Immunomodulation

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5.4.1 Introduction

The mammalian immune system consists of many cells and signal molecules which act in concert to protect the organism from that which is "nonself". The chief cellular effectors are macrophages ("big eaters") and white blood cells. Neutrophils and lymphocytes are the most important of the white blood cells. Some of the signal molecules are interleukin-1 (IL-1), tumor necrosis factor-a (TNF-a), and y-interferon (IF-y, also known as IL-6). Cells that come in contact with foreign organisms begin to secrete signal molecules to call other effector cells into the area and to activate them. The invaders are immobilized or killed by numerous strategies including phagocytosis, antibody production, and radical oxygen species production. There is increased blood flow and the area becomes swollen, red, warm, and painful. This next section will first examine two plants, Echinacea and Aloe vera that may act to boost the response of the immune system in fighting disease. Then we will discuss how plants stimulate the immune system in ways that cause the organism discomfort, i.e., allergic or hypersensitivity reactions.

5.4.2 Echinacea

Echinacea has long been known in the Native American materia medica.31 It was also known in Europe for its immune stimulating effects and skin repairing properties as early as 1831.32 Today Echinacea products are widely used in

Europe as an aide to boost the immune system in its struggle with the viruses that cause colds and flu. Recent clinical trials in Germany have supported this usage.33 In addition, research with extracts of Echinacea have begun to elucidate the interactions between this herb and the mammalian immune system.

Initially, echinacoside, a caffeic-acid glycoside that showed weak antibacterial activity, was thought to be the active ingredient. Further work showed this was not the case.33 In a series of elegant experiments spanning more than a decade, M. L. Lohmann-Matthes, H. Wagner, and colleagues have steadfastly expanded our knowledge of how Echinacea works.34-38 Early on, this group pinpointed polysaccharides from the aqueous extracts of E. purpurea as the active fraction. Further work showed that the effective polysaccharides were cell wall-derived arabinogalactan and two fucogalactoxyloglucans. They developed a plant-cell-culture system whose supernatant provided them with a solution of the polysaccharides that could be standardized. Then they applied this purified extract in a host of carefully executed experiments. They have shown that this polysaccharide fraction stimulates macrophages to produce signal molecules, TNF-a, IL-1, and IL-6 (interferon). These signals activate other parts of the immune system and promote the migration of other effector cells, such as neutrophils, from the bone marrow to the blood. The activated macrophages produce more oxygen radicals, phagocytize more and are more cytotoxic to tumor cells. Overall, there is a higher rate of killing of Listeria monocytogenes bacteria and Candida albicans yeast, such that a lethal dose of either can be withstood by both immunocompetent and immunosuppressed mice that have been treated with the polysaccharides. Similar results have been obtained in humans. Although the polysaccharides stimulate the immune system, much as an invading organism would, they are completely nontoxic. Another group has done preliminary work using E. purpurea extracts in combination with cyclo-phosphamide and thymostimulin to stimulate the immune system of patients with hepatocellular and advanced colorectal cancer. Their results are encour-aging.3940

These experiments give new credence to the herbalists' claims of the immune-enhancing effects of Echinacea spp. Soon it may be an integral part of accepted therapy for withstanding cancer and other infectious diseases.

5.4.3 Aloe vera

Humans have used the aloe plant since the ancient times of Egypt and Greece for skin infections and wound healing.41 The leaf contains three medically important and distinct parts: the leaf exudate, the leaf epidermis, and the leaf pulp. Much of the medical literature on aloe use is confusing because the part and formulation is not specified clearly. This may account for the often widely divergent results obtained. While researchers divide and extract these different parts to find the active ingredients, many others advocate for study of the use of whole leaf preparations, since that is the way it has been used throughout history.

The leaf exudate, a bitter yellow liquid, is produced by pericyclic cells.42 This can be heated, concentrated, and dried to a black powder. This is the source of drug aloes, also known as Cape Aloes USP, which is used as a purgative.43 Aloe ferox is grown commercially for this purpose. Of the dried exudate, 70 to 97% is made up of aloeresin, aloesin, and aloin in a ratio of 4:3:2.44 The exudate also contains aloe-emodin, and anthraquinone which is a gastrointestinal irritant, hence the purgative effects.42

Recent studies have centered on a lectin purified from the leaf epidermis of Aloe arborescens Miller.45 An aloe lectin has been reported to inhibit the growth of a fibrosarcoma in mice through a host-mediated effect.46 A possible mechanism may be activation of the immune system as purified aloe lectin has been shown to increase mitogenic activity in mouse lymphocytes.47 This will undoubtedly be an area for further research.

