ADJUVANTS (Latin adjuvans — helping, supporting) — nonspecific stimulators of an immunogenesis, substance of various origin and structure.
And. can have antigenic properties (the killed microorganisms or polysaccharides of a bacterial origin) and not to possess them (mineral oils, alum, etc.). Effect of the adjuvant stimulating substances is noted in 1925. G. Ramon which established activation of products of antitoxins (see) at horses at joint administration of anatoxins (see) with alum, Calcium chloratum, tapioca, lecithin, cholesterol, lanolin, benzoin.
K A. the inorganic nature carry aluminum hydroxide, aluminum phosphate, calcium phosphate, Calcium chloratum, potassium aluminum sulphate, ferric hydroxide, active coal, etc. Among organic matters adjuvant action the agar-agar, glycerin, gelatin, starch, lanolin, lecithin, pectic substances, protamins, etc. possess. More difficult And. consist of mixes of oils or lipopolisakharid with addition of emulsifiers, and also mixes of lipids with mineral sorbents.
Only a small amount of adjuvant substances is most carefully studied and is widely applied to strengthening of effect of antigens at production of vaccinal drugs (see Vaccines). As sorbents at production of vaccines most often apply aluminum hydroxide — Al (ON) 3 and aluminum phosphate — AlPO4. Aluminum hydroxide represents the mineral gel containing 6 — 22 mg of Al (ON) 3 in 1 ml with good sorption properties; it is harmless to an organism. Aluminum phosphate also high-disperse drug.
At production of associated vaccines use in quality And. the killed bacteria.
Various adjuvants find application in production of medical serums (see) and especially in pilot studies on immunology. At the same time quite often use more reactogenic drugs (1% solution of potassium aluminum sulphate, lanolin, cholesterol, oil-water sludges, a Freund's adjuvant). The full Freund's adjuvant supports BCG or lipopolisakharida received from mycobacteria of tuberculosis, complex fatty acids (derivatives of lanolin), oils and emulsifiers (Arlatsel And or Tvpn-80). The Freund's adjuvant deprived of fraction of mycobacteria of tuberculosis call incomplete. It is a powerful stimulator of an immunogenesis, but is not applied in preventive vaccination in connection with its toxicity and allergenic action. Use of a Freund's adjuvant promotes induction of hypersensitivity of the slowed-down type and development of autoimmune processes (see Autoantigens, Autoantibodies).
Bacterial endotoxins, nucleic acids and products of their disintegration, synthetic nucleotides and polyanions possess the expressed adjuvant action.
Mechanism of a promoting effect And. on an organism it is finally not found out. Strengthening of antigenic influence depends first of all on development in an organism of inflammatory process and stimulation of proliferative and phagocytal activity of reticuloendothelial system, strengthening of plazmokletochny reaction and generalization of immunological process in lymphoid bodies and sharp increase in the general synthesis of protein. A probable role is played by also slowed down resorption of antigen from depot with delay of destruction of antigen and its discrete action on an adenoid tissue.
And. widely apply as stimulators of an immunogenesis at introduction to a human body and animal specific antigens. The anatoxins occluded on aluminum hydroxide, complete antigens and antiviral vaccines (against a tick-borne encephalitis, flu), and also the associated drugs, napr, the adsorbed pertussoid and diphtheritic and tetanic vaccine (AKDS) concern to the last. Usually purified antigens occlude in a certain ratio on standard suspension of aluminum hydroxide, check for an immunogenicity and reactogenicity, and also consider a row physical. - chemical constants: rn, the maintenance of a sorbent etc. (see. Vaccines , Immunization ).
In the sixties tried to use in medical practice of a vaccine with And. from mineral oils. Tests showed that these vaccines more immunogens, than not sorbed, cause formation of wider range of antibodies. However at their use on site introductions were sometimes formed granulomas that served as the reason of the termination of their use.
For preparation of highly active serums from animals, and also for obtaining hypersensitivity of the slowed-down type, except full N of an incomplete Freund's adjuvant, successfully use the simple and double oil-water sludges emulsified with solution of antigen before receiving spontaneous emulsion. Double emulsions receive at further emulsification with an equal capacity of 2% of solution of the Twin-80 usually on mechanical emulsifier.
In pharmacology adjuvants are called the substances strengthening or prolonging effect of medicines.
Adjuvant disease — the disease at animals caused by introduction of a Freund's adjuvant and which is characterized by a complex of inflammatory changes with dominance of a proliferative component, the localized hl. obr. in joints and periartikulyarny fabric. This disease has looking alike such diseases of the person as a pseudorheumatism, a knotty erythema and is used as a pilot model for their studying.
For the first time «adjuvant arthritis» was described by Pearson (C. M. Pearson, 1956) at rats in the form of an acute inflammation in joints of a tail, foot and an anklebone with the subsequent development of periostites and exostoses. It is established that inflammatory changes develop not only in joints, but also in skin, c. N of page, lungs, eyes, liver, kidneys, urinary tract and many other bodies. Therefore in 1961 the term «adjuvant disease» which more corresponds to essence of changes was offered.
