Does not cause a rejection reaction. Graft rejection

Transplantation is the act of transferring cells, tissues or organs from one organism to another. A malfunctioning organ system can be corrected by transplanting an organ (such as a kidney, liver, lung or pancreas) from a donor. However, the immune system remains the greatest barrier to transplantation as a routine treatment. The immune system has developed complex and effective mechanisms to combat foreign agents. These mechanisms are also involved in the rejection of transplanted organs that are recognized as foreign by the recipient's immune system.

The extent of the immune response to the graft depends in part on the degree of genetic inadequacy between the grafted organ and the host. Xenografts, which are grafts between members of different species, have the greatest divergence and produce the greatest immune response. Autografts, which are grafts from one part of the body to another (such as skin grafts), are not foreign tissue and therefore do not cause rejection. Isografts, which are grafts between genetically identical individuals (monozygotic twins), are also not subject to rejection.

Allografts are grafts between members of the same species that differ genetically. This is the most common form of transplantation. The extent to which allografts undergo graft rejection depends, in part, on the degree of similarity or histocompatibility between donor and recipient.

The extent and type of response also varies depending on the type of graft. Some organs, such as the eye and brain, are immunologically privileged (that is, they have minimal or no immune system cells and can tolerate even inappropriate implants). Skin grafts are not initially vascularized, so there is no failure until the blood supply develops. The heart, kidneys and liver are powerful vascular organs and result in an intense cellular mediated response in the host.

The antigens responsible for the rejection of genetically inappropriate tissues are called histocompatible antigens. They are products of histocompatibility genes. Histoconjugate antigens are encoded at more than 40 loci, but the loci responsible for the most severe allograft rejection reactions are found on the major histocompatibility complex.

In humans, the major histocompatibility complex is called the human leukocyte antigen system. Other antigens cause only weaker reactions, but combinations of several small antigens can cause strong rejection reactions. The main histocompatibility complex molecules are divided into 2 classes. Class I molecules are typically expressed on all nucleated cells, whereas class II molecules are expressed only on special antigen-presenting cells such as dendritic cells, activated macrophages, and B cells. The physiological function of MHC molecules is to present antigenic T cell peptides, since T lymphocytes only recognize antigen if they are presented in complex with the MHC. Class I molecules are responsible for presenting antigenic peptides from the cell (e.g., antigens from intracellular viruses, tumor antigens, autoantigens) in CD8 T cells. Class II molecules contain extracellular antigens as extracellular bacteria for CD4 T cells.

The immune response to a transplanted organ consists of cellular (lymphocyte-mediated) and humoral antibody-mediated mechanisms. Although other cell types are also included, T cells are central to the graft rejection reaction. The rejection reaction consists of a sensitization stage and an effector stage.

During the sensitization stage, CD4 and CD8 T cells recognize allogeneic expression on foreign transplant cells by their T cell receptors. Two signals are required to identify an antigen. The first of these is provided by the interaction of the T-cell receptor with the antigen presented by histocompatibility complex molecules, and the second by the interaction of the costimulatory receptor/ligand on the surface of T-cells.

At the sensitization stage, there are so-called direct and indirect pathways, each of which leads to the generation of different complexes of all specific T-cell clones.

In the direct pathway, host T cells recognize intact MHC allomolecules on the surface of the donor or stimulating cell. The host's T cells recognize the donor tissue as foreign. This time, it is likely the dominant pathway involved in the early alloimmune response.

In an indirect manner, T cells recognize the processed alloantigen, presented as peptides from individual antigen-presenting cells. Secondary responses, such as those that occur in chronic or late acute rejection, involve proliferative T cell responses involving peptides that were previously immunologically silent. This change in the pattern of T cell responses is called epitope transition or proliferation.

Aloantigen-dependent and -independent factors contribute to effector mechanisms at the effector stage. Initially, non-immunological “injury responses” cause a nonspecific inflammatory response. Therefore, the antigenic presentation of T cells increases as the expression of adhesion molecules, major histocompatibility complex class II, chemokines, and cytokines increases. It also promotes the release of unchanged soluble MHC molecules. Once activated, CD4-positive T cells initiate delayed-type hypersensitivity reactions mediated by macrophages and provide B cells for antibody production.

After transplantation, various T cells and cytokines, such as IL-2 and IFN-γ, are activated. L-chemokines, IP-10 and MCP-1 were then expressed, promoting intense macrophage infiltration into the allograft. IL-6, TNF-α, inducible nitric oxide synthase and growth factors also play a role in this process. Growth factors, including TGF-β and endothelin, cause smooth muscle proliferation, intimate thickening, interstitial fibrosis, and renal transplantation and glomerulosclerosis.

