IMMUNOLOGY RADIATION (Latin immunis free, saved from something + grech, logos the doctrine; radiation) — the section of immunology studying action of ionizing radiation on immunity. I.R. there were in the 50th 20 century in connection with detection of extremely high susceptibility to infections at animals and the person at an acute radial illness. In the next years questions immunology (see) in a problem biol, actions of radiation came out far beyond studying of immunity to causative agents of infectious diseases. The directions on a research of action of ionizing radiation on transplant immunity, a possibility of creation immunol, tolerances, success of treatment of radiation injuries by transplantations of the hemopoietic fabrics, the importance of post-radiation autoimmune frustration in a pathogeny of a radial illness and other questions of noninfectious immunology became extremely urgent.
Hypersensitivity of the irradiated animals to causative agents of infectious diseases is confirmed in experiments with various activators of bacteritic, viral, rickettsial and fungus diseases. An exception of this rule are causative agents of the diseases not inherent to this species of animals. Specific immunity remains after radiation though sensitivity to nonspecific intoxication at introduction of large numbers of microbic weight increases.
Studying of terms of sensitization to infection showed that they are not identical and depend on a dose of radiation, a species of animals and the nature of infectious process. E.g., recovery of natural immunity of white mice to the causative agent of gas gangrene happens in 2 weeks after radiation. In simulated condition of recovery of resistance to the causative agent of icteric leptospirosis does not occur during 10 weeks.
Sensitization to infectious agents is followed by quantitative and qualitative changes of normal microflora of a body of animals after radiation. Flora of intestines is most in details investigated: there is an increase in total number of microbes in intestines, change of a ratio between certain representatives, emergence of a large number of the bacteria possessing hemolitic, proteolytic, an indole - and serovodorodoobrazuyushchy properties. Developing dysbacteriosis (see) undoubtedly plays a pathogenetic role since the influences directed to prevention of the specified changes exert beneficial effect on the current radial illness (see). It is clear as quickly developing increase in permeability biol, barriers provides already in 2 days after radiation penetration of large numbers of microbes into mezenterialny limf, nodes, and then into blood. The next periods in development of autoinfection at a radial illness are allocated:
1. Period of sterility. Duration its 1 days. It is characterized by lack of microbes in all fabrics.
2. Period of an obsemenennost regional limf, nodes. It covers time from 2nd to the 3rd days after radiation. It is characterized by presence of bacteria only in limf, nodes.
3. Bacteriemic period. It is characterized by emergence of a large number of microbes in a spleen. In blood of bacteria it is not enough or they are not allocated absolutely. This period proceeds from 3rd to the 7th days and can be called the period of relative compensation of protective mechanisms since ability of clarification of blood from bacteria is completely not lost though decrease in the absorption and especially digesting ability of reticuloendothelial system in relation to live microorganisms, certainly, takes place.
4. Period of a decompensation of protective mechanisms. It covers the last days (8 — 10) lives of an animal and is characterized by sharp increase of quantity of microbes both in bodies, and in blood. This increase is explained by active reproduction of microbes in tissues of the irradiated animal. This period can be called septic.
Sensitization of the irradiated animals to causative agents of infectious diseases and development of the autoinfection which is in many cases a proximate cause of their death is a consequence of the oppressing action of radiation on all major factors of natural resistance. At the same time permeability biol increases, barriers, nonspecific bactericidal systems are oppressed — bactericidal activity of skin decreases, the quantity of a lysozyme, complement in liquids of the irradiated organisms decreases. Sharply phagocytal activity macro - and microphagocytes is suppressed (see. Phagocytosis ).
Characterizing action of ionizing radiation on antibody formation, first of all it is necessary to stop on two most cumulative effects — a dosage effect and effect of time of immunization in relation to the moment of radiation. The curve dose — effect has the S-shaped form typical for the corresponding curves of death of the breeding cells under the influence of different doses of radiation. Time of immunization in relation to the moment of radiation renders essential value on extent of suppression of antibodyformation. In a habit view it is formulated as follows: radiation of animals in lethal and sublethal doses of ionizing radiation before immunization oppresses development of antibodies; the radiation which is carried out after immunization or does not influence products of antibodies, or slows down a little, it, but does not interfere with accumulation of high antiserum capacities in blood. The maximum oppression of synthesis of antibodies is observed at immunization in 1 — 2 days after radiation. Administration of antigens in later terms testifies to the beginning of recovery of function. Normalization occurs not earlier than in 1 — 2 month.
