From Big Medical Encyclopedia

UNRESPONSIVENESS (Latin tolerantia patience, endurance; lat. immunis is the free, saved from something + Greek logos the doctrine) — loss or easing of ability of an organism to an immune response on this antigen as a result of the previous contact with the same antigen. T. and. to foreign proteins sometimes call immunological meekness or areactivity.

At T. and. are absent or supressirovana (are suppressed) immunocompetent cells (see), capable to react to this antigen products of antibodies or formation of effector T lymphocytes. From T. and. it is necessary to distinguish the seeming lack of an immune response caused by binding of antibodies excess of antigen (so-called peripheral neutralization) and also blockade of target cells and effector T lymphocytes antibodies and complexes antigen — an antibody, i.e. a phenomenon of an immunoenhancing effect (see. atrepsy ).

Studying of a role of T. and. in normal life activity of an organism and in the conditions of pathology is important. Depending on character patol. process can be a task of the doctor or creation of T. and., or, on the contrary, recovery of ability to a normal immune response.

Various phenomena combined later by the general term «unresponsiveness» were originally described out of communication of one with another. In 1900 — 1901 P. Ehrlich established that the organism in normal conditions is incapable to produce antibodies to the majority of autoantigens. In 1945 Mr. R. D. Owen found out that the calfs who are dizygotic twins and having the general placenta in the embryonal period do not answer with an immune response the blood cells of the partner which got into their organism though they react normally to erythrocytes of other calfs (see Chimeras). On the basis of these observations F. Vernet and F. J. Fenner in 1949 and irrespective of them G. V. Lopashov and O. G. Stroyeva in 1950 for the first time assumed that the contact of immune system of an organism in the embryonal period with antigens of an endogenous or exogenous origin leads to development specific immunol. areactivity. This assumption was experimentally confirmed in 1953 with Billingkhem, Brent (R. E. Billingham, L. Brent) and P. Medavar who showed that mice, the Crimea in the embryonal or neonatal period entered the hemopoietic cells of mice of other line, afterwards did not tear away a transplant of leather of mice of the line of the donor though tore away transplants of leather of mice of the third line. Similar data were at the same time obtained in 1953 by M. Gashek in experiences on hens. For discovery of unresponsiveness to F. Burnett and P. Medavar in 1960 the Nobel Prize is awarded.

Further earlier known facts of loss by an adult organism specific immunol were correlated to a concept of unresponsiveness. reactivity as a result of immunization by a foreign protein (a phenomenon of «overload») or polysaccharide of a pneumococcus in an excess dose — the so-called immunological paralysis found in 1942 by Feltonom and Ottin-ger (L. D. Felton, V. Ottinger). In 1959 Mr. Shvartts and Dameshek (R. S. Schwartz, W. Dameshek) applied a new way of creation of T. and. at mature animals by consecutive injections of antigen and an immunosuppressant. In 1967 Diner and Armstrong (E. Diener, W. D. Armstrong) found emergence of T. and. at an incubation of lymphocytes with antigens in experiences of in vitro, in 1970 — 1971 Gershon and Kondo (R. To. Gershon, To. Kondo) established a role of T-suppressors at nek-ry forms T. and.

Ability to formation of T. and. it is found in representatives of all classes of vertebrate animals. Distinguish natural T. and., napr, to autoantigens, and T. and., artificially induced by graft-specific or microbic antigens. Unresponsiveness can be full (full areactivity), incomplete (partial areactivity) and split. The split T. and. means loss of ability to formation of one of immune responses on this antigen (e.g., lack of hypersensitivity of the slowed-down type) at preservation of other reactions to the same antigen. Depending on the nature of changes of cellular substrate of an immunogenesis (see Imma incompetent cells) distinguish T-cellular and V-cellular unresponsiveness.