Endothelial cells activated by T cell-derived cytokines and macrophages express class II major histocompatibility complex, adhesion, and co-stimulatory molecules. They may present an antigen and thus recruit more T cells, enhancing the rejection process. CD8-positive T cells mediate cell-mediated cytotoxicity responses by either “lethal shock” or, conversely, the induction of apoptosis.

Transplant rejection reactions are classified as hyperacoustic, acute and chronic.

In hyperacute graft rejection, the transplanted tissue is rejected within minutes to hours as the vascularity is rapidly destroyed. Automatic humoral rejection is mediated and occurs because the recipient has pre-existing antibodies against the graft, which can be caused by a previous blood transfusion, multiple pregnancies, a previous transplant, or xenografts against people who already have antibodies. The antigen-antibody complex activates the complement system, causing massive thrombosis in the capillaries, which prevents vascularization of the graft; the kidneys are most susceptible to excessive rejection. The liver is relatively resistant, probably due to its dual blood supply, but most likely due to incomplete immunological properties.

Acute graft rejection is mediated by lymphocytes that are activated against donor antigens, primarily in the recipient's lymphoid tissues. Donor dendritic cells (also called other white blood cells) enter the bloodstream and function as antigen-presenting cells.

The delayed response to graft rejection develops several months to several years after episodes of acute rejection have subsided. Both antibodies and cells are mediated. Chronic rejection occurs as fibrosis and scarring in all transplanted organs, but the specific histopathological pattern depends on the transplanted organ. In cardiac transplants, chronic rejection occurs as accelerated atherosclerosis of the coronary artery. Transplanted lungs appear as bronchiolitis. In liver transplantation, chronic rejection is characterized by the disappearance of bile duct syndrome. In kidney recipients, chronic rejection (called chronic allograft nephropathy) occurs as fibrosis and glomerulopathy.

Histological changes in the graft rejection reaction occur in several stages:

The early stage is inflammatory infiltration in the transplantation around the capillaries and venules of lymphocytes, macrophages and plasma cells. Thrombosis develops in the graft vessels, which leads to tissue ischemia and the beginning of its destruction.
On days 2–3, the perivascular inflammatory infiltrate increases in number as a result of invasion of new cells and proliferation of existing cells. Lymphocytes, plasma cells and pyrophilic cells dominate here. Fibronoid necrosis, which causes thrombosis in new vessels, often develops in the vessel wall.
The final stage - leukocytes and macrophages appear in the inflammatory infiltrate. Damage to the graft membrane occurs in transplantation due to enzymes released from the activated lymphocyte membrane. This leads to disruption of the potassium-sodium pump of the target cell, followed by swelling and disintegration. The breakdown of the cellular and tissue components of the graft leads to the discovery of its antigenic structures, which induce an immune response, turning the immune response into a vicious circle.
Graft failure - The term for allogeneic graft failure is 7-14 days.

(ROT) is an immunological process directed against tissues foreign to the body, transplanted during a transplantation operation. It is accompanied by a complex of local (swelling, inflammation) and general (intoxication phenomena, fever, weakness) manifestations, the severity and speed of development of which depend on the type of reaction. Diagnosis is made by studying the clinical picture, histological examination of transplanted tissues, and a number of laboratory and instrumental methods, depending on the type of transplant. Treatment boils down to immunosuppressive therapy, the use of cytotoxic agents, and some drugs are prescribed for life.

General information

Immunological reactions of transplant rejection occur when using allogeneic (transplanted from person to person) or xenogeneic (from animal to person) tissues and organs. Autografts, such as skin transplanted from the thigh to the face, have the same antigenic structure as other body tissues, so they do not cause reactions. Rejection extremely rarely occurs when transplanting avascular structures - the cornea, some cartilage - since in this case there is no contact of foreign tissues with immunocompetent cells. The condition was the most common complication in the early days of transplantation, but has become increasingly rare in recent years, despite an increase in the number of surgeries of this type. This is due to advances in determining the histocompatibility of donor and recipient tissues and the development of more effective methods of immunosuppressive therapy.