As for value of a time slice at immunization before radiation, the last days before radiation — considerable oppression immunol are critical, the answer develops only at administration of antigen in 12 — 24 hours prior to radiation.
The analysis of experiments on a research of temporary ratios of immunization and radiation allowed to postulate existence of two phases of synthesis of antibodies: initial, radio sensitive — short, connected with reception of antigen, and the subsequent — radio resistant — products of antibodies covering the entire period.
The radio sensitive period matches a latent phase of development of antibodies, edges begins with the moment of contact with antigen and lasts before emergence immunoglobulins (see). At this time the intimate cellular mechanisms preceding emission of antibodies — stimulation of T lymphocytes, their interaction with B-lymphocytes and the beginning of reproduction and a differentiation of the last are carried out (see. Immunocompetent cells ).
Due to the sharp oppressing impact of radiation on the main mechanisms of immunity great practical importance is gained by researches on research of ways of recovery of the broken functions, the most effective ways of active and passive immunization at a radial illness: fight against increase in fabric permeability, the actions directed to a raising of level of bactericidal substances in blood, activation of phagocytosis, hemotransfusion and leukocyte weight, transplantation of the hemopoietic fabrics.
Experiments on artificial immunization in the conditions of radiation injury of an organism yielded results, various for anti-toxic and antimicrobic (including antiviral) immunity. It is established that radiation of immunizirovanny animals leads to considerable oppression of degree of their immunity at infection with live activators in the first days after radiation and to full suppression of artificial immunity during the testing in its way infections in the period of developed a wedge, pictures of an acute radial illness. Though active antimicrobic immunity is also oppressed very sharply, it provides a little higher resistance of the irradiated animals to the corresponding activator in comparison with the irradiated neimmunizirovanny animals. As for active anti-toxic immunity, its tension created before radiation more remains after radiation.
Efficiency of active immunization of the irradiated animals depends on terms of administration of antigen. Vaccination in the first 2 — 3 days after radiation does not increase the resistance reduced as a result of radiation. Later immunization leads to increase of immunity. This rule is the general for antibacterial and anti-toxic immunity. At the same time it must be kept in mind that during the acute period of a radial illness animals show hypersensitivity to vaccination. Immunization burdens a current of a radial illness and increases mortality.
Distinctions in efficiency of anti-toxic and antibacterial immunity come to light at passive immunization of the irradiated animals. Introduction of ready antibodies does not protect them from the subsequent infection with live microorganisms, but it is very effective at administration of toxins. If sensitivity of immunizirovanny animals under the influence of radiation increases in relation to live activators in hundreds of times, then two - triple doses of anti-toxic serums it appears enough for creation of datum level of anti-toxic immunity. The described distinctions can be explained with features of antibacterial and anti-toxic immunity (see. Immunity ).
As rejection of the replaced fabrics and bodies is function immunol, systems of an organism, influence by ionizing radiation is a powerful factor of suppression of transplant immunity. At the same time there are all bases to expect a possibility of engraftment of transplants at the inert recipients irradiated immunological. However mechanisms of this phenomenon are more difficult, than simple beam suppression of immunity.
The main phenomenon of action of radiation on transplant immunity consists in lengthening of the period of experience of the allogenic and xenogenic transplants replaced by the irradiated animal (see. Immunity transplant ). So, e.g., at unirradiated mice average life expectancy of allogenic transplants 12,6 ± 0,8 days. After x-ray radiation of recipients in a dose 870 I am glad life expectancy of skin rags it was extended: at change in 5 hours after radiation up to 22,0±4,8 days, and at change in 13 days after radiation up to 15,4±2,9 days. Normalization of average life expectancy of a transplant (11,2±2,0) is recorded at change for the 30th day after beam influence. The average life expectancy of xenogenic (rat) transplants equaling at unirradiated mice 7,6±0,7 days was extended to 25,8±3,3 days at change in 5 hours after radiation and to 14,5±3,4 days at change in 13 days after radiation. In all cases beam influence only extends life expectancy of a transplant, but cannot provide true engraftment. It is explained at least by two features of action of radiation on immunity. First, dose dependence, according to a cut suppression of immunity of subjects is stronger, than a high dose of radiation; so high extent of suppression of immunity, edge is necessary for engraftment of alien fabric, is reached only at lethal and superlethal doses of radiation. Secondly, suppression of immunity at radiation injury has nonspecific character. Together with the increasing possibility of engraftment of an alien transplant possibility of an infectious complication increases in a bigger measure. Thus, before the effect of true engraftment of alien fabric is reached, the animal perishes from a beam pancytopenia or the joined infection.
