© 2003 Robert A. Freitas Jr. All Rights Reserved.

Robert A. Freitas Jr., Nanomedicine, Volume IIA: Biocompatibility, Landes Bioscience, Georgetown, TX, 2003

15.2.6.1 Allergic Reactions (Hypersensitivity)

An allergic reaction or “hypersensitivity” is the most common disorder of immunity, affecting ~20% of the U.S. population. This reaction is an acquired and abnormal immune system response to a substance, called an allergen, that normally does not cause a reaction. An allergy requires an initial exposure to an allergen, which produces sensitization to it. Subsequent contact with the allergen then results in a broad range of inflammatory responses. Common allergic conditions or symptoms include eczema or atopic* dermatitis, allergic rhinitis, bronchial asthma, urticaria (hives) and food allergy. Allergens may be introduced by skin contact (e.g., cosmetics, jewelry), ingestion (e.g., food), inhalation (e.g., pollen), or injection (e.g., drugs). Most allergic reactions are mediated by IgE antibodies (Section 15.2.3.3). Hypersensitivity reactions may be trivial, resulting in a rash, or serious, causing potentially lethal anaphylactic shock. Could nanorobots become allergens and provoke an allergic reaction?

* An “atopic” allergy differs from normal hypersensitivity reaction in that there exists a genetic predisposition for the reaction in the patient’s histocompatibility genes. Atopic diseases typically produce IgE antibodies to harmless inhalants such as pollens, molds, animal danders and dust mites. Hay fever and asthma (~20% of the population [2005]) are two of the most common inherited allergies.

Allergic reactions are usually classified by the type of tissue damage that they cause. Some allergic reactions produce more than one type of tissue damage, and other reactions involve antigen-specific lymphocytes rather than antibodies. The four recognized types of allergic reaction are:

Type I: Anaphylaxis. Anaphylaxis is the most extreme systemic form of immediate-type hypersensitivity in which the antigen-antibody complex binds to mast cell and basophils, causing their degranulation and release of histamine, leukotrienes and prostaglandins responsible for hypotension, bronchoconstriction and edema [5489]. Anaphylaxis occurs when a specific allergen combines and cross-links IgE* affixed to basophils in the circulation and to mast cells in the tissues to induce a major mast cell response [2052], as for instance in the reaction to ragweed pollen, or in allergic bronchial asthma. The primary function of mast cells – which reside in connective tissue just below epithelial surfaces, in serous cavities, and around blood vessels – is to synthesize and store histamine (a strong vasodilator and bronchoconstrictor), serotonin, bradykinin, and other mediators of inflammation such as neutrophil and eosinophil chemotactic factors, in intracellular granules. During the mast cell response, the cells release these stored substances. This causes flushing, urticaria, asthma, angioedema, change in smooth muscle tone, increased secretion of thickened mucus, lower blood pressure, changes in cardiac contractility, and local recruitment of leukocytes. Major systemic reactions can be life-threatening and may involve vomiting, severe bronchial obstruction and vasodilation, increased venule permeability and diminished blood volume, laryngeal or pulmonary edema, and cyanosis. Another major systemic reaction is shock (i.e., circulatory collapse), a systemic response which is secondary to profound vasodilation and rapid decrease in systemic blood pressure. Shock can also involve a limited, localized reaction. For instance, complement-derived anaphylatoxins can stimulate intravascular neutrophil aggregation and embolization to the pulmonary microvasculature, where neutrophil products including elastase and free radicals may cause the condition of shock lung [955]. Symptoms begin within 2 hours of exposure to allergen. Clinical examples of IgE-mediated anaphylaxis include reactions to serum proteins, venoms and insect stings, enzymes, vaccines, allergen extracts, hormones, seminal plasma, foods, polysaccharides and drugs [2052].

* Non-IgE-mediated anaphylaxis-like reactions, called anaphylactoid reactions, may occur (1) by activation of complement (e.g., during transfusions in IgA-deficient patients), leading to generation of C3a and C5a anaphylatoxins (Section 15.2.3.2); (2) by arachidonate mediated pathways (e.g., aspirin or nonsteroidal anti-inflammatory agents); (3) by direct mast cell-releasing agents (e.g., opiates); or (4) by physical stimuli or exercise [2052]. Anaphylactoid reaction may occur at first exposure to an allergen, unlike anaphylaxis.