Causes of transplant rejection

Antigenic compatibility of tissues is determined by the combination of a number of antigens - first of all, the major histocompatibility complex (six major antigens and a number of minor or minor ones). In addition, other protein antigenic complexes (AB0, connective tissue proteins) can also have an effect. In many ways, rejection reactions are similar to the normal immune response when foreign antigens enter the body or (in some cases) hypersensitivity reactions of types 2 and 3. Humoral and cellular mechanisms of immunity take part in their development. The rate of occurrence of pathological changes in the graft depends on the type of reaction, the activity of the recipient’s immune system, and the magnitude of the antigenic differences between the tissues.

The cause of fulminant types of transplant rejection is sensitization of the recipient's body, as a result of which, during transplantation, processes similar to intolerance reactions occur with the formation of immune complexes and activation of the complement system. More common acute types of immunological reactions to transplanted tissues usually develop due to incompatibility with MHC antigens; a predominantly cellular immune response is involved in the pathogenesis. Chronic forms of ROT are caused by both cellular and humoral reactions; they are often caused by incorrect immunosuppressive therapy prescribed after surgery.

Pathogenesis

The pathogenesis of transplant rejection differs in different forms of this condition. Hyperacute or lightning-fast reactions are caused by the body’s sensitization to the antigens of the transplanted organ, and therefore occur as an intolerance or allergy. When allograft tissue comes into contact with the recipient's blood, the formation of immunocomplexes is stimulated, settling on the inner surface of the vessels. They provoke activation of the complement system, severely damaging the endometrium of the transplant vascular network, which causes the formation of multiple microthrombi and vascular embolization. This leads to ischemia of the transplanted tissues, their swelling, and, in the absence of therapeutic measures, to necrosis. The rate of development of pathological processes is only a few hours or days.

Acute and chronic types of ROT are based on the processes of the cellular immune response, so such reactions develop somewhat more slowly - over several weeks. In case of antigenic incompatibility of the graft and recipient tissues against the background of adequate or increased immune activity, recognition of foreign cells by macrophages and T-lymphocytes (helpers or inducers) occurs. The latter activate killer T cells, which secrete proteolytic enzymes that destroy the cell membranes of allograft structures. The result is the development of an inflammatory reaction in the transplanted organ, the severity of which depends on the level of activity of the immune system. With a long-term process, it is possible to involve humoral immune factors with the synthesis of specific antibodies directed against transplant antigens.

Classification

There are several forms of the rejection reaction, differing in the speed of development and a number of clinical manifestations. The reason for this difference is different types of ROT, which have different rates of occurrence, as well as predominant damage to certain graft structures. Knowing the approximate timing of the formation of a particular type of immune response, a specialist can determine its nature and prescribe the optimal treatment. In total, there are three main clinical forms of graft tissue intolerance reactions:

Lightning fast or super sharp. It occurs in the first minutes or hours after the transplanted organ is “connected” to the recipient’s systemic bloodstream and is caused by the latter’s sensitization to the transplant antigens. It is characterized by massive microcirculatory disorders with ischemic phenomena in the allograft and the development of necrosis, while inflammation is secondary.
Spicy. Registered during the first three weeks after transplantation, the pathogenesis is based on the cellular immune response when the donor and recipient are incompatible. The main manifestation is the development of inflammatory processes in the transplanted tissues, their severity depends on the activity of the immune system.
Chronic. It occurs several months after transplantation, can be recurrent, and is highly dependent on the immunosuppressive therapy regimen. It develops through both cellular and humoral mechanisms of the immune response.

Symptoms of transplant rejection

All manifestations of allograft rejection are divided into systemic, depending only on the pathogenesis of the process and the reactivity of the immune system, and local, associated directly with the transplanted organ or tissue. Among the general symptoms, there is always an increase in temperature, chills, and fever of greater or lesser severity. Manifestations of general intoxication are recorded - headache, nausea, vomiting, decreased blood pressure. Symptoms of intoxication of the body sharply intensify with the development of necrosis processes in the graft; in severe cases, against this background, toxigenic shock may occur.

Local manifestations of ROT are associated with the transplanted organ, and therefore may vary in different patients. When transplanting a whole organ, symptoms caused by dysfunction of its function come to the fore - for example, cardialgia, arrhythmias, heart failure during heart transplantation. Acute renal failure may be associated with a rejection reaction of a transplanted kidney, hepatic failure - with the liver. When allotransplantation of a skin flap occurs, it becomes swollen, red, even purple, and a secondary bacterial infection is possible. The timing of the appearance of local and general symptoms of rejection depends on its form - the fulminant type is characterized by a severe reaction within 2-3 hours after transplantation, while acute and chronic types can appear after several weeks or even months.

