Nonallergen-specific Treatments for Food Allergy

Jay A. Lieberman, MD; Julie Wang, MD

Disclosures

Curr Opin Allergy Clin Immunol. 2012;12(3):293-301. 

In This Article

Chinese Herbal Therapy

Although traditional Chinese medicine, which encompasses various practices including herbal therapy, acupuncture, dietary therapy, and mind–body therapy, has been in use for centuries in Asian countries, it is still considered alternative medicine in the Western societies. This stigma is beginning to change, however, as researchers are putting many of these therapies through stringent, scientific trials in order to prove or disprove their efficacy.[7] In the field of allergic diseases, the majority of the randomized controlled clinical trials studying traditional Chinese medicine involve herbal therapies for atopic dermatitis or asthma.[8–16] There are fewer trials studying traditional Chinese medicine in food allergy, although this trend is changing with some promising data in both animal models and in human clinical trials being reported in the last few years.

Murine Model in Food Allergy

In 2001, Li et al.[17] first reported the effects of a formula containing 11 different herbs, termed the Food Allergy Herbal Formula (FAHF)-1, in a mouse model of peanut allergy. The formula was initially based on the herbal therapy, Wu Mei Wan, which has been used to treat gastroenteritis and asthma.[18] In that report, C3H/HeJ mice sensitized to peanut were treated with either FAHF-1 or water twice daily for 7 weeks after sensitization. Upon posttherapy peanut challenge, mice treated with FAHF-1 had no symptoms of anaphylaxis, whereas the sham-treated mice had significantly elevated anaphylaxis scores and had significant decreases in body temperature. This clinical effect was associated with significantly lower plasma histamine levels, lower numbers of degranulated tissue mast cells, and lower levels of peanut-specific serum IgE.

In an attempt to simplify the formula and increase its safety, the researchers later modified FAHF-1 by removing two of the herbs, which were potentially toxic if processed improperly. The resultant nine-herb formulation was termed FAHF-2, and its efficacy and safety were studied in the same murine model of peanut anaphylaxis.[19] In that report, FAHF-2-treated mice, unlike sham-treated mice, had no signs of peanut-induced anaphylaxis upon challenge 1-week posttherapy. The effect did not appear to be transient, as FAHF-2-treated mice continued to have completely abrogated responses to peanut challenges at 3 and 5 weeks posttherapy, whereas sham-treated mice continued to exhibit anaphylaxis. This clinical effect was again associated with decreased plasma histamine levels, decreased vascular leakage, decreased peanut-specific IgE levels, and increased peanut-specific IgG2a level.

In a follow-up study of the duration of action, Srivastava et al.[20] showed that at 26 weeks posttherapy, all of the FAHF-2-treated mice remained completely protected from anaphylaxis upon peanut challenge, whereas all of the sham-treated mice exhibited signs of anaphylaxis (including one death). The effect was persistent at 36 weeks posttherapy, although it was not as effective at this point, as three of the eight mice treated with FAHF-2 exhibited moderate allergic reactions.

Mechanism of Action

The therapeutic effect of FAHF-2 appears to be at least partially dependent upon a shift in immune response from a T helper (Th)-2 response to a Th1 response. All of the murine studies[19–21] have shown decreases in IL-4, IL-5, and IL-13 levels and increases in IFN-γ from splenocytes or mesenteric lymph node cells of FAHF-2-treated mice. The elevated levels of IFN-γ, later discovered to be the product of CD8+ T cells, appeared to be one of the keys to the formula's effect.[21] In fact, depletion of IFN-γ or CD8+ T cells blocked the suppression of IgE and Th2 cytokine responses generated by FAHF-2.[20] Interestingly, this immune-modulatory effect did not correlate completely with the clinical effect. Although the anti-IFN-γ antibody could block the Th2 to Th1 shift caused by FAHF-2 throughout treatment, it did not block the clinical effects of FAHF-2 immediately (1 week) posttherapy, rather abrogation of the clinical effects of FAHF-2 by anti-IFN-γ were not seen until the second peanut challenge 4 weeks later.[20] The researchers hypothesized that FAHF-2 could, therefore, be working on mast cells and basophils through both IFN-γ-dependent and IFN-γ-independent mechanisms. They went on to show that FAHF-2-treated mice had lower numbers of peripheral blood basophils and peritoneal mast cells than sham-treated controls. In addition, in a mast cell line, FAHF-2 inhibited IgE-stimulated mast cell proliferation and IgE-mediated upregulation of the high affinity IgE receptor (FcεRIα).[22] Therefore, it appeared that FAHF-2 had more than a single mechanism of action, which may reflect the fact that it is a combination of multiple herbs that may have different effects on the immune system.