T. and. it can be received practically to any antigen or hapten, however its formation depends on character and a dose of antigen. To the strong, coded by the main complex of genes of histocompatibility graft-specific antigens (see Immunity transplant) T. and. it is more difficult to receive, than to weak antigens. To more foreign serum proteins T. and. it is more difficult to receive, than to proteins of sibling species. Introduction of a conjugate of hapten with erythrocytes or immunoglobulin of the same species of animals promotes formation of T. and. to hapten.

To corpuscular antigens (microbic cells, alien erythrocytes) to receive T. and. difficult; on the contrary, the foreign serum protein exempted from the aggregated particles causes T. and. even at mature animals. To formation of T. and. resistance of antigen to effect of the catabolizing enzymes favors (therefore it is easy to receive T. and. to polypeptides of D-amino acids and a nek-eye to polysaccharides) and its long stay in an organism. To emergence of T. and. to polysaccharides their big molecular weight (weight), frequent repeatability of identical antigenic determinants in a molecule promotes. The role of the last factor is shown also for nek-ry artificial antigens. The high dose of antigen favors to formation of T. and. However nek-ry foreign proteins and polysaccharides can cause T. and. and in very small (subimmunogene) doses (low-zonal, or low-dose, T. и). Development of T. and. depends on a way of administration of antigen: at intravenous administration of antigen or hapten T. and. arises easier, than at hypodermic or intramuscular introduction. There are T given about receiving. and. as a result of peroral administration of antigen or hapten.

Very essential value for emergence of T. and. have age and genetic factors. Stage of ontogenesis optimum for formation of T. and., sometimes call the immunoadaptive period. At the person it comes to an end till the birth (at normally proceeding pregnancy), at small experimental animals (a rat, a mouse) — later 1 — 2 days after the birth. In old age ability to formation of T. and. worsens. Genetic regulation of T. and. it is carried out both by 1 major histocompatibility locus, and other genes which are not entering the specified complex. Their products are expressed on T lymphocytes and macrophages (see. Immunity transplant ).

To formation of T. and. immunodepressive agents — ionizing radiation in high doses, anti-lymphocytic serum (see), Cyclophosphanum, antimetabolites of nucleinic exchange, etc. promote. Their efficiency depends on character of an immunosuppressant and terms of its use. New experimental clinical reception of formation of T. and. the TLI method (total lymphoid irradiation) — general irradiation of an organism with shielding of nek-ry especially sensitive bodies is. Among chemical immunodepressants Cyclophosphanum possesses the most effective action. Nonspecific stimulators of an immunogenesis (see. Adjuvants ), and also preliminary immunization by the corresponding antigen, usually interfere with formation of T. and. Problem of receiving T. and. to the majority of antigens, important for clinic, continues to remain urgent.

Speed of formation of T. and. depends on character of antigen and conditions of its impact on an organism. Partial T. and. can arise in several hours after administration of antigen, but for full development of T. and. several days are required. At an incubation of lymphocytes with in vitro T antigen. and. arises quicker. To formation of T. and. sometimes the short-term phase of products of antibodies precedes.

If antigen constantly is present at an organism as it, e.g., takes place at a himerizm of the hemopoietic fabric (coexistence in an organism of genetically diverse hemopoietic cells), then T. and. the T remains beyond all bounds long, otherwise. and. sooner or later it is lost. To loss of T. and. immunization by cross reacting antigens, and also nek-ry nonspecific influences, napr, stimulators of an immunogenesis promotes. Introduction of immune lymphocytes leads, as a rule, to loss of T. and. Additional injections of antigen allow to prolong T. and.

Place of formation of T. and. in an organism lymphoid bodies are central (a thymus gland, marrow) and peripheral (a spleen, limf, nodes). T. and. arises in population of unripe lymphoid cells easier. T-cellular T. and. develops at smaller doses of antigen, forms earlier and remains longer, than V-cellular. Macrophages and A-cells, similar to them (the cell capable to be attached to glass), as a rule, interfere with formation of T. and. to proteinaceous antigens.