Complications

The earliest and most severe complication of the reaction of rejection of transplanted tissue is the development of shock associated with immunological processes or caused by intoxication of the body. Necrosis and tissue damage of a transplanted organ, the work of which is vital for the body (for example, the heart), often leads to death. Some experts also consider infectious diseases caused by enhanced immunosuppressive therapy to be complications of ROT. In the long term, against the background of an artificial decrease in the activity of cellular immunity, the development of cancer is possible.

Diagnostics

A feature of diagnosing a transplant rejection reaction is the need for it to be carried out as quickly as possible, which allows not only to improve the patient’s condition, but also to preserve the transplanted organ. Some researchers include in the diagnosis of ROT a number of immunological studies performed before surgery at the stage of donor selection - typing the spectrum of transplantation antigens, determining the biological compatibility of tissues. High-quality performance of these tests allows you to avoid the development of a hyperacute reaction and significantly reduce the likelihood of other forms of rejection. Among the diagnostic procedures performed after transplantation, the most informative are the following:

Laboratory research. During the rejection process, a general blood test will reveal signs of nonspecific inflammation - lymphocytosis, an increase in ESR. A study of the immune status makes it possible to detect immune complexes, an increase in the level of complement components (in fulminant forms), and immunoglobulins. Under the influence of immunosuppressive therapy, test results may be distorted, which must be taken into account when interpreting them.
Instrumental research. Instrumental diagnostic methods (radiography, ultrasound, ultrasound, CT, MRI) are used to assess the functional activity and structure of the transplant - kidney, liver, heart, lung. In general, ROT is manifested by swelling of the organ, disruption of its functioning, and the presence of circulatory disorders (ischemia, infarction, necrosis). In chronic and recurrent types of reaction, areas of sclerosis can be detected in the graft structure.
Histological studies. Biopsy of allograft tissue and their subsequent histological and histochemical study is the gold standard in determining ROT. With the fulminant type of reaction, the biopsy specimen reveals damaged capillaries, perivascular edema, signs of ischemia and tissue necrosis, biochemical studies determine immune complexes on the surface of the endometrium. In chronic or acute types of rejection, lymphocytic infiltration of the graft tissue and the presence of areas of ischemia and sclerosis are detected.

Approaches to diagnosing rejection reactions may vary depending on the specific transplanted organ. For example, during kidney transplantation, general and biochemical urine analysis, ultrasound examination and other ultrasound examinations of the organ are indicated, with caution - excretory urography. In case of heart transplantation, electrocardiography, echocardiography, and coronary angiography are necessary.

Treatment of transplant rejection

Treatment of ROT consists of reducing the activity of the immune response; the development of the most effective methods is still ongoing. An immunologist in collaboration with a transplantologist is involved in drawing up a treatment regimen. The development of immunological tolerance to allograft antigens is considered a promising technique, but its mechanisms are quite complex and have not yet been sufficiently studied. Therefore, practically the only method of treatment and prevention of rejection is nonspecific immunosuppressive therapy, carried out by several groups of drugs:

Steroid drugs. This group includes prednisolone and its derivatives, dexamethasone and other drugs. They reduce the rate of lymphocyte proliferation, are antagonists of many inflammatory factors, and effectively reduce the severity of the immune response. In some cases, a course of use of these drugs after transplantation is prescribed for life.
Analogs of nitrogenous bases. These drugs are able to integrate into the process of nucleic acid synthesis and inhibit it at a certain stage, reducing the rate of formation of immunocompetent cells and the severity of rejection processes. For preventive purposes, they are used soon after organ transplantation.
Alkylating agents. A group of drugs that can attach to the DNA of cells and block their division. Medicines are used for acute forms of this condition due to their rapid and reliable cytotoxic effect.
Folic acid antagonists. Vitamin B9 is involved in the synthesis of certain nitrogenous bases and the proliferation of lymphocytes; its antagonists slow down the development of the immune response during ROT. The drugs are used for chronic forms of reaction as part of complex therapy.
Antibiotics. Some drugs in this group (cyclosporine, chloramphenicol) block RNA synthesis, inhibiting both cellular and humoral immune responses. Sometimes used for life after transplantation to prevent rejection.

According to indications, other medications may be prescribed to improve the patient’s condition - detoxification drugs, diuretics, cardiac stimulants, anti-inflammatory and antipyretic drugs. In case of severe complications (shock, acute cardiac or renal failure), resuscitation measures and hemodialysis are necessary. When an infection occurs against the background of immunosuppression, timely administration of antibiotics, antifungal or antiviral (taking into account the nature of the pathogen) agents is required.