When examining each herb individually, Kattan et al.[23] found that no single herb in the FAHF-2 formula could reproduce the clinical effect of the entire formula. Even when attempting to create a simplified version of the formula using what appeared to be the three most potent ingredients, the authors found that the simplified formula was only partially effective. Therefore, the combination of the nine herbs in FAHF-2 acting in concert is required to achieve the full effect.

Human Studies

Based on the success of FAHF-2 in the murine model, studies[24•,25•] of the efficacy and safety of FAHF-2 have now been initiated in humans. The initial phase I trial of FAHF-2 examined the safety and dose tolerability of FAHF-2 using a randomized, double-blind, placebo-controlled, dose-escalation trial design.[24•] Three doses of FAHF-2 were used: 2.2 g (four tablets), 3.3 g (six tablets), or 6.6 g (12 tablets), which were taken three times daily for 7 days. Overall, the treatment was very well tolerated. Adverse events included one patient in the placebo group reporting vomiting and one patient in the active group reporting loose stools. In addition, one patient in the active arm did withdraw due to a rash, but after evaluation, this was deemed to be a flare of his underlying atopic dermatitis and unlikely related to the medication. Initial immunologic analysis after 7 days of treatment showed no effect on allergen-specific IgE levels or skin prick test results, but those in the active arm did have significantly lower levels of IL-5 after treatment, which was not seen in the placebo group.

More recently, results of the extended, open-label phase I trial of FAHF-2 have been reported.[25•] In this study, participants received 3.3 g (six tablets) of FAHF-2 three times daily for 6 months in order to look at long-term safety. Eighteen individuals were enrolled and 14 completed the study, with the reasons for withdrawal being pregnancy (one), difficulty with compliance due to time commitment and number of tablets to swallow (two), and abdominal pain (one). Among the 14 individuals who completed the study, there was only one adverse event noted during the 6 months of treatment; this patient had eosinophilic esophagitis thought to be in remission prior to study entry, but experienced a recurrence of symptoms (abdominal pain, dysphagia, and food impaction) during the treatment period. After initiating treatment for her eosinophilic esophagitis, this patient was able to complete the 6 months of FAHF-2. In regard to laboratory findings, there were no changes seen in hematology or chemistry laboratory values, pulmonary function tests, or electrocardiographic findings at baseline, 2, 4 or 6 months of treatment. In this extended phase I trial, the authors also showed some mechanistic data, with evidence of decreased percentages of CD63+ basophils in peripheral blood upon antigen stimulation after 6 months of treatment.

Future Endeavors and Obstacles

Currently, a multicenter, double-blind, placebo-controlled phase II trial is ongoing (Clinicaltrials.gov identifier: NCT00602160). In this study, participants are randomized to receive FAHF-2 or placebo tablets at a dose of 10 tablets three times daily. This large tablet load is a barrier to adherence; therefore, newer extraction techniques are being explored. One such technique, butanol extraction, is able to decrease the effective volume of the compound by approximately five fold. The clinical efficacy of this product has been demonstrated in the mouse model.[26] Additional studies are planned to determine the safety of this product in humans.

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