INCOMPATIBILITY IMMUNOLOGICAL

From Big Medical Encyclopedia

INCOMPATIBILITY IMMUNOLOGICAL (synonym tissue incompatibility) — genetically caused distinction in antigenic structure of cells of the donor and the recipient leading to development of an immunological havoc. Main manifestations of N. and. the cellular and humoral reactions of an organism directed against antigenically alien cells and fabrics, leading to their damage and death and also nek-ry patol, the processes happening in an organism in response to introduction of alien cells are.

Scientific and practical value H. and. the transplant against the owner, its value in pathology of pregnancy is defined by its key role in development of transplantology and transfusiology, need of detailed studying of its patterns for prevention of reaction. Practical importance of studying of a problem H. and. was one of powerful incentives of a detailed research of antigen in and genetic control of their education. Development of a problem H. and. led to creation of a new branch of science — a transplant immunogenetics, and the doctrine about the main complex of histocompatibility Major Histocompatibility Complex (Ministry of Taxes and Tax Collection) formed the basis of development of rational trial and error methods of the donor and recipient. The independent direction of researches is also studying of communication of antigens of histocompatibility with various diseases. The saved-up data demonstrate that the immune response is under genetic control. Accurate correlation between genes of the Ministry of Taxes and Tax Collection, a susceptibility to diseases and force of an immune response is experimentally proved. A wedge, researches confirm this pattern. Thus, it was found out that chromosomal area, in a cut genes of HLA are located, determines an immune response in general in this connection the doctrine about N. and. outgrew a framework of a medical problem and turned into a problem all-biological.

Systematic studying of patterns of N. and. and the mechanisms which are the cornerstone of it reactions 20 century when P. Gorer opened the main system of histocompatibility at mice were begun in the 30th, having called its N-2 system (from Histocompatibility — compatibility of fabrics). However also. I. Mechnikov with sotr. (1883, 1900) showed existence immunol. the reaction of an organism to alien fabrics which is expressed in formation of cytotoxic antibodies in blood of one animals at immunization by their tissue of a kidney or myelocytes of other animal.

In 1898 — 1899 Zh. Borde and N. Ya. Chistovich found antibody formation at introduction to an organism of alien erythrocytes or blood sera. Further studying of patterns of N. and. it is connected with K. Landshteyner's works (1900) and Ya. Yansky (1907), the erythrocytes of people investigating antigenic distinctions and the allocated 4 blood groups differing on existence A-and V-isoantigens in erythrocytes and alpha and beta isoantibodies in blood serum (see. Blood groups ). These researches formed a basis for development immunohematologies (see). Further development of problems H. and. it was caused by development transplantologies (see). In 1945 P. Medavar formulated immunol, essence of incompatibility of tissues of the donor and recipient that was an incitement to studying of the patterns which are the cornerstone of N. and. The concept offered by F. Burnett immunol, supervision (see. Immunity , Immunogenetics ), promoted the statement of the point of view that a basis of immune phenomena at the highest animals, including and the person, is recognition of genetically alien antigens and development of reaction of immunological incompatibility.

At the heart of N. and. function immunol, supervision of this system, directed to maintenance of a homeostasis of an organism and carried out, first of all, by system lies lymphocytes (see), being the main cells providing recognition of genetically alien substances and their elimination (removal). In development of reactions of N. and. also participate macrophages (see), to-rye carry out transfer of antigenic information and elimination of alien cells. An essential role in manifestations of reactions of N. and. belongs as natural isoantibodies (at hemotransfusions), and to the antibodies formed at immunization by the corresponding antigens.

N and. arises with antigenic distinctions between the donor and the recipient and sufficient level immunol, reactivity of an organism. N and. it can be shown at organ transplantation and fabrics, at hemotransfusion, and also sometimes in late durations of gestation, edges represents a peculiar form of allotransplantation. Besides, under natural conditions N. and. can develop at change of antigenic properties of cells as a result of mutations or infection with viruses.

Immunological incompatibility at organ and tissue transplantation

Immunological incompatibility at organ and tissue transplantation, being in the basis immunol, a phenomenon, it is shown in the form of a difficult morfofiziol. the process which received the name of reaction of rejection. The main antigens determining an immune response at N. and., graft-specific antigens are (see. Immunity transplant ), the representing components of a cellular membrane. The cells distinguishing alien antigens, initiating and substantially the carrying-out N. and., lymphocytes are, among to-rykh the main role belongs to T lymphocytes (see. Immunocompetent cells ). Value of humoral factors of immunity (antibodies) in N.'s development and. is conventional; terms of emergence and dynamics of accumulation vary them depending on a number of factors: N.'s degrees and. the donor and the recipient, level immunol, reactivity of the last, character and intensity of the carried-out immunodepressive therapy and other influences. The mechanism of the damaging action of antibodies on a transplant can be caused by linkng of antibodies with superficial receptors of cells of a transplant, activation of lymphocytes and macrophages of the recipient at the expense of their opsonization antibodies and (or) action of the complexes which are formed in a blood channel antigen — an antibody.