The adjuvant disease best of all is reproduced at rats of various lines of both sexes. Dependence between weight of a disease and linear accessory of rats is established.
And. prepare as on a classical copy-book (mineral oil, lanolin, water, the cut contains in 1 ml 3 ml of mycobacteria of tuberculosis, heat-killed), and in various variations. Variations concern composition of emulsifier, replacement of mycobacteria of tuberculosis with separate fractions from them or other bacteria. The most effective way of reproduction of an adjuvant disease — a single injection And. in small pillows of hinder or all four legs of an animal in a dose of 0,05 — 0,1 ml.
Damages of joints. The first signs of an inflammation of joints and surrounding fabrics appear in 10 — 16 days after introduction And. Joints swell up, in a cavity of joints there is an exudate, the periostitis develops. Arthritises have the migrating character and arise at rats in 70 — 100% of cases. Preferential carpal and metacarpal, intermetacarpal, metacarpophalangeal and shoulder joints on front extremities, and also a tarsus-plusnevye are surprised. intermetatarsal, metacarpophalangeal and hip joints of a pas back extremities of rats.
Severe forms of arthritises tend to a long current, destruction of a cartilaginous surface of joints, development of connecting fabric, a sclerosis and anchylosis of joints. In the first days of development of arthritises puffiness of periartpkulyarny connecting fabric and synovial membranes, infiltration of their mononuklearama (monocytes, lymphocytes, histiocytes), proliferation of fibroblasts histologically is defined.
In 3 — 4 weeks among cells of infiltrate lymphocytes prevail, proliferative processes, in a bone tissue of joints — a hyperplasia of osteoblasts amplify. At the majority of animals arthritises come to an end with recovery with recovery of mobility in joints.
Damages of skin. After development of arthritises in rats sites of baldness and rash in the form of papules and hillocks can appear. Histologically in the field of small hillocks perivenous mononuclear infiltrates preferential from histiocytes and lymphocytes and more diffusion hyperplasia of histiocytes without the expressed perivenous localization come to light. In big nodes — massive cellular infiltration with the isolated focuses of a necrosis containing the material similar to fibrin. In 1 — 1 1/2 months late skin changes in a type of a hair loss, a peeling, cracks which keep up to 3 — 4 months develop.
Damages of a spleen and lymph nodes. In a spleen the hyperplasia of cellular elements, formation of the light centers in limf, follicles comes to light. The hyperplasia limf, nodes, increase in the light centers of reactivity (reproduction) in follicles, proliferation of plasmocytes in pulpy cords is characteristic.
Damages of the central nervous system are similar to those which are found at introduction of Ampere-second homogenate of tissue of spinal cord and are followed by development of experimental allergic encephalomyelitis. However introduction of one And. does not give demiyelinizatspyu.
Damages of eyes in the form of conjunctivitis, an episcleritis, a uveitis, an iridotspklit arise after development of arthritis in a small part of animal N stick usually to from 2 to 14 days. All phenomena pass in mild cases. In hard cases in an anterior chamber of an eye accumulation of fibrinous exudate, development of back synechias and an atrophy of an iris, formation of precipitated calcium superphosphate on the interior of a cornea and its opacification is observed.
Gastrointestinal tract diseases. Sharply expressed diarrhea is noted approximately in 20% of cases. It proceeds from several days to two weeks.
Damages of a liver. Histologically proliferation of cells of reticuloendothelial system, formation of cellular infiltrates comes to light.
Damage of kidneys and urinary tract. Different types of nephrite develop.
Defeats of bodies and systems at different types of animals, and also different bodies within one species of animals are generally same though there are specific and organ differences. So, e.g., in a liver, a spleen and easy mice, Guinea pigs and hamsters proliferation of elements of reticuloendothelial system is well-marked, but it is absent in heart and kidneys of these animals. The amyloidosis of a liver, kidneys and a spleen is observed at mice, but is absent at Guinea pigs and hamsters.
Pathogeny. There are two theories of a pathogeny of an adjuvant disease. 1. The infectious theory assumes activation of an endogenous infection (e.g., at rats — activation of the microbes of the Mycoplasmataceae family which are often found in almost healthy animals). This theory did not receive confirmation since crops of blood, tissue of joints and fabric from the place of an injection And., liquids from chambers of the eye were sterile, and introduction of high doses of various antibiotics did not brake a course of a disease. 2. The Autoallergichesky theory assumes participation of immunologic mechanisms. This theory confirm the following facts: a) stage of latency at an adjuvant disease same as at development of other experimental autoallergichesky processes, at a reinokulyation of a stimulator it decreases; b) development of a disease is slowed down by the influences oppressing an immune responsiveness — X-irradiation in a dose 600 r, introduction of immunodepressants, in particular 6 Mercaptopurinums and high doses of glyukokortpkoid, preliminary (for 4 — 12 weeks) thymectomy, administration of anti-lymphocytic serum; c) reproduction of an adjuvant disease is impossible at newborn and young rats since mechanisms of an immune responsiveness at them are not developed yet or only form; d) character of autoallergichesky mechanisms of a course of a disease indicates their relation to reactions of the slowed-down type that it is confirmed by a possibility of passive transfer of an adjuvant disease a suspension of cells of a lymphoid row and impossibility of transfer by blood serum, and also the histologic picture of fabric changes characteristic of reactions of the slowed-down type, stopping of reaction of migration of macrophages, lack of decrease in a caption of a complement during the acute period of a disease; e) reproduction of a phenomenon of unresponsiveness (see unresponsiveness), i.e. suppression of development of an adjuvant disease in the animals who received at the birth of mycobacteria of tuberculosis is possible.