For this reason use of radiation of recipients does not solve a problem of overcoming a barrier of incompatibility of fabrics. Researches in this area go on the way of creation specific immunol, tolerances of the irradiated organism by means of transplantation to it cells of the hemopoietic fabrics protecting it from beam death. At the same time radiation of the recipient, providing oppression of immunity and extension of life of transplants, does not induce a condition of true tolerance. It is connected with sharp lengthening of a latent phase of an immunogenesis in the absence of absolute suppression immunol, reactivity in all cases of sublethal radiation. At superlethal doses of radiation the recipient perishes earlier, than the transplant will manage to be torn away. This rule extends to everything gomo-and heterografts, except for those fabrics which, being replaced to the irradiated recipient, save it from lethal radiation injury. Such fabrics are the hemopoietic fabrics — marrow, a spleen, limf, nodes.
Transplantation of cells of the listed bodies from allogenic and even xenogenic donors prevents death of the irradiated recipients from an acute radial illness. It is explained by engraftment and proliferation of the replaced cells in the conditions of oppression of an immune response and substitution of the hemopoietic tissue of the recipient destroyed by radiation. Transplantation of the hemopoietic fabrics significantly differs from change of skin rags and fabrics of other bodies. The hemopoietic cells actively proliferate. During a post-radiation immunol. inertness there is their reproduction and substitution of the hemopoietic tissue of the recipient. There is an organism chimera bearing the hemopoietic sprout of donor type. This sprout, being a strong permanent antigenic incentive, provides induction of specific tolerance in relation to tissues of the donor. The arisen tolerance provides, on the one hand, a possibility of vaguely long persistention of the replaced donor hemopoietic fabric and emergence of so-called long-living radiation chimeras. On the other hand, the developing tolerance gives the chance to replace to recipients other donor fabrics and bodies. High degree of tolerance at radiation chimeras in relation to various fabrics (to tissue of skin, a kidney, etc.) donors of the hemopoietic cells is shown in experiences on mice, rats, rabbits, dogs (see. unresponsiveness ).
Transplantation of the hemopoietic fabric renders therapeutic effect at a form of the acute beam pathology defined as hemopoietic. Such form of a radial illness develops at mammals at radiation in the range of doses of 200 — 1000 r depending on a species of animals. It is characterized by insolvency of the hemopoietic system leading to death of the irradiated recipient from the 6th on the 30th post-radiation days. High to lay down. efficiency of the hemopoietic fabric was repeatedly proved in experiments and clinic.
Unlike all other ways of treatment of an acute radial illness, transplantation of compatible hemopoietic fabric provides to 100% treatment of the animals irradiated in absolutely lethal doses. Optimum term for transplantation of the hemopoietic fabric to the irradiated recipient is the interval during the first 24 — 72 hours after radiation. Transplantation in later terms leads to decrease to lay down. efficiency of marrow.
It is necessary to emphasize, however, that protective efficiency of the hemopoietic fabrics is repeatedly shown. The phenomenon accurately is reproduced. For example, at singenny, i.e. compatible, transplantation for providing 100% of survival letalno of the irradiated mice needs introduction only to 1 million viable yadrosoderzhashchy cells of marrow or 10 million splenic cells.
It is proved what to lay down. action of transplantations is caused by engraftment and functioning in an organism of the irradiated recipient of donor cells. At the same time it must be kept in mind that all hemopoietic fabrics (marrow, a spleen, limf, nodes) to a greater or lesser extent contain immunological competent cells — lymphocytes. PI if or in cases of autotransplantation does not represent a protective effect in the conditions of genetic identity of the donor and the recipient immunol, interest, then the fact of engraftment and functioning immunological of competent cells in immunological the inert irradiated organism was extremely interesting.
The main feature characterizing to lay down. the effect immunological of incompatible hemopoietic fabric, consists that this effect temporary. Letalno the irradiated animal thanks to transplantation endures the period of an acute radial illness. But then perishes from the so-called secondary (homologous) disease developing in several weeks after radiation and transplantation of incompatible fabric. Death of animals during 3 — 5 weeks after transplantation of alien marrow is caused immunol. the conflict of incompatible tissues of the donor and recipient (see. Incompatibility immunological ). Without overcoming this conflict widespread introduction of marrowy therapy in a wedge, practice is impossible. The most careful selection among people of antigenically compatible donor and the recipient for the isoantigenic AB0 systems, a Rhesus factor, HLA, etc. is necessary (see. Immunity transplant ).