N.'s reaction and. can proceed in the form of the reaction the recipient against a transplant leading to oppression of functions and the subsequent death of a transplanted organ or fabric and in the form of the reaction a transplant against the owner which is especially expressed at organ transplantation and the fabrics rich with own lymphoid elements (e.g., marrow, a spleen).

Force of manifestations of N. and. depends, first of all, on degree of antigenic distinctions between the donor and the recipient. N and. does not arise at autologous (within one organism) either isogenic, or singenny (between genetically homogeneous lines), change owing to lack of genetic distinctions between an organism and a transplant, i.e. at histocompatibility of the donor and recipient. Most N. and. it is shown at xenogenic (trans-species) interaction of the recipient and cells of the donor.

At the heart of N. and. the phenomena essentially similar to other manifestations immunol, the reactions of an organism which are carried out by immunocompetent cells and humoral factors of immunity lie immunol — antibodies (see).

On mechanisms of development reaction of rejection is close to reaction of hypersensitivity of the slowed-down type (see. Allergy ). J. Snell, Zh. Dosse, S. Nathenson in reaction of rejection allocate 3 phases: phase of recognition, phase of immunization and effector phase. The phase of recognition is carried out by T lymphocytes (T-helperami) in a transplant and is more active in limf, nodes. The distinguishing substances of lymphocytes — receptors, are located on a surface of lymphocytes, the nature and structure them are not studied yet. The nature of primary contact of lymphocytes with alloantigens of a transplant and response of the owner is defined by a type of change. In the presence of primary vascularization of a transplant, napr, at renal transplantations, the main recognition results from contact of lymphocytes with an endothelium of vessels, and also their penetration into fabrics of a transplant. In the absence of primary vascularization, napr, at skin transplantation, recognition results in a spleen and limf, nodes from hit of particles of cells in them or lymphocytes of a transplant.

In a phase of immunization after recognition of alien antigens there is an allocation lymphocytes of humoral substances — mediators of cellular immunity (see), and then capture of antigen macrophages and its transformation into an immunogene form. The phase of immunization comes to the end with interaction T-helperov with cells effectors, In - lympho-tsitami both macrophages and mobilization of potential cells-effek-torov from a blood-groove. At the same time the type of drainage of a transplant is of great importance: at hit of antigen with a flow of a lymph in limf, nodes preferential cellular immunity develops, and at its transport blood humoral immunity develops.

The effector phase leads to damage and death of a transplant; it is carried out by the combined impact on a transplant initially and for the second time activated lymphocytes, macrophages, and also humoral factors, first of all antibodies. The main reason for death of cells — action on them the lymphotoxin emitted by lymphocytes representing protein with the molecular weight of 90 000 (at the person), and also cytotoxic action of antibodies (IgM is preferential) with participation complement (see). An essential role in graft rejection is played also by macrophages.

The main morfol, N.'s signs and. the fabric reactions which are expressed in damage of an endothelium and fibrinferment of small vessels of a transplant with the subsequent hypostasis and lymphocytic infiltration of fabrics are. Degree of manifestation and speed of development of these signs significantly vary depending on a type of the replaced fabric, degree of antigenic differences and initial immunol, the status of the recipient. At primary transplantation the leading mechanisms of reaction of rejection are cellular phenomena while at repeated change or in the presence of the previous sensitization of the recipient the role of antibodies sharply increases in development of reaction of rejection.

Wedge, symptoms of reaction of rejection are caused by disturbance of structure and function of a transplant and respectively differ at change of various bodies and fabrics. Terms of its manifestation at primary allogenic changes fluctuate from 5 to 15 and more days depending on degree of antigenic distinctions м^жду the donor and the recipient and features of the transplanted bodies or fabrics. So, at renal transplantation in experimental conditions selection of couples of baboons compatible only for antigens of erythrocytes, extended the term of functioning of a renal transplant, according to J. J. Zyl et al. (1968), to 22,1 days instead of 14,8. Whyte (N. J. The island of White, 1968) in experiences on rats established that at transplantation of kidneys to the recipients different from the donor on a strong locus of Ag-B of system of histocompatibility, the transplant functioned 7 — 59 days, and at weak antigenic distinctions on Sex-antigen — more than 300. Similar data were obtained also at allogenic heart transplantation to mice with different degree of N. and. (M. A. Frolova et al., 1972). The analysis of results of the renal transplantations which are carried out in clinic revealed dependence of term of engraftment of a transplant on degree of antigenic distinctions between the donor and the recipient.