Type II: Cytotoxic Reactions. These are antigen-antibody reactions mediated by IgG and IgM at cell surfaces that result in the lysis of blood cells (red cells, white cells, and platelets) due to the release of complement. Clinical examples include the body’s reaction to transfusion with incompatible blood cells (producing hemolytic transfusion reaction with symptoms of fever, chills, headache, hypotension, and even vascular collapse in severe cases); erythroblastosis fetalis; and Goodpasture’s syndrome.

Type III. Immune Complex Reactions. These are antigen-antibody reactions mediated by IgG and IgM in fluid spaces. The reactions produce toxic antigen-immunoglobulin complexes that circulate in the blood. There, the complexes cause damage by adhering to blood vessel walls and initiating an inflammatory response (vasculitis). Serum sickness, characterized by fever, joint and muscle pain, lymphadenopathy and urticaria, can occur in sensitized patients who are receiving penicillins, sulfonamides, or animal-derived antitoxins. Localized immune complex reactions (Arthus reactions) can damage organs, joints, and other structures.

Type IV. Delayed-Type Hypersensitivity (DTH) or Cell-Mediated Immunity (CMI) Reactions. These are reactions between antigens and sensitized antigen-specific T lymphocytes, not antibodies. The reaction subsequently releases inflammatory substances, toxic substances, and lymphokines that attract other white cells. Clinical examples include tuberculosis, transplant rejection, and contact dermatitis in response to common allergens such as rubber in elastic materials, chromium in leather, and nickel in costume jewelry (which alter skin protein self-antigens to create new foreign antigens).

As of 2002, a comprehensive picture of the precise characteristics of allergenic molecules [2009, 5042, 5043] had not yet emerged in the field of molecular “allergology” [5044]. Most allergens are 15-40 kD acidic proteins or glycoproteins [2006, 2007], or other chemicals [2008]. Many of the known food allergens are homologous to pathogenesis-related (PR) proteins [2009] – proteins induced by pathogens, wounding, or certain environmental stresses. Many non-PR allergens [2009] belong to other protein families such as alpha-amylase and trypsin inhibitors from cereal seeds, profilins from fruits, vegetables and pollen [2010], and proteases from fruits. Food allergens typically have molecular weights from 10-70 kD [2011]. These allergens induce the production of antigen-specific IgE and are stable molecules resistant to processing, cooking and digestion [2011]. Non-food allergens may cross react with food allergens [2012, 2013]. For example, latex-allergic patients are also sensitive to a broad class of plant proteins called patatins found in potatoes and bananas [2013].

Nonprotein “allergens” (a term usually reserved for IgE reactions) may include nickel [2014-2018, 2021-2026], chromium [2022-2027], cobalt [2022-2024, 2033], gold [2024, 2030-2032], palladium ions [2019-2021, 2024], and other metals and metal-containing substances [2015, 2026-2029]; acrylic compounds [2034, 2035], epoxies [2036], hydrocarbons [824, 2037] and Teflon implants [1188]; and a few mineral substances such as aluminum silicate [2038], crystals of zirconium silicate and clay minerals [2039], at least one tricalcium phosphate ceramic [1048], and possibly silica dust [2040] (silica is a well-known antigenic adjuvant).* On the other hand, synthetic porous ceramic (Triosite) [2041, 2042], at least one bioactive glass-ceramic [2043], hydroxyapatite ceramic [1048], alumina ceramic [1048, 2028, 2044] and graphite [824, 2045] are considered nonallergenic. Ceramic coatings are used to eliminate metal allergies on implant surfaces [2046, 2047], and hypersensitivity to oral ceramic is reported only rarely [2048-2051]. Particles of carbon black can have a significant adjuvant effect on systemic specific IgE response to conventional protein allergens [867], and a few rare cases have been reported of allergic reaction to India ink particles used in endoscopic colonic tattooing [855]. There is one report [5026] that intraperitoneal injection of Teflon particles in mice can have an adjuvant effect, elevating serum levels of allergen-specific antibodies IgE and IgG2a. There are no reports in the literature of allergenicity for diamond (cf. possible contact dermatitis by adamantane derivatives [5569]), sapphire, fullerenes, or other probable diamondoid nanorobot exterior materials. Such allergenicity appears unlikely, but experiments should be done to positively confirm this expectation. Intriguingly, the possibility of a purely crystallographic allergenic sensitivity is suggested by tests of cellular allergic reactions to zircon crystals, as assessed by variation in arachidonic acid metabolite production in mouse macrophages [2044] – the tests were negative for crystals of quadratic zircon but positive for crystals of monoclinic zircon.

