Rubber Elongation Factor and Natural Allergy-Oncology

Natural allergy therapy is a non-conventional medical approach that utilizes natural allergens to treat cancer. The term “natural allergy” is created from “natura” (Latin root for birth) and “allergy” an idea created by Clemens von Pirquet (1874-1929) in the understanding that the function of the immune system should be rationalized not in terms of exemption of disease but in terms of change of reactivity. The natural allergy-oncology perspective explores how forced immunity to allergens from the rubber tree H. brasiliensismay inhibit tumor growth and metastasizing. The over expression of mast cells and proteins from the Rho family of GTPases has been shown to manifestin multiple types of cancer. Rubber elongation factor (Hev-b 1) is an allergen from Hevea brasiliensis that has structure homology with members of the Rho family of GTPases. Forced immunity to Hev-b 1may provide IgEprimed mast cells that cross-react with members of the Rho family of GTPases and affect angiogenesis in tumors. Research efforts should be directed at exploring if forced immunity to H.brasiliensis allergens can be used as a supplementary-treatment to inhibit tumor growth and metastasizing.


Introduction
Natural allergy therapy is a non-conventional medical approach that utilizes natural allergens to treat cancer. The term "natural allergy" is created from "natura" (Latin root for birth) and "allergy" an idea created by Clemens von Pirquet  in the understanding that the function of the immune system should be rationalized not in terms of exemption of disease but in terms of change of reactivity. In an article from the International Journal of Green Pharmacy titled, Plant latex: a natural source of pharmaceuticals and pesticides, author Ravi K.. Upadlhyay writes, "In recent times use of plant natural products has increased tremendously, and there is a very high demand of herbal products for therapeutic, clinical, agricultural purposes. Plant latex is a rich source of pharmaceuticals, pesticides and immune allergens. It also contains important biomolecules such as glycosides, tannins, phytosterols, flavonoids, acetogenins and saponins, which show diverse biological activities against bacteria, fungi, viruses, protozoans, nematodes, insects, and cancer and tumors" [1].
The objective of natural allergy-oncology is to reveal the function of IgE-mediated immune responses against cancer cells in order to enhance the understanding of its biology and to develop novel IgEbased treatment options against malignant diseases. In a research article from Allergy titled, Allergo-oncology: the role of IgE-mediated allergy in cancer the researchers state, "IgE antibodies may not only act in natural tumor surveillance, but could possibly also be exploited for tumor control in active and passive immunotherapy settings" [2].
Research has shown that an elevated expression of IgE antibodies may reduce the risk of cancer. In an article from the Journal of the National Cancer Institute titled, Association between Prediagnostic IgE Levels and Risk of Glioma, the researchers concluded, "An inverse association between IgE levels and risk of glioma was detected; the association was present at least 20 years before tumor diagnosis" [3].
Cancer suppression is suspected with IgE antibodies in that they are extremely biologically active despite low concentration in the blood stream, approximately one-thousandth of a percent. IgE bind to high affinity receptors on the surface of effector cells (e.g., mast cells, basophiles, and eosinophils) to provide IgE-primed effector cells, making them very sensitive to allergens. In an article from the Journal of Allergy and Clinical Immunology titled, IgE, Mast Cells, Basophils, and Eosinophils, the researchers state, "Total IgE levels are also influenced by genetic makeup, race, immune status and environmental factors" [4].
Research indicates that mast cells and Rho GTPases may play and important role in in tumor cell survival and propagation. In an article from Biochimica et Biophysica Acta (BBA) -Molecular Basis of Disease titled, Mast cells, angiogenesis, and tumour growth, the authors write, "These cells actively take part to innate and acquired immune reactions as well as to a series of fundamental functions such as angiogenesis, tissue repair, and tissue remodeling [5]. Furthermore, proteins from the Rho family of GTPases have been shown to be over expressed in multiple types of cancer. In an article from the journal Biochemistry & Molecular Biology titled, Overexpression of RhoA promotes the proliferation and migration of cervical cancer cells, the authors write, "We found a positive correlation among RhoA with the progression of cervical cancer by in vivo and in vitro evidences. A high RhoA expression in cervical cancer may predict a high metastatic potential of cervical cancer" [6].
There continues to be a need for a supplementary-treatment that inhibits tumor growth and metastasizing. Rubber elongation factor (Hev-b 1) is an allergen from H. brasiliensis that has structure homology with members of the Rho family of GTPases. Forced immunity to Hev-b 1 may provide IgE-primed mast cells that cross-react with members of the Rho family of GTPases and affect angiogenesis in tumors. Therefore, natural allergy-oncology research efforts should explore if Hev-b 1 can be used as a supplementarytreatment to inhibit tumor growth and metastasizing.