On time of manifestation, mechanisms of development and a wedge, a picture H. and. allocate four forms of rejection: superacute, accelerated, acute and chronic. The first two types of reaction develop at the recipients having the circulating antibodies against antigens of histocompatibility of the donor. Usually it is observed at repeated organ transplantation at the persons which were exposed to repeated hemotransfusions or a hemodialysis. Besides, antibodies to graft-specific antigens occur also at the multigiving birth women. Superacute graft rejection comes during the first hours after change, accelerated — on 1 — the 2nd days. In experimental conditions these forms develop at sensibilized recipients, and leaders are the humoral reactions causing bystry disturbance of blood circulation and massive hypostasis of fabrics. Also the delay in a circulatory bed of a transplant of uniform elements of blood of the donor, first of all lymphocytes and thrombocytes matters.

Acute graft rejection is the leading form H. and. at primary changes at not sensibilized recipients in the conditions of the natural course immunol. process. Disturbance of vital processes in a transplant is caused generally by defeat of small vessels (defeat of an endothelium, fibrinferments) and mononuclear infiltration of fabrics with the subsequent their necrosis.

Development hron, rejection is observed during the performing immunodepressive therapy or at differences of the recipient from the donor on weak loci of histocompatibility. Characteristic morfol, changes are focal cellular infiltration of fabrics of a transplant, the intersticial sclerosis which is followed by a necrosis and an obliteration of vessels.

Immunological incompatibility at hemotransfusions

Immunol. reaction at hemotransfusions can develop at the incompatibility caused by all components of the transfused blood, however first of all matters N. and., connected with erythrocytes. In this case N.'s reaction and. can arise owing to incompatibility on antigenic factors, isoimmunization and existence of rare «natural» antibodies.

Especially topical issue about N. and. for patients, the Crimea repeated and massive hemotransfusions, a hemodialysis were carried out, at to-rykh from immunization it is shown most accurately.

At the heart of N.'s manifestations and. at hemotransfusions reaction between isoantigens of the entered erythrocytes and isoantibodies of blood serum of the recipient lies. In a human body the large number of isoantigens, or group factors of blood is revealed (see. Blood groups ), value to-rykh in N.'s development and. unequally. The main role at the person is played by AB0 isoantigens and isoantibodies to them (an alpha and a beta). From options of isoantigen A the greatest value has the isoantigen Ah which is found at 88% of people. The A2 isoantigen revealed at 12% of people is the reason of reaction of incompatibility less often. A smaller role belongs to other options of isoantigen A. Group isoantigen B is characterized by bigger uniformity, than isoantigen A. Its contents in erythrocytes differs only in quantitative parameters, however in serum of people of groups 0 and A 3 kinds of antibodies P were revealed: rg, r2 and r3.

At incompatibility on the AB0 system when in blood of the recipient are available and - or R-isoantibodies, and the entered erythrocytes possess And - or V-isoantigens, as a result of reaction antigen — an antibody (see. Antigen — an antibody reaction ) quickly agglutination of erythrocytes and hemolysis develop. The agglutinates of erythrocytes formed under the influence of antibodies quickly eliminirutsya from a blood-groove with the subsequent destruction of hl. obr. in a liver.

Except the AB0 system, a number of isoantigens, from to-rykh the greatest value in N.'s manifestations is found in people and. the Rh system has (see. Rhesus factor ).

The main role in N.'s manifestations and. at hemotransfusions plays a ratio of antigen and antibodies.

In a wedge, conditions transfusion of sick 500 — 1000 ml of incompatible blood in the presence at it antibodies of a small avidnost (a measure of interaction with antigen) in a small caption can lead to adsorption them without wedge, manifestations. However developing at the same time from immunization leads to products of antibodies, their optimum adsorption on erythrocytes and to the subsequent late hemolitic reaction. The conflict can come also at hemotransfusion, in plasma a cut there are isoantibodies specific to isoantigens of erythrocytes of the recipient. In these cases of manifestation of N. and. depend on amount of the transfused blood, and also a caption and an avidnost of isoantibodies. Are especially dangerous in this respect from an antibody of immune type. Education them can be connected not only with hemotransfusions, but also with pregnancy, and also immunization by bacterins, to-rye may contain antigens, related with isoantigens of group A. It is shown that 70% of donors of group 0 contain in blood serum imun-ny of hemolysins anti-And, is more rare Anti-century.

At transfusion of the erythrocytes containing isoantigen D of the Rh system, to the persons deprived of it approximately in 50% of cases immune antibodys are developed. Immunol. the conflict at this incompatibility can proceed in the form of bystry elimination of erythrocytes with the antibodies occluded on them from a blood-groove or late (in 5 and more days) development of a hemolitic syndrome. Other isoantigens of erythrocytes seldom are the reason of development of N. and.