* Most of these substances do not cause IgE reactions, most of the time. For instance, nickel allergy is usually contact dermatitis, a Type IV reaction that does not involve IgE.

Medical nanorobot designers must first attempt to ensure that no surface component (including any organic biocompatibility-related coatings) or chemical emission of a nanomedical device can serve as a human allergen, or can elicit any of the above four allergic reactions. If this cannot be reliably accomplished in all cases, other approaches may be available to eliminate the unwanted allergic response. For example, tryptases [2053], the predominant proteins of human mast cells (~6-19 pg/cell [2053]), have been implicated as pathogenic mediators of allergic and inflammatory conditions, most notably asthma [2054]. Although tryptases are distinguished from other serine proteases in being resistant to most proteinaceous inhibitors [2054], several classes of tryptase inhibitors have recently been found [2056-2058] which inhibit enzyme activity after enzyme release from cells. However, since the amount of tryptase that could be released from mast cells might overwhelm nanorobot-released tryptase inhibitors (because any free enzyme can activate many molecules of substrate), mast cell tryptase-release inhibitors [2055, 5796-5800] that might reduce or even prevent enzyme release from mast cells might be more useful in the present context. In principle, these or similar inhibitors could be rapidly dispensed by medical nanorobots or secreted by dedicated internal nanorobotic organs, instantly quenching the allergic response.

The traditional treatment of choice for anaphylaxis is an injection of epinephrine (0.183 kD), a potent vasoconstrictor and sympathomimetic, in a therapeutic dose of ~6 x 10^-8 gm/cm³ or ~200 molecules/micron³ in whole blood [382, 5497]. One 0.3-mg whole-body dose (~10¹⁸ molecules) could be delivered in ~1 second by 3 billion 10-micron³ bloodborne nanorobots each using only 1% of internal volume for drug storage and ~300 sorting rotors on the nanorobot exterior. Of course, epinephrine has severe systemic consequences and can cause cardiac arrest or a stroke if not properly monitored.

To prevent common symptoms of allergic rhinitis, the usual approach is to target histamine directly, perhaps using cetirizine [2066], a fast-acting histamine-blocker drug, or any of a large number of other antihistamine H1 receptor antagonists that inhibit histamine release from mast cells and/or basophils, such as ambroxol [2067], CGP 41251 [2068], chlorpheniramine maleate [382], epinastine [2069], loratadine [2070, 2071], or oxatomide [2055]. Of course, most antihistamine drugs have widely varying undesired or adverse side effects. Hence a superior approach may be to use nanorobotically-embedded molecular sorting rotors (Section 3.4.2) to rapidly absorb, chemically neutralize, and then release the primary inflammatory mediator molecules such as histamine, tryptase, serotonin, and so forth. For maximum effectiveness, rotor binding sites should ideally be more numerous and possess greater binding affinity than the natural mediator receptors, and the rotors should be positioned to intercept the mediators as close as possible to the site of their release. Even patients who are experiencing a strong allergic reaction have been found to have serum levels [2072] of only >1 ng/cm³ of plasma histamine (0.111 kD, >5 molecules/micron³) and >15 ng/cm³ of total tryptase (144 kD, >0.08 molecule/micron³), largely because of rapid degradation by the body when not bound to the intended natural receptors. Such small amounts may be handled relatively quickly by a modest number of bloodstream-resident medical nanorobots. One sorting rotor can transfer ~5 molecules/sec of histamine from a ~1 ng/cm³ serum concentration (Section 3.4.2), so a single nanorobot with 10,000 surface rotors could clear ~1000 micron³/sec of serum of ~99% of its histamine content. (Histamine is most plentiful in nasal secretions, ~2000-7000 ng/cm³ [2073], but the rate of extraction from solution by sorting rotors can increase almost in direct proportion to solute concentration.)

Last updated on 30 April 2004