The aloe leaf pulp or gel is a clear mucilaginous substance which is 98.5% water.48 The mucilage is predominantly made up of polysaccharides which are partially acetylated glucomannans.49 Recently, an acetylated mannan, aceman-nan, extracted from Aloe vera, has been shown to have immune-system modulating effects. This appears to be mediated through macrophages which synthesize and release nitric oxide, IL-1, and TNF-a when activated by acemannan.5051 The activated macrophages and other immune cells are then able to respond to viral or cancer cells. This product of aloe plants will be studied more thoroughly in the future.

The whole leaf of Aloe vera, or products extracted from whole leaf, have been used directly on radiation burns, thermal burns, partial thickness wounds, stasis ulcers, and diabetic ulcers. Most researchers report an initial increase in necrosis and then more rapid healing when compared to other treatments or no treatment.41-43 This may be a reflection of the above-identified immune modulating effects. Aloe vera has enjoyed a great popularity in household remedies and cosmetics. Research is just beginning to unravel the reasons why this botanical has been highly regarded by healers and the healed alike.

5.4.4 Plant Contact Dermatitis

There are several different ways in which plants can affect the skin of humans, some beneficial and some causing discomfort. Many plants, like Aloe vera, promote healing of wounds. Other plants, such as poison ivy (Toxicodendron spp), are well known for their toxicity to the skin. Plant contact dermatitis is subdivided based on causative mechanisms. One such division is: (1) irritant contact, (2) immediate contact, (3) phytophotosensitivity, and (4) allergic con-tact.52,53 As more is learned about these mechanisms, it is clear that there is some overlap. The divisions are useful, however, in determining appropriate treatment. In each of the following sections, we will define and describe the clinical picture of each type of dermatitis. Each will be illustrated with one or two examples, along with more detail about the mechanism of interaction when known.

Irritant contact dermatitis occurs when humans encounter thorns, spines, irritant hairs, and chemical substances which primarily protect plants from herbivores. In the human, these plant defenses usually cause some kind of persistent skin reaction which may be due to physical trauma or chemical interaction with skin or nerves.54 Stinging nettles, Urtica diocia and U. ureus, are commonly known for the intense burning and stinging that begins just a few minutes after brushing up against the plant. The skin turns red and warm and itchy. There may be persistent itching or tingling for about 12 h. These Urtica spp. have glandular hairs which inject four chemicals into the skin, namely, histamine, acetylcholine, serotonin, and a fourth unidentified compound. The histamine causes immediate vasodilatation and edema, producing redness and swelling. The serotonin is responsible for the pain and itch.55 Another irritant contact dermatitis is caused by capsaicin, an alkaloid in red peppers, chili peppers, and paprika of the genus Capsicum. It produces redness and intense burning. Capsaicin stimulates a specific receptor on cutaneous sensory neurons which in turn probably increases intracellular calcium ions. This causes massive release of neuropeptides, including substance P. These molecules are responsible for both pain signal transmission to the brain via depolarization of unmyelinated type C and thin myelinated A delta sensory neurons and modulation of the local inflammatory response. Repeated application depletes the neuropeptides, and therefore, pain signals can no longer be transmitted. This is the basis for the use of capsaicin in products used to treat diabetic neuropathy, post herpetic neuralgia, and arthritis.56,57

Immediate contact dermatitis occurs when skin previously sensitized is re-exposed to the offending agent. In some people, strawberries, kiwifruit, tomato, castor bean, and others trigger a type I hypersensitivity response typified by redness, swelling, and itching.52 On first exposure, the plant antigens stimulate B lymphocytes to produce immunoglobulin E (IgE) antibodies which then bind mast cells. No reaction is apparent. At the second exposure, when the antigen cross-links the antibodies on the mast cell, there is an influx of calcium ions into the cell. This causes release of preformed mediators, such as histamine, heparin, enzymes, chemotactic, and activating factors, and stimulates formation of longer acting mediators, such as prostaglandins and leukotrienes. These mediators, among other things, cause vessel dilatation fluid leakage and recruitment of other blood cells to the area. These changes cause the observed skin reactions.58 A third type of dermatitis associated with plants is phytophotodermatitis. This occurs when there is direct or airborne contact or ingestion of plant furo-coumarins and then exposure to sunlight. The result is a painful, red, itchy rash with watery blister formation which lasts 1 to 2 weeks. Hyperpigmentation follows which can last for months. This type of reaction can be caused by rue (Ruta spp), gas plant (Dictamnus albus), citruses (Citrus spp), Apiaceae (angelica, parsley, parsnip) and others.52 The best studied of the furocoumarins are psoralens. They cross-link DNA in the cells and, when exposed to ultraviolet light, cause cell death, inhibit normal mitosis, or cause mutations. Dermatologists use ingested psoralens (Figure 5.12) and ultraviolet-A light in the treatment of psoriasis.53

FIGURE 5.12 Chemical structure of Psoralen, which is used in combination with ultraviolet light for the treatment of psoriasis.