Wedge. N.'s manifestations and. at hemotransfusions are expressed as posttransfusion shock and hemolitic reactions, to-rye are caused by the interaction of erythrocytes with isoantibodies leading to destruction of cells (see. Hemotransfusion, complications ). Depending on speed of destruction of cells the wedge, symptomatology can be observed in several hours and even days. By data the Scarf (R. Sharf, 1974), similar reactions arise in 1 case on 1630 transfusions. The isoantigens specific to leukocytes (NA1, NA2, NB1) and thrombocytes (PIA, R1E, To), also play a role in N.'s development and. It is caused by presence of the antileukocytic or antithrombocytic antibodies induced by the previous hemotransfusions, pregnancy or allotransplantation. Antileukocytic and antithrombocytic antibodies can be found in one person that is caused by the general for leukocytes and thrombocytes antigens. Frequency of detection of these antibodies is proportional to number of hemotransfusions and makes, according to a number of researchers, at repeated transfusions of 50 — 80%. Immunol. the conflict in these cases is expressed in feverish reaction, a fever, a leukopenia and thrombocytopenia. Temperature reaction arises in connection with release of endogenous pyrogens from the leukocytes damaged by antibodies.

Immunological incompatibility at pregnancy

N. and. plays an important role in development patol, processes at pregnancy. Merge of maternal and fatherly haplotypes at fertilization of an ovum a spermatozoon leads to the fact that the genotype of a fruit always differs from maternal on many signs, including and according to the antigenic characteristic. Therefore, pregnancy represents the form of allotransplantation created in phylogenesis which is coming to an end with a peculiar rejection of a fruit at childbirth.

For the first time P. Medavar paid attention to similarity of reactions at pregnancy and artificial organ transplantation in 1953. However the mechanisms providing a possibility of long engraftment of a fruit and causing its rejection are still insufficiently studied. In 1925. L. Girshfeljd suggested that at pregnancy there can be an immunization of mother antigens of a fruit of a fatherly genotype, the mechanism a cut is similar to the processes happening at hemotransfusion. This hypothesis was experimentally proved by F. Levin with sotr. in 1941.

At normally proceeding pregnancy between organisms of mother and a fruit develop difficult immunol. relationship (see. Immunology of an embryogenesis ). In these conditions to the normal course of pregnancy and N.'s prevention and. a number of the devices created in the course of phylogenesis promotes: the placental trophoblast which is the barrier delimiting a blood stream of mother from a blood-groove of a fruit; the blocking factor in blood serum of pregnant women and immunodepressive effect of steroid hormones, products to-rykh increases during pregnancy. Cytotoxic action of maternal antibodies on cells of an embryo is neutralized by their binding by the antigenic complexes of a fruit which are in amniotic waters. The powerful anatomo-functional barrier regulating exchange of mother and child of cells and humoral factors is placenta (see).

Permeability of a placenta for erythrocytes of a fruit varies depending on compatibility on group factors and duration of gestation: at compatibility on AB0 and Rh-An-tigenam erythrocytes of a fruit are found out in blood of mothers in 81%, at incompatibility — almost in 20% of cases that it is connected with their bystry destruction.

The erythrocytes of a fruit, incompatible on antigenic properties, which got to an organism of mother induce antibody formation, to-rye, getting through a placenta into an organism of a fruit, can be the reason hemolitic disease of newborns (see). At normally proceeding pregnancy the quantity of the erythrocytes of a fruit passing through a placenta is small. Is more expressed immunization of a maternal organism at repeated childbirth and abortions therefore at the first pregnancy a wedge, N.'s signs of the item, as a rule, are absent.

At pregnancy in blood of mother also accumulation of anti-lymphocytic antibodies (lim-fotsitotoksin) to the HLA antigens of a fruit which are absent at it is observed; time of emergence, credits and duration of a persistention of antibodies depend on frequency rate of pregnancy. At the first pregnancy of a limfotsitotoksina appear on 16 — the 24th week, accruing by the end of pregnancy and quickly decreasing after the delivery. According to Hartmann (D. Hartmann, 1974) et al., the alloimmunization of mother to fatherly HLA antigens of an embryo develops depending on number of pregnancies, coming to light after the first pregnancy at 25%, and after the 6th at 60% of women.

Anti-lymphocytic antibodies meet at incompatibility on antigens of a sublocus Four more often (on sovr, the nomenclature of HLA-B), than LA (HLA-A) — in 66 — 72% and 28 — 34% of cases respectively.

There are instructions on communication between existence of antileukocytic antibodies and various pathology of pregnancy (death of a fruit, premature births, usual abortions, development of an isoimmune leukopenia of newborns). By data A. V. Mazurina (1967), N. and. mother and a fruit on platelet to antigens, especially P1 A1, is the most frequent reason of the isoimmune Werlhof's disease at newborns which is found in 1 case on 5000 childbirth and a different high lethality.

Immunogenetic features of the donor and recipient in the phenomena of a tissue incompatibility

Development of this question could not be carried out without progress in studying of bases of histocompatability and genetic structures (H-loci) controlling synthesis of graft-specific antigens (see. Immunity transplant ). Huge help in a research of these questions was given by experiments on chistolineyny (inbredny) animals, the genetic characteristic to-rykh is in detail studied. Animal experiments (usually on mice) pure lines on change of fabrics with the known genetic characteristics allowed to study the main patterns of a tissue incompatibility. It was established that sin-gene (genetically identical) transplants are successfully replanted, and allogenic, i.e. taken from other individuals of the same look, are torn away (see. Immunogenetics ). In a heterozygous state all genes controlling synthesis of antigens, kodominantna i.e. show the action. Thus, the phenotype of an organism according to the antigenic characteristic repeats a genotype.