Discussion
In the present medical hypothesis, it is speculated that forced immunity to the allergen rubber -elongation-factor (Hev-b 1) may provide IgE-primed mast cells that may cross-react, based on β-sheet structure homology, with members of the Rho family of GTPases to inhibit tumor growth and metastasizing. H. brasiliensis natural rubber latex contains about 2-5% protein by weight. Analysis indicates about 200 dissimilar proteins therein and about 50-60 are suspected allergens which may induce Type-I hypersensitivity called latex allergy. The World Health Organization International Union of Immunological Societies has assigned names to thirteen allergenic proteins Hev-b 1-13.
The Hev-b1 allergen is a water-insoluble protein with a molecular weight of 14.6 Kda [7]. Research has shown that the Hev-b1 allergen shows all the characteristic of an amyloidal protein with high aggregation properties. The researchers believe that this is the first report of anamyloidal protein observed in the plant kingdom.A study has shown that Hev-b1, a major allergen component in H. brasiliensis natural rubber latex has amyloidal (β-sheet) properties [8].
Members of the Rho family of GTPasesare often over expressed in many malignant tumors that metastasize.The Rho family of GTPases is a family of small (~21 Kda) signalling G-protein and is a subfamily of the Ras super family. Rho proteins are structurally comprised of six-stranded β-sheets and five α-helices [9].
Forced immunity to Hev-b1 may be induced in cancer patients using the natural allergen(nHev-b) or an effective combination of the natural allergen and recombinant allergen(rHev-b1). The rHev-b1 fusion protein has been shown to exhibit a corresponding IgEbinding reactivity to nHev-b1 [10]. Mixtures of Hev-b allergensin the presence of immunologic adjuvants are also contemplated to increase the prevalence of IgE primed mast cells that may cross react with the Rho family of GTPases.
Preferably, forced immunity to the Hev-b1 allergen is accomplished through intracutaneous (IC) exposure and/or intraperitoneal (IP) exposure. Research has shown that IC and IP latex exposure can induce a striking increase in specific immunoglobulin E (IgE) levels along with the induction of T-helper type 2 (Th2) cytokines and β-chemokines [11].
An allergy blood test or skin prick test may be used to determine if members of the Rho family of GTPasescross-react with IgE-primed mast cells induced by natural allergy therapy.
Effective cancer immunotherapy, cross-reacting IgE-primed mast cells with members of the Rho family of GTPases, may depend heavily on secondary structure (β-sheet) homology. Research has disclosed that it is expected that similarity in short stretches of the linear amino-acid sequence is unlikely to result in relevant crossreactivity between two proteins unless there is similarity in the protein fold [12].
A contraindication is a medical condition or medical factor that serves as a reason to withhold treatment. Forced immunity to H. brasiliensis natural rubber latex (e.g., Hev-b 1) is a relative contraindication in that the risks of complications from latex allergy often do not outweigh the serious condition of a tumor metastasizing and growing.
In a communication from the Centers for Disease Control and Prevention (CDC) titled, Leading Causes of Death, statistics showed that cancer was the second leading cause of death in the year 2014 [13].
Alternatively, the American Latex Allergy Association writes that latex allergy symptoms can range from mild too severe, and can include one or more of the following: Hives or welts; Swelling of affected area; Runny nose; Sneezing; Headache; Reddened, itchy or teary eyes; Sore throat, hoarse voice; Abdominal cramps; Chest tightness, wheezing, or shortness of breath (asthma period).
If exposure to latex continues, allergy symptoms may include a severe and life threatening allergic reaction called anaphylaxis [14].
The Advisory Committee on Immunizations Practice from the CDC provides the following general recommendation on immunizations and latex allergy, "If a person reports a severe (anaphylactic) allergy to latex, vaccines supplied in vials or syringes that contain natural rubber, or whose product information does not say "not made with natural rubber latex" should not be administered unless the benefit of vaccination outweighs the risk for a potential allergic reaction. In these cases, providers should be prepared to treat patients who are having an allergic reaction. For latex allergies other than anaphylactic allergies (e.g., a history of contact allergy to latex gloves), vaccines supplied in vials or syringes that contain dry natural rubber or rubber latex may be administered" [15].
A limitation of natural allergy therapy as a supplementary-treatment relates to the understanding that a number of anticancer drugs may cause impairment of antibody synthesis and cell-mediated immunity. In an article from Transplantation Proceedings titled, Immunosuppression and Cancer, the authors write, "While cancer chemotherapy has had some notable successes, the overall results have been rather disappointing. These have been blamed on unresponsiveness of the tumor to a particular agent, or to the subsequent development of resistance by the cancer cells, or to the toxic effects of the compounds used. Another factor, which has received relatively scant attention, is the prolonged immunosuppressive effect of the agents when administered continuously. Could this be the explanation for the observation that a better objective response and longer survival was observed when chemotherapy was given intermittently rather than continuously?" [16].