Mechanisms T. and. are diverse. Distinguish two main types of T. and.: clonal and scarce and suppressor. Clonal and scarce Etc. it is characterized by absence or areactivity of the immunocompetent cells capable to answer this antigen. Suppressor T. and. it is caused by suppression of activity of immunocompetent cells antigenospetsifichesky T-suppressors, V-suppressors, complexes antigen — an antibody, and also anti-idiopathic antibodies (the antiantibody developed by an organism against own antibodies) or the anti-idiotypic T lymphocytes having anti-idiotypic receptors on a surface. At suppressor T. and. lymphocytes or blood serum have ability to specifically suppress an immune response of normal lymphocytes on the corresponding antigen. Introduction of normal lymphocytes, and also nonspecific immunodepressive influences differently influence on clonal and scarce and suppressor Etc.

During the formation clonal and scarce Etc., as well as at an immune response, antigen contacts receptors of a cellular membrane of a lymphocyte in the beginning. Further, however, process of activation, usual for an immune response, proliferation and a differentiation of a lymphocyte is broken in one or several links. Sometimes (especially if antigen represents polymer with the repeating determinants) the lymphocyte appears incapable to be exempted from a complex antigen receptor and to rezintezirovat new receptors. Such, loaded with antigen, lymphocytes are incapable to answer a new immune incentive and eventually can be destroyed by macrophages or normal antibodies. In other cases the correct relationship between two signals necessary for an immune response is broken (one of these signals shall receive the V-lymphocyte from own μ-receptors to antigen, and another — or from the δ-retseitor, or from T lymphocytes and makrofagopodobny A-cells). So the situation if the unripe V-lymphocyte (which does not have δ-receptors) contacts to antigen))))))))), and also in case of functional or genetic insufficiency of T-assistants or A-cells is. As a result of an imbalance between signals the immunocompetent lymphocyte loses ability to be differentiated in an antiteloobrazuyushchy cell («clonal abortion») or loses ability to share and create a memory cell (the terminal or exhausting differentiation). Clonal and scarce T. and. can form also thanks to the combined effect of antigen and an immuiodepressant (e.g., Cyclophosphanum), to-ry selectively destroys the lymphocytes involved by antigen in proliferation.

Suppressor T. and. can initially arise (by direct stimulation by antigen of T-suppressors) or for the second time (owing to formation of anti-idiotypic immune cells and antibodies). T-suppressors represent a special class of immunekompetentny cells (see). By means of the mediators lymphokines allocated by them they suppress activity of other T - and V-lymphocytes. Ability of T-suppressors to answer various antigens is controlled by the specific Is-genes localized in the main complex of genes of histocompatability. T-suppressors are selectively stimulated with deagregirovanny foreign proteins (especially serum globulin), small doses of nek-ry polisakharidny antigens and complexes antigen — an antibody. Activity of T-suppressors can be increased by nek-ry nonspecific impacts on an organism (e.g., At F-radiation). Small doses of the rigid ionizing radiation, and also nek-ry alkilpruyushchy connections (e.g., Cyclophosphanum) at introduction in small doses selectively inactivate T-suppressors.

T. and. treats the main (basic) immunological phenomena. Its opening led to failure from outdated theories of immunity (see) and to development in 1957 — 1959 by F. Burnett of the clonal and selection theory of an immunogenesis. Studying of T. and. it is closely connected, on the one hand, with a molecular and immunological perspective (interaction of antigen with receptors of a lymphocyte, character and features of the signals sent by cellular receptors, etc.), and on the other hand — with a problem of interaction of various populations of lymphocytes. In recent years there were cybernetic approaches to studying of T. and., at the same time special attention is paid to specific feed-backs in immune system and to their mathematical modeling (see).