On hybrids of firstgeneration (Fx) successfully beget transplants of both parent lines while fabrics of hybrids of firstgeneration at their change on any of parent lines are torn away. On the hybrids of second generation received during the crossing of the animal two lines differing on one locus of compatibility (kongenny) the frequency of engraftment of transplants from parent lines submits to the law of splitting (3:1) offered by G. Mendel. The described patterns extend to the isoantigens and antigens of histocompatibility playing the greatest role in N.'s manifestations and. Quantity of the loci controlling synthesis of histocompatibility antigens, variously: at the person 4, at mice more than 14, at rabbits 7, at fishes 3 — 4. Value of various loci in N.'s induction and. not equally. So, at mice the greatest role in N.'s development and. plays a locus of N-2, the system of genes to-rogo received the name of the main system of histocompatibility.

On offered in 1976. Committee of WHO experts to the new nomenclature fabric sovkhmesti-pave a genetic complex of the main system the person received the designation HLA. It includes 4 loci of HLA designated as HLA-A, HLA-V, HLA-G and HLA-D. The greatest value in N. and. have the first (And) and the second (In) the loci of HLA defined serological and controlling according to Nomenclature committee of WHO (1977), respectively 20 and 33 antigens. The third locus (HLA-C) includes 5 spetsifichnost, still finally not systematized. The fourth locus (HLA-D) controls synthesis of the antigens located on lymphocytes and identified in reactions of the mixed cultures of lymphocytes — Mixed Lymphocyte Culture (MLC). These antigens are also of great importance in engraftment of transplants.

Reaction a transplant against the owner

N. and. between cells of the donor and recipient the transplant against the owner can be shown not only in the form of reaction of the recipient to a transplant leading to its rejection, but in certain cases and in the form of reaction. Reaction a transplant against the owner — the symptom complex developing at the recipient with lowered or weakened immunol, reactivity in response to transplantation of immunocompetent allogenic cells. This type of N. and. it is for the first time described at introduction to chicken embryos or newborn chickens of several million cells of a spleen or blood of adult allogenic donors and received the name of a phenomenon of Simonsen. At chickens increase in a liver and spleen with signs of defeat due to reproduction in lymphoid bodies of cells of the donor was observed. Further the possibility of receiving similar reaction and at mammals was established, edges it was characterized by a splenomegaly with an atrophy of own lymphoid bodies, anemia, lag of animals in growth and weight, and at a high dose of the entered cells came to an end with death of animals. The described syndrome is known under the name welt disease (see) or diseases of nanism. Reaction a transplant against the owner can be shown also at mature animals from the weakened owing to a disease, radiation or immunodepressive therapy immunol, reactivity at change of the allogenic immunocompetent cells or bodies rich with them by it. In these cases reaction carries the name of a secondary, allogenic or homologous disease. Reaction of the entered cells to the antigens of the owner which are absent at them i.e. reaction a transplant against the owner is its cornerstone immunol.

Immunol, the nature of reaction a transplant against the owner is proved by impossibility of its reproduction in singenny system, its dependence on degree of antigenic distinctions of the donor and the recipient and heavier disease at introduction of the cells taken from the donor, previously immunizirovanny by tissues of the recipient.

Reproduction of reaction a transplant against the owner requires existence in a transplant of enough mature immunocompetent cells, at the recipient — the strong antigens which are absent at the transplanted cells and a condition of areactivity or hyporeactivity of an organism of the recipient in relation to a transplant. Otherwise reaction of the recipient to a transplant causes bystry elimination of the entered cells and reaction a transplant against the owner does not manage to develop.

Activity of lymphoid cells of various bodies in induction of reaction a transplant against the owner decreases in the following sequence: limf, nodes, spleen, blood, thymus, marrow, embryonal liver.

At people the most often homologous disease develops at changes of the cells of marrow (more rare than other hemopoietic bodies) which are carried out with the therapeutic purpose the patient with immunodeficiency and also the patient with leukoses, aplastic anemia, an acute radial illness and nek-ry other diseases. In these cases patients or have primary areactivity of immune system, or it is reached by preliminary intensive immunodepressive care and the replaced cells begin to breed freely. However in several days after change of cells of marrow recipients can have symptoms of the homologous disease caused by reaction of the replaced cells to someone else's antigens of the owner. Its earliest manifestation is the diarrhea which is followed by anorexia and vomiting. Then there is erythematic rash passing into papules, the liver is surprised, the necrosis of a liver is possible. Disease severity varies, in some cases the lethal outcome is observed. Except an acute form, forms of a disease with long (up to several months) a current are known hron. Clinically hron, the form of a homologous disease is shown by a lose of weight, diarrhea, a lymphopenia, histologically — - an atrophy of an adenoid tissue and the necrotic centers in marrow and a liver. In an experiment the homologous disease at radiation chimeras, at to-rykh oppression immunol is most well studied, reactivity X-irradiation or gamma-rays leads to the fact that their organism cannot answer with an immune response introduction of genetically alien cells. Transplantirovanny cells continue to exist in an organism of the owner — the so-called cellular himerizm develops. This feature made radiation chimeras (see) convenient model for studying of questions at issue of immunology.