The large number of researches is concentrated in the field of studying immunol, relationship between transplantirovanny hemopoietic fabric and the recipient. In all cases of allogenic changes of the hemopoietic fabrics to the irradiated recipients there are temporary or long-living radiation chimeras, i.e. coexistence of cells of various genotypes. The reaction «a transplant against the owner» caused immunol, activity of competent cells of a transplant and leading to development of a secondary (homologous) disease was one of the first immunol, phenomena described in these conditions.
The subsequent researches showed that it is not only immunol. reaction of relationship of a transplant and owner that immunol. the status of radiation chimeras is much more difficult. At long-living radiation chimeras immunol, relationship between immunol, competent cells of a transplant and the recipient develops as a result of development of both processes of a mutual sensitization, and processes of mutual tolerance. At the same time from letalno the irradiated recipient, according to most of researchers, the condition of tolerance develops though some authors provide data on inconstancy of development of tolerance of the recipient and on development of reaction «the recipient against a transplant». Donor elements are sensibilized in the beginning, and then in small percent of cases when the himerizm does not disappear and animals do not perish, pass into a condition of tolerance of this or that degree of manifestation.
Apparently, from in what party will develop immunol, relationship between a transplant and the recipient, the destiny of radiation chimeras depends. The majority of radiation chimeras perishes from a secondary (homologous) disease owing to development of reaction «a transplant against the owner». A part survives in one of 3 states: the himerizm disappears, demonstrating regeneration of own hemopoietic system and graft rejection; the himerizm remains, testifying to mutual tolerance of sprouts; a hemopoiesis is completely replaced on donor type.
And. the ruble studies also post-radiation autoimmune frustration. Existence of two childbirth of the autoantigens capable to lead to autoimmunization of an organism is established. Some normal fabrics (a brain, testicles, a thyroid gland, etc.) can be autoantigens at their hit in a bed of blood where they in normal conditions do not get. The changed proteins and the related substances can be autoantigens also patholologically. After impact on an organism of ionizing radiation a real opportunity for its collision with autoantigens of both childbirth, sweat mu is created that quickly developing fabric destruction in combination with sharp a hyperpermeability biol, barriers and change of antigenic properties of fabrics takes place. The last is shown for different fabrics and bodies with use of the tissues of the same animal taken before beam influence, that is in the conditions excluding isoantigenic distinctions of the compared proteins.
After establishment of the fact of change of antigenic properties of tissues of the irradiated animals repeatedly were suggested about a possibility of development in the irradiated organism of autoimmune frustration. The following sequence of autoimmune frustration was assumed: radiation defeat of cells and fabrics -> change of antigenic specificity -> circulation of the changed antigens —> autoantigenny irritation and development of autoantibodies and an autoserotherapy. Such scheme, however, caused two most serious objections. The first is connected with what after radiation is sharply oppressed immunol, reactivity of an organism. Thereof reaction to an autoantigenny incentive shall be suppressed too. And in spite of the fact that the fact of oppression of reactivity does not reject completely a possibility of autoimmunization since absolute suppression of immunity does not happen, it very sushchestven, especially in a combination to the second objection (means immunol, tolerance, edges develops owing to radiation). At contact of the irradiated organism with fabric antigens there is a state immunol. tolerances in relation to them. Therefore, in the presence of a fabric autoantigenny incentive in the irradiated organism immunol, reactions shall proceed not in the direction of immunization or a sensitization, and in the direction of tolerance induction in relation to autoantigens.
In connection with told the probability of development of autoimmune frustration in the provided scheme is represented the small or at least specific weight of such process in pathogenetic origins of effects of radiation injury cannot be essential.
Bibliography: Clem of ii and r with to and I am H. N, etc. Questions of an infection, immunity and an allergy at an acute radial illness, M., 1958, bibliogr.; Petrov R. V. and 3 a p e of c to and I 10. M. Radiation immunology and transplantation, M., 1970; Troitsk V. L., etc. Radiation immunology, M., 1965, bibliogr.; van In e k k u m D. W. a. de V r i e s M. J. Radiation chimeras, N. Y., 1967.
P. B. Petrov.