical Society of Japan. The study focused on the use of cooling sheets on eye itching associated with allergic conjunctivitis. The cool sheets should give a soothing effect to alleviate itchiness, while producing a small extent of vasoconstriction in the blood vessels lining the conjunctiva. This would ideally decrease the infiltration of fluid and white blood cells into the conjunctiva, reducing swelling. 

The researchers used six subjects with allergic conjunctivitis, which served as the experimental group. The control group consisted of four subjects without allergies. Using a five-level itching score, researchers measured the severity of itching. They also measured the concentration of histamine in the subjects' tears; remember that there is an increased release of histamine during an allergic reaction.

The researchers measured the severity of itching and the concentration of tear histamine before cooling the eyelids. After five minutes of cooling the subjects' eyelids, an itching score and tear histamine concentration was obtained. The results showed a lower itching score and improvement in itchiness, when the cooling sheet was used. However, the cooling sheet had no effect on histamine concentration in the tears.

The researchers did discover that combining Livostin (Levocabastine Hydrochloride) with the cooling sheets, effectively decreased histamine concentration in the tears and eye itchiness. It would be safe to say that the cooling sheets are more of a supplemental therapy to use in conjunction with more reliable and effective pharmacological treatments. However, cooling sheets are an easy way to relieve the itchiness associated with allergic conjunctivitis and may be an easy-to-apply therapy for the pediatric population.