Methods of definition of immunological compatibility, selection of the donor and recipient

For prevention of development of N. and. compliance of the donor and recipient on isoantigens of erythrocytes and graft-specific antigens (histocompatibility antigens) which are localized on a surface of lymphocytes is necessary. In recent years much attention is paid to also leukocytic antigens found on granulocytes and the specific antigens which are found only on thrombocytes. Compatibility of the donor and recipient on basic groups of blood is established by means of an agglutination test with the typing serums (see. Blood groups ). Detection of compatibility of the donor and recipient on graft-specific antigens of lymphocytes is much more difficult.

Definition of a range of antigens of histocompatibility includes identification of the antigens controlled by loci And, In and With, defined serol, cytotoxic reaction with a set of anti-HLA-syvorotok, so-called SD antigens (from English Serum detected), and the antigens of a locus of D found in a MLC response (MLC), designated as LD antigens (from English Lymphocyte detected).

Sets of specific serums receive by selection of blood sera of the people supporting anti-HLA - the antibodies formed owing to hemotransfusions or repeated pregnancies. As a rule, each of these serums contains antibodies to several antigens therefore for establishment of the antigenic characteristic of cells it is necessary to use several serums revealing this antigen. Recently attempts of receiving monospecific serums by immunization of people by the lymphocytes different from their own only on one graft-specific antigen are carried out.

Technique of definition of HLA antigens. Typing of the lymphocytes allocated from blood with a set of serums is carried out by means of the mikrolim-fotsitotoksichesky test on P. I. Terasaki. This test the accounting of death of lymphocytes at contact is the cornerstone of them with the serum containing the corresponding antibodies with the participation of a complement. Definition of LD antigens is carried out by means of reaction of the mixed cultures of the studied lymphocytes with a set of lymphocytes from specially selected test donor with the famous composition of antigens of a D-locus.

Development of methods of definition immunol, compatibility, just as search, typing and creation of sets of the typing serums, is carried out around the world by groups of immunologists at the obligatory international cooperation regulated by special committee of WHO.

The Mikrolimfotsitotoksichesky test is the most often used method of identification of HLA antigens of lymphocytes giving accurate and reproducible results at exact observance of reaction conditions. Reaction is carried out in special payments, in holes to-rykh the typing serums revealing a set of the spetsifichnost inherent in each of the studied samples of lymphocytes are in advance poured. Usually bring 0,001 ml of the typing serum in each hole and, having closed a cover, store the payments prepared thus at t ° — 70 °. Just before statement of reaction the payment is defrozen and add 0,001 ml to each hole allocated from blood inspected the suspension of lymphocytes containing in 1 ml 2 million of cells. After an incubation within 30 min. add 0,005 ml of a rabbit complement to each hole and again incubate within 1 hour. Reaction is considered by definition under a microscope of percent of the died cells revealed during the coloring by solution of eosine or tripano-vy blue.

Philosophy of carrying out the mikrolimfotsitotoksichesky test in the centers which are engaged in fabric typing are universal. The accounting of reaction is made by definition under a microscope of percent of the died cells and assessment of intensity of mikrolimfotsitotoksichesky effect in points. Usually cytotoxic effect is considered slabopolozhitelny if the died cells make not less than 15 — 20% (±1 points); more expressed death of cells is estimated by the increasing number of points (to 4 points: - { - j — I — [-).

For identification of each phenotype of lymphocytes a set of serums numbering several tens of samples is used. Since each serum can give reactions with several antigens of lymphocytes, for obtaining reliable results for each antigen it is reasonable to take 2 and more serums, giving preference to the drugs possessing narrower spetsifichnost. At the same time it can be defined on 2 antigens of each locus (And, In, C) if inspected is heterozygous on all three loci. At homozygosity on one of loci the number of the defined antigens is equal 5, on two — 4. In many institutions which are engaged in typing, definition of SD antigens is for practical purposes carried out on two loci (And yes In). In this case the maximum number of the defined antigens is equal 4 that demonstrates identification of all main spetsifichnost.