Bibliography: Vorobyov A. A. and Vasilyev N. N. Adjuvants, M., 1969, bibliogr.; Gurvich G. A., etc. Endotoxins as nonspecific biostimulators of antibodyformation, Vestie. USSR Academy of Medical Sciences, L» 8, page 50, 1964; Zdrodovsky P. F. Problems of an infection, immunity and allergy, page 192, M., 1969; Cabot E. and Meyer M. Experimental immunochemistry, the lane with English, page 316, etc., M., 1968; Ramone G. is forty years old of research work, the lane with fr., page 235, M., 1962; Teacher I. Ya. and Hasman E. L. About the mechanism of adjuvant action of nonspecific stimulators of antibodyformation, Vestn. USSR Academy of Medical Sciences, No. 3, page 23, 1964, bibliogr.; Chase M. W. Production of antiserum, in book: Methods in immunol. immunochem., ed. by C. A. Williams a. M. W. Chase, v. 1, p. 197, N. Y. — L., 1967; Freund J. The mode of action of immunologic adjuvants, Advanc. Tuberc. Res., v. 7, p. 130, 1956; Herbert W. J. Methods for the preparation of water-in-oil, and multiple, emulsions for use as antigen adjuvants, Handbook exp. immunol., ed. by D. M. Weir, p. 1207, Oxford — Edinburgh, 1967, bibliogr.; International symposium on adjuvants of immunity, ed. by R. H. Regamey a. o., Basel — N. Y., 1967; Merritt K. Johnson A. G. Studies on the adjuvant action of bacterial endotoxins of antibody formation, J. Immunol., v. 94, p. 416, 1965, bibliogr.; Schmidtke J. R. a. Jоhnsоn A. G. Regulation of the immune system by synthetic polynucleoti-des, ibid., v. 106, p. 1191, 1971, bibliogr.
Adjuvant disease — Kanchurin A. X., Askerov M. A. and Lazko I. E. Adjuvant disease, Stalemate. fiziol. and ekspery. ter., t. 13, No. 2, page 78, 1969, bibliogr.; Amkraut A. A., Solomon G. F. a. Kraemer H. C. Stress, early experience and adjuvant-induced arthrits in the rat, Psychosom. Med., v. 33, p. 203, 1971; Bonhomme F. o. Arthritogenicity of unaltered and acetylated cell walls of mycobacteria, Int. Arch. Allergy, v. 36, p. 317, 1969; Carter R. L., Jamison D. G. a. Vоllum R. L. Histological changes evoked in mice by Freund's complete adjuvant, J. Path. Bact., v. 97, p. 503, 1969; Laufer A., Tal C. a. Behar A. J. Effect of adjuvant (Freund's type) and its components on the organs of various animal species, Brit. J. exp. Path., v. 40, p. 1, 1959; Pearson C. M. Development of arthritis, periarthritis and periostitis in rats given adjuvants, Proc. Soc. exp. Biol. (N. Y.), v. 91, p. 95, 1956; Pearson C. M. a. Wооd F. D. Studies of arthritis and other lesions induced in rats by the injection of mycobacterial adjuvant, Amer. J. Path., v. 42, p. 73, 1963; Pearson C. M., Waksman B. H. a. Sharp J. T. Studies of arthritis and other lesions induced in rats by injection of mycobacterial adjuvant, J. exp. Med., v. 113, p. 485, 1961, bibliogr.; Rosenthale M. E. A comparative study of the Lewis and Sprague Dawley rat in adjuvant arthritis. Arch. int. Pharmacodyn., v. 188, p. 14, 1970, bibliogr.; Steiner J. W., Langer B. Schatz D. L. The local and systemic effects of Freund's adjuvant and its fractions. Arch. Path., v. 70, p. 424, 1960, bibliogr.; Waksman B. H. a. Bullington S. J. Studies of arthritis and other lesions induced in rats by injection of mycobacterial adjuvant, Arch. Ophthal., v. 64, p. 751, 1960, bibliogr.; Waksman B. H. a. Wennersten C. Passive transfer of adjuvant arthritis in rats with living lymphoid cells of sensitized donors, Int. Arch. Allergy, v. 23, p. 129, 1963.
I. N. Kokorin; V. I. Pytsky (Adjuvant disease).