Unresponsiveness to autoantigens

To the majority autoantigens (see) the organism is naturally tolerant. This T. and. it is caused by absence or suppression of activity of the corresponding T-assistants and predecessors of T-killers, and also effectors of hypersensitivity of the slowed-down type (see. Immunocompetent cells) in combination with a superactivity of T-suppressors. T. and. to antigens of the fabrics delimited from the general vascular system of an organism fiziol. barriers (a brain, seed plants), and to the covert antigenic determinants is absent. Natural T. and. to autoantpgena forms generally in a thymus gland during the immunoadaptive period and after it. Loss of T. and. can lead to development of an autoimmune disease. Reason of loss of T. and. immunization cross reacting microbic antigens, nonspecific stimulation of V-lymphocytes bacterial endotoxins, weakening of products of T-suppressors as a result of genetic defects or age involution of a thymus gland, and also loss by a thymus gland of ability to eliminate the «prohibited» (autoreaktivny) clones of lymphocytes (see can be. Autoallergichesky diseases , Thymus ). By means of various methods it is possible to recover T. and. to autoantigens and by that to prevent development of an autoimmune disease. Introduction of massive doses of antigen or in the form of high-disperse drug, or in a combination with an immunosuppressant, and also injections of a conjugate of autoantigen or hapten with immunoglobulin of an animal same view or with polypeptide of D-amino acids concerns to them.

Unresponsiveness in system mother — a fruit

At the normal course of pregnancy of T. and. at a fruit to the majority of antigens of mother it does not forkhmirutsya. T. and. there is also no mother to antigens of a fruit. It is explained by barrier function of a placenta (its decidual fabric and a trophoblast). However in some cases at a fruit unresponsiveness to Rh-antigen develops (see. Rhesus factor ) mothers. At blood of pregnant women often there is a blocking factor suppressing reaction of lymphocytes of mother to graft-specific antigens of a fruit. Possible immunol. the conflict is interfered also by nonspecific immunodeires-sivny factors, napr, a chorionic gonadotrophin (see). In the conditions of pathology, at increase in permeability of a placental barrier (e.g., the rigid ionizing radiation) unresponsiveness of a fruit to graft-specific antigens of mother or, on the contrary, immunol can result. the conflict between mother and a fruit.

Unresponsiveness to tumoral antigens

the Question of a role of T. and. in processes of a carcinogenesis is debatable. Reasons to believe are had, however, that in the course of education and growth of a malignant tumor the T forms. and. to a nek-eye to specific tumoral antigens, supported with natural T. and. to cancer embryonic antigens. In blood of people and animals with malignant tumors the specific blocking factor suppressing an immune response of an organism on tumoral antigens is found (see atrepsy). The nature of a factor is not clear, different researchers consider it or a tolerogenic complex antigen — an antibody, either an anti-antiself antibody or an antibody to tumoral antigen. At animals with the tumors caused by various agents (viruses, metilkholantreny, UV rays), found the T-suppressors interfering an immune response and by that the tumors promoting growth and its intensive innidiation. Partial T. and. arises also to oncogenous viruses (see) if they are present at an embryo. To formation of T. and. to antigens of tumors the nonspecific immunodepressive effect of many oncogenous agents promotes, probably. Attempts to eliminate T were made. and. to tumoral antigens by heteras of an ogeni-zation of a tumor, immunization by cross reacting alien cancer embryonic antigens, administrations of adjuvants, etc.

Unresponsiveness to graft-specific antigens and overcoming a tissue incompatibility

At organ transplantation in experimental conditions and in clinic is possible to receive steady T. and. to a transplant if antigenic distinctions between the donor and the recipient are rather small and if the patient receives immunodepressive therapy — anti-lymphocytic serum, Azathioprinum (imuran), Cyclophosphanum, a methotrexate, Prednisolonum, etc. (see. Immunodepressive substances). T. and. the recipient it is caused partly by specific areactivity of lymphocytes, and partly T-suppressors, the blocking serum factor and anti-antiself antibodies. In experimental conditions to formation of T. and. to weak graft-specific antigens preliminary administration of extracts of tissue of the donor and anti-lymphocytic serum favors. T. and. to strong graft-specific antigens and even to fabrics of animal other look mature animals of the hemopoietic cells of the donor and Cyclophosphanum manage to receive by consecutive injections.