Definition of antigens of a D-locus (LD antigens) is carried out by statement of reaction blastotransformation of lymphocytes (see) in the mixed cultures. Lymphocytes inspected, allocated from blood in various ways (by upholding of blood, its centrifuging, etc.)? mix with a row test lim-fotsitov, received from donors with already known antigens; previously these cells kill with radiation or action of a mitomitsin of Page. Mixing is made in payments, as a rule, in small volumes (on 0,1 ml) and cultivate 4 — 5 days at t ° 37 ° in the presence of the air containing 5% of C02. Bring a radioactive label in each of payments (thymidine, marked hyzone of a certain radioactivity), and in 12 — 18 hours of a cell collect on special filters and measure by the scintillation counter intensity of inclusion in them of a radioactive label, i.e. estimate degree of compatibility of the studied lymphocytes with test cells. Typing of the donor and recipient on a D-locus still is a difficult and long research therefore for practical purposes (definitions of degree of compatibility of the donor and the recipient) usually use reaction of a blasttransforma-tion of their lymphocytes in the mixed culture. At the same time instead of test lymphocytes use the lymphocytes of the donor allocated from blood or limf, the nodes withdrawn along with the replaced body and the results of reaction which are previously killed with action of a mitomitsin of S. Raznits in the mixed culture and reflects degree of incompatibility of the donor and recipient in a monoculture of lymphocytes of the recipient.

Observation that the gene (or genes) coding antigens of V-lymphocytes is closely linked to a locus of HLA-D, formed the basis for use of the antigens specific to V-lymphocytes as markers for typing of antigens of a D-locus (so-called DR специфичностей) in serol. the mikrolimfotsitotoksichesky test it is similar to antigens A - and B-loci. The number of spetsifichnost of HLA-DR exceeds 7.

At selection of the donor and recipient at organ transplantation achievement of their complete match on all HLA antigens is almost unreal. Therefore in practical transplantology the principle of selection of the most suitable recipients to each body, suitable for transplantation, is carried out. The transplant centers «Intertrans-plant» are for this purpose created, combining countries entering SEV, «Evrotransplant» combining countries of Western Europe, etc. the purpose to-rykh the accounting of all patients needing organ transplantation is. The total antigenic characteristics of these patients brought on special cards are put in the COMPUTER, and at introduction to the COMPUTER of data on antigens of the donor recipients, the most corresponding to it on a phenotype automatically are selected. As a rule, changes are made at the antigenic differences of the donor from the recipient which are not exceeding 1 — 2 specificity (during the typing on And - and Itself).

The pathological anatomy at immunological incompatibility

Pathological anatomy at immunological incompatibility is characterized by the general and local morfol, changes of an immune and not immune origin. The general immunomorfol. changes develop in lymphoid bodies at once after change and do not depend on character of a graft-specific antigen. The general, not immune, changes, as a rule, are a consequence of dysfunction or death of a transplant. Manifestations of local immune fabric response substantially depend on antigenic properties of a transplanted organ or fabric, and not immune — on weight and the nature of the nonspecific disturbances arising in a transplant to or after change.

At once after transplantation in regional limf, nodes increase in quantity of pi-roninofilny cells on the course pulpy tyazhy, around sine and in their gleams is observed. Three days later the plethora, expansion of a cortical layer due to accumulation of big lymphocytes, proliferation in the germinal centers of average and big lymphocytes and plasmocytes is noted. Further, when in a transplant signs of rejection already differ, along with a hyperplasia limf, follicles and plazmokletochny reaction signs of death of lymphoid cells and the expressed Macrophagic reaction up to an eritrofagiya are observed. The characteristic arrangement of erythrocytes around macrophages and lymphocytes in the form of the socket pays attention. In remote limf, nodes and in a spleen the same changes, but less expressed are observed.

In a transplant in the first days after operation without use of immunodepressive therapy usually are found morfol, the changes caused by ischemia, preservation of the isolated body or fabric, weight and duration of an agony of the donor if the transplant was taken from a corpse. Patomorfologiya of a tissue incompatibility in many respects depends on character of a course of reaction of rejection. For superacute crisis of rejection, to-ry develops at once or during the first hours after change, lack of a cellular immune response is characteristic. Into the forefront the phenomena of an acute disorder kro-vo-and lymphokineses, hypostasis of interstitial fabric with plasmatic treatment of walls of blood vessels and necrobiotic changes act from parenchymatous elements. Such reaction arises in the presence at the recipient of predsu-shchestvuyushchy antibodies to a transplant therefore superacute crisis of rejection arises at repeated changes more often. However similar morfol, changes can be caused by ischemia of a transplant.

At the acute course of reaction of incompatibility morfol. N.'s signs and. differ later 2 — 3 days after operation. In the beginning it is shown in sticking in capillaries and venules of small lymphocytes to an endothelium with the subsequent substitution by their big lymphocytes with piro-ninofilny cytoplasm and plasmocytes. Such cells closely contact to an endothelium of capillaries, walls of capillaries are strongly changed. In the subsequent (4 — the 6th days) perivascular limfogistiotsitarny infiltrates appear, to-rye gradually increase to the extensive fields consisting of mononuclear cells. At the same time hemorrhages, the hypostasis of interstitial fabric expanded lymphatic and blood vessels, dystrophic changes of parenchymatous cells of a transplant are found. At acute crisis of rejection mononuclear infiltration becomes so intensive and diffusion that the drawing of a structure of a transplant is erased. Besides, limfogi-stiotsitarny infiltration, plasmatic treatment and a fibrinoid necrosis of walls of blood vessels, formation in them of blood clots, sharp hypostasis of interstitial fabric, a hemorrhage and death of a parenchyma is observed.