FIGURE 5.12 Chemical structure of Psoralen, which is used in combination with ultraviolet light for the treatment of psoriasis.

The most well-known plant-skin interaction in North America is that caused by poison ivy, poison oak, and poison sumac (Taxicodendron spp.). These plants cause allergic contact dermatitis typified by red, itchy skin with weeping blisters, scabs, and crusts which peaks about 48 h after exposure. Affected areas may appear in a linear distribution because of the mechanism of contact or early scratching. The lesions may erupt over 3 weeks, which is the time it takes the plant resin to evaporate. It is not spread through leakage of the blisters. Delayed eruption is due to re-exposure from resin on clothes, tools, or pet fur. There is usually no long-term scarring or hyperpigmentation.59 Similar type IV or delayed-hypersensitivity reactions can be caused by sesquiterpene lactones in the Asteraceae (thistle) family and quinones in toxic woods.52,60 In the Toxico-dendron spp. The allergen is urushiol, a catechol nucleus with a 15-carbon lipophilic tail containing 2 to 3 unsaturated bonds. Urushiol binds to epidermal cells (keratinocytes, Langerhans cells, and endothelial cells) stimulating release of mediators (ICAM-1, ELAM-1, VCAM-1) which form adhesive networks and promote migration (via IL-8) of T-cell lymphocytes to the area. Pathology is then T-cell mediated through lymphokine production, antigen-specific and nonspecific cytotoxicity, and recruitment of other effector cells.61,62

5.4.5 Summary

We have seen how plant and human interaction can have significant immuno-modulatory affects. In the case of Echinacea and Aloe, plant polysaccharides stimulate the immune system in a beneficial way, promoting healing and increased defensive capacity. When human and plant defense systems clash, the interaction can leave humans with painful, red, swollen, itchy, and blistered skin through a variety of mechanisms. Sometimes these very mechanisms can be used to lessen symptoms of other diseases like psoriasis and neuropathy.

5.5 TOXIC EFFECTS 5.5.1 Introduction

The last section on plant contact dermatitis serves as a good bridge to this portion on the harmful affects of plants. We have already seen that plants have powerful potential in their interactions with humans. This can benefit or harm.

Some significant aspects of the negative interactions will be covered with respect to congenital anomalies (teratogenesis), carcinogenesis, and toxicity.

5.5.2 Teratogenesis

Teratogenesis (literally "monster formation") occurs when cell proliferation, cell migration, or cell differentiation in a developing human embryo is altered. Human embryos are most vulnerable to the effects of teratogens during the third through the ninth week of pregnancy during a time when women may not be aware they are pregnant. About one quarter of all birth defects are genetic aberrations, and 65 to 70% are from unknown causes. Drugs and chemicals account for only about 1% of birth defects.63 There are several plant-derived compounds that are known teratogens, notably some alkaloids from angiosperms such as: colchicine, reserpine, tubocurarine, caffeine, nicotine, and quinine.64

Ethyl alcohol derived from fermentation of grapes or grains is a commonly ingested plant product with recognized teratogenic effects. The fetal alcohol syndrome is diagnosed by its constellation of growth retardation, microcephaly, atrial septal defects, short palpebral fissures, maxillary hypoplasia, and other minor anomalies. The mechanism behind these effects is multifactorial. Fetal hypoxia and nutrient deficiencies may be involved. At the cellular level, enzyme activities, cell division, and maintenance of membrane integrity are altered by exposure to ethanol.65

In general, it is very difficult to establish causality in a situation where multiple factors may play a role. The high proportion of unknown causes of birth defects indicates that much that we are exposed to may be less benign than we think. Accordingly, most drugs should be avoided in pregnancy, including plant-based remedies and beverages, unless the benefit to be obtained far outweighs the often unknown risk to the developing offspring.

5.5.3 Carcinogenesis

In Section 5.2 we discussed various phytochemicals and their role in treating cancer. Natural products or their metabolites can also be implicated in causing cancer, although far more synthetic chemicals are known culprits at this time. Viruses and irradiation are also responsible for much neoplastic transformation. Chemical carcinogenesis is proposed to occur via a two-step process of initiation and promotion. Initiation is accomplished when damaged DNA is passed on to daughter cells unrepaired. Particular portions of DNA known as proto-onco-genes may be transformed through mutation to become active oncogenes. Other genes known as tumor suppresser genes may be inhibited. These genes would normally control cell growth and differentiation. Once damaged, the state is set for uncontrolled proliferation. This will not occur, however, unless there is a second type of stimulus called promotion. One well-studied promoter exerts its action through multiple effects including activation of protein kinase C. This in turn causes a host of protein phosphorylations which regulate multiple cel lular functions including membrane receptor, ion channel, and enzymatic activity. The result is altered proliferation and differentiation and neoplasia.66 67