At transplantation of marrow (e.g., for treatment of agshasti-chesky anemia or nek-ry immunodeficiency) there can be a T. and. lymphoid cells of a donor origin to antigens of the recipient. If T. and. does not arise or will be lost, the recipient can die owing to the immune response of cells of the donor directed against it (see Incompatibility immunological). For prevention of the specified immune conflict usually apply immunodepressive therapy.

The role of unresponsiveness in infectious pathology

is Assumed that nek-ry pathogenic microorganisms use natural T. and. the owner to autoantigens. The antigens which are contained in microorganisms sometimes are close to specific, fabric, group or graft-specific antigens of the owner that protects a parasite from immune elimination. Similar «an antigenic mimicry» is described at nek-ry types of pneumococci, streptococci, at gram-negative bacteria, pasterell, klebsiyell, a virus of smallpox, nek-ry parasitic protozoa and helminths. Nek-ry viruses include antigens of the owner in the cover. If microbes have antigens similar with group-specific (see. Blood groups ) or graft-specific antigens, inf. bolevn can strike that part of the population, edges are born by the corresponding antigen. If antigens of a parasite and the owner are only partially similar, inf. the disease can lead to loss natural Etc. to autoantigen and, respectively, to an autoimmune disease. The similar situation takes place at nek-ry streptococcal and viral diseases.

T. and. to microorganisms can arise and when their antigens have nothing in common with antigens of the owner. So, to the viruses (a virus of a rubella, a virus of a lymphocytic horiomeshshgnt) infecting a fruit often there is a split T. and., the investigation the cut happens a long carriage of virus.

T. and. in the immunoadaptive period can arise not only to virus, but also to other microbic antigens (antigens of shigellas, the cook-tsidy, etc.). In immunological mature organism microbic polysaccharides (e.g., a pneumococcus of the III type) can cause a so-called immunological paralysis, to-ry is caused partially by unresponsiveness of V-lymphocytes, and partially binding of antibodies is long persistent antigen. To other microbic antigens full T. and. in immunological mature organism usually does not develop. However at nek-ry it is long the current diseases (a leprosy, a leushmaniosis, nek-ry chronic diseases of a fungal and virus etiology) there is a split T. and., playing an essential role in a pathogeny inf. process, With possibility of the full or split T. and. to various microbic antigens it is necessary to be considered when the patient suffers from the inborn or acquired immunological insufficiency (see) owing to, e.g., antineoplastic, antiinflammatory and specially immunodepressive therapy according to other indications (malignant tumors, autoimmune and allergic diseases, organ and tissue transplantation, etc.).

Immunologichesk I am tolerance to allergens

For prevention of a serum disease in an experiment and in clinic successfully apply a method of induction of T. and. by intravenous administration of the serum protein purified by centrifuging of proteinaceous units and other adjuvant impurity. In experiments on animals the desensibilizing effect of introduction of tolerogenic complexes of various allergens and their haptens (penicillin and its derivatives, allergens of pollen, etc.) with polypeptides of D-amino acids, polysaccharides, homologous IgG, polyvinyl alcohol is found. There are separate messages on successful use of these methods in clinic.

See also Immunity .

Bibliography: Fontalin L. N. and P e in N and c to and y L. A. Unresponsiveness, M., 1978, bibliogr.; Billingham R. E., Brent L. and. Medawar P. B. «Actively acquired tolerance» of foreign cells, Nature (Lond.), v. 172, p, 603, 1953; Cellular and molecular mechanisms of immunological tolerance, ed. by T. Hraba a. M. Hasek, N. Y., 1981; Immunological tolerance and enhancement, ed. by F. P. Stuart a. F. W. Fitch, Lancaster, 1979; Immunological tolerance, mechanisms and potential therapeutic applications, ed. by D. H. Katz a. B. Benacerraf, N. Y., 1974; Immunological tolerance to self and non-self, ed. by J. R. Battisto a. o., N. Y., 1982.

L. H. Fontalin.