During the performing immunodepressive therapy terms of development of fabric reaction are extended, and lympho-histiocytic infiltration and others morfol, changes are expressed less. Therefore weight a wedge, pictures of rejection can not correspond to intensity of immune and cellular infiltration. In such cases of dysfunction and death of a transplant can be connected also with not immune reasons (thrombosis of the main vessels, disturbance of a hemodynamics in a zone of microcirculation, inf. complications etc.). In the remote terms after change at a good immunosuppression or compatibility of a transplant intensity of a cellular immune response considerably decreases, but at the same time the phenomena of a sclerosis of interstitial fabric, and also secondary dystrophic and atrophic changes of parenchymatous elements of a transplant gradually accrue.

In an experiment at change of various bodies reaction of incompatibility in them is shown is more or less similar. Nek-roye distinction is only that in heart morfol, signs of reaction of rejection differ in a subendo-cardial layer of a myocardium in the beginning, and further there is a picture of diffusion myocarditis with the expressed lgsh-fogistiotsitarny infiltration, necrobiotic and destructive changes of heart hmy-shechny fibers. In the replaced liver focal necroses of parenchymatous cells join mononuclear infiltration around the central veins in process of progressing of immune process. In lungs reaction of incompatibility is shown in the form of perivascular mononuclear infiltrates, hypostasis of perivascular fabric and interalveolar partitions, the extensive hemorrhages taking sometimes the whole share, death of pulmonary fabric and development on this background of usual inflammatory changes. In the replaced gut Mononuclear infiltrates consist almost entirely of plasmocytes.

Fullestly patol, the morphology of a tissue incompatibility is studied in kidneys. In the first days in them signs of extramedullary shunting of a blood-groove owing to disturbance of a hemodynamics of body in an organism of the donor or influence of not immune biologically active agents already in an organism of the recipient are found. As a result of such disturbance the phenomena of sharp ischemia of cortical substance and a plethora of pyramids are more often observed, the cortical necrosis, heart attacks and spontaneous ruptures of a transplant is much more rare. A significant amount mitotic of the sharing cells of an epithelium of proximal and distal departments of gyrose tubules, and also proliferation of yukstavaskulyarny cells and cells of the juxtaglomerular device is found. Morfol, signs of an immune response are found later 2 — 3 days after change in cortical substance in the form of small lympho-histiocytic infiltrates around small blood vessels and capillary balls. Later infiltration extends to a medulla and the cellulose surrounding a pelvis and ureters. The most rough changes in a type of disappearance of a brush border, emergence of granularity and vacuolation of cytoplasm are observed in an epithelium of proximal departments of gyrose tubules. In balls only the thickening of membranes due to accumulation of CHIC-positive substances is noted. Extensive limfogistiotsitarny infiltrates and destructive changes can be observed in walls of large vessels and in an ureter of a transplant. In late terms after transplantation into the forefront sclerous changes act, to-rye in process of lengthening of life time of a transplant in an organism of the recipient there are the leading reason of secondary disturbances and death of the replaced kidney. At the same time the usual ratio of average mass of tubules and interstitial fabric towards significant increase in the last changes. As a rule, signs of a perversion of regeneration of a canalicular epithelium in the form of emergence of a large number of multinucleate cells are noted. Sclerous changes of blood vessels and narrowing of their gleam due to reorganization of an intima are noted.

In skin allotransplant immune and cellular reaction is found on the region of the replaced site of skin in the beginning. In infiltrate there are almost no plasmocytes. Further along with expansion of a zone of cellular infiltration death of a transplant, gradual substitution of dead masses by granulyatsionny fabric with its subsequent transformation in cicatricial is noted. Rejection of a skin transplant can be caused also by a growth of epidermis from own skin of the recipient surrounding it.

In the implanted bones and a cartilage incompatibility, typical for acute reaction, morfol, changes is not observed; the phenomena of a gradual rassasyvaniye them and substitutions are noted by similar tissue of the recipient.

At introduction to an organism of immunodepressants or immunocompetent cells (hemotransfusion, bone marrow transplantation) reaction a transplant against the owner, for patomorfol can develop, pictures a cut in an acute phase are characteristic increase in a spleen, limf, nodes and intraorganic limf, образовании^ a hepatomegalia; in a spleen and limf, nodes at the same time transformation of small lymphocytes in big lymphocytes, proliferation of pironinofilny cells, reticulocytes and hemocytoblusts, hypostasis of a stroma is observed. In a liver formation of perivenous infiltrates, the consisting hl is noted. obr. from T lymphocytes, proliferation of reticular macrophages. In late terms there comes the aplasia and an atrophy limf, nodes, a spleen, a thymus, a liver with the subsequent development in them fibrous fabric.


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M. A. Frolova, A. E. Ivanov (stalemate. An.).

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