The most well-known plant carcinogen is tobacco, the leaf of Nicotiana tabacum. It contains many compounds that may be volatilized during burning. More importantly, several aromatic hydrocarbons are known to be formed during combustion. Wherever these are applied experimentally they cause local cancer formation. They are metabolized to dihydrodiol epoxides, which are strong electrophilic reactants. They exert their cancer initiating effects by combining with nucleophilic sites on DNA, RNA, and proteins. Tobacco aromatic hydrocarbons may be complete carcinogenic agents in that they are sufficient to cause tumors without a promoter. On the other hand, tobacco acts synergis-tically with betel nut juice (Areca catechu) chewed in south Asia. The betel nut alone causes tumors in 38% of hamster cheek pouches, but when combined with tobacco the number rises to 78%. In this study tobacco alone did not induce malignancy; however, it caused leukoplakia, which may enhance the susceptibility to cancer.66,68

5.5.4 Toxicity

Many plant-based medicines and herbal remedies have side effects just as prescribed synthetic medicines do. Gastrointestinal effects, such as nausea and diarrhea, and skin reactions are common to many ingested products. There are a few plant-based products with well-known toxicities to the liver and the central nervous system. The next section will explore the mechanism of toxicity of comfrey root and jimsonweed seed.

Comfrey (Symphytum officinale) has been used for the treatment of stomach ulcers and as a blood purifier among other things. The roots are the part most often used. They contain pyrrolizidine alkaloids (Figure 5.13) which can cause p' ¿2

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FIGURE 5.13 Chemical structures of pyrrolizidine alkaloids, which can cause liver toxicity, as well as carcinogenesis and teratogenesis.

liver toxicity, as well as carcinogenesis and teratogenesis. These alkaloids have a 1,2 double bond and esterified hydroxymethyl groups (see Figure 5.13). In the liver they are dehydrogenated to pyrrole derivatives, which then act as potent alkylating agents. They react with bases in the DNA strand, cross-linking strands and causing strand breakage. Studies in rats have supported the hepa-totoxic, carcinogenic, and teratogenic role of comfrey root.69 In humans, a form of Budd-Chiari syndrome known as veno-occlusive disease has been the primary concern. Clinical manifestations are hepatomegally and refractory ascites, often progressing to hepatic failure. Untreated, there is a high mortality rate. Pathologically, the liver shows tissue necrosis in the center of lobules as well as dilation of the central vein. The small venules of the liver have fibrous deposition in and around them, which leads to obstruction of blood outflow and the resultant ascites. Many cases have been reported in the world literature, attributable to Symphytum, as well as pyrrolizidine alkaloid-containing species of Heliotro-pium, Senecio, or Crotalaria.70,71 Internal consumption of comfrey is officially banned or discouraged in Australia, New Zealand, the United Kingdom, and Germany.69

Neurotoxicity is another common result of ingestion of plant products. In another section, we have discussed interaction of phytochemicals with various cellular membrane signaling mechanisms. Neurotoxicity can occur when the plant molecule acts as a blocker to neurotransmission. Jimson weed (Datura stramonium) has been used as a tea for treatment of asthma. The atropine-like substances, hyoscyamine and scopolamine (Figure 5.14), are in all portions

FIGURE 5.14 Chemical structures of scopolamine, a drug which can be neurotoxic to humans and other animals.

of the plant. They act to block neurotransmission by acetylcholine which is the predominant neurotransmitter of the parasympathetic nervous system. The signs and symptoms of Datura toxicity pervade many organ systems including: dry mouth, dry skin, blurred vision, disorientation, excitability, aggressiveness, tachycardia, tachypnea, and hyperpyrexia. Death can occur from cardiac arrest.72

5.5.5 Summary

In this final section we have discussed some of the problems associated with ingestion of certain toxic, teratogenic, and carcinogenic plant products. Medical literature has often focused on these negative effects alone. As we have seen in

FIGURE 5.14 Chemical structures of scopolamine, a drug which can be neurotoxic to humans and other animals.

other portions of the chapter, plants can have a host of salutary effects as well. While usage of plants medicinally may be steeped in tradition, scientific investigation often uncovers the mechanisms by which phytochemicals interact with the human body. This area of investigation currently offers more questions than answers. There is a growing need for well-trained and thoughtful ethnobotanists, basic scientists, and clinicians to carry forward the work of understanding how best to join with the plants to create good health.

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The Synergy Principle at Work in Plants, Pathogens, Insects, Herbivores, and Humans

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