Prognosis and prevention

The prognosis for fulminant types of transplant rejection is unfavorable in almost 100% of cases - surgery to remove the transplanted organ, selection of a new donor and re-transplantation are required. At the same time, the risk of developing ROT during a secondary transplant increases several times. Timely initiation of immunosuppression in acute or chronic variants of the condition often allows preserving the allograft, but increases the risk of infectious complications and the likelihood of cancer in the future. An effective prevention of rejection is careful selection of a donor for transplantation, checking compatibility for all possible antigenic systems - especially for MHC; at least 4 of the 6 main alleles must be compatible. The presence of a direct blood relationship between the donor and recipient sharply reduces the likelihood of developing pathology.

Transplant rejection

Rejection of transplanted organs and tissues can occur almost immediately (hyperacute rejection) or after some time (acute rejection and delayed graft rejection). The immune response during transplant rejection is mediated by both T cells and antibodies. Helper T cells are very important in the immune response in patients who have not been previously sensitized, while cytotoxic T cells play a minor role. In patients who have been sensitized, T-cytotoxic cells are the main effectors of the response. Other cells, such as macrophages, play a secondary role; antibodies are also involved in acute and delayed transplant rejection.

Acute rejection – this is a delayed-type hypersensitivity (see Allergization of the body). Graft failure occurs several days or months after transplantation. At first, it seems that the engraftment is going well, and the organs or tissues begin to function as expected. However, after a few days, these functions weaken, and in the case of skin grafts, the skin turns purple and then black. After 11-17 days, the graft is rejected.

This type of rejection is characterized by the infiltration of several types of immune system cells into the allograft, including macrophages, lymphocytes, and other plasma cells. Sometimes bleeding and swelling of varying severity occur, although the blood vessels usually remain intact. Cell-mediated rejection may be reversible with enhanced immunosuppressive therapy. In this case, the damaged areas heal and scarring begins. Such grafts often “survive” and persist for a long time, even if treatment with immunosuppressants is minimized.

Delayed rejection transplantation sometimes occurs in patients undergoing immunosuppressive therapy. This is thought to be the result of antibody-mediated damage. First of all, the membranes lining the blood vessels are involved in the process. Over time, the blood vessels become blocked and blood stops flowing to the graft, which leads to its complete destruction.

Hyperacute rejection usually occurs in people who have been previously sensitized to human leukocyte group A antigens present in the graft. Presensitization may occur due to pregnancy, blood transfusion, or previous transplant surgery. In these cases, the role of antibodies relative to transplantation antibodies in graft rejection is obvious. The destruction of the graft occurs within a matter of hours or even minutes after it has been attached to the host’s circulatory system.

This antibody-mediated rejection involves complement components, phagocytes, and macrophages. They act so quickly that the transplant has no chance. The graft may become engorged with blood, which can clot inside the donor organ. Sometimes this happens so quickly that the transplanted organ will need to be removed within minutes. The process is irreversible; no known methods of immunosuppressive therapy will help.

This antibody-mediated rejection usually occurs when the blood types of the donor and recipient do not match. This is similar to the reaction that occurs during a blood transfusion because the antigens involved are present in all cells of the body. This fact is important to consider when assessing the suitability of the graft.

Medical sections: general diseases

Associated diseases: allergization of the body

Get well!

The concept of transplantation immunity Transplantation immunity is an immune reaction to the transplantation of foreign tissues, which usually ends in their rejection.

Transplantation barrier. This concept is associated with genetic differences between the donor and recipient. Between organisms of the same species Allotransplantation

. . . But... if the xenograft is preliminarily subjected to a treatment that reduces its immunogenicity, then the outcome of the transplant may be favorable. That. Skin, blood vessels, and pig heart valves can be transplanted into humans. But attempts to transplant whole organs into humans have been completely unsuccessful.

Genetically identical donor and recipient, for example, identical twins or animals of the same inbred line Isotransplantation No rejection reaction

The participation of the immune system in the rejection of foreign tissue was first demonstrated by the English immunologist Peter Medawar in 1945.

When transplanting a skin flap from one rabbit to another, P. Medawar discovered antibodies in the recipient that were specific to the donor's antigens. These first observations were the starting point in the formation of transplantation immunology

General characteristics of rejection During primary allograft transplantation, in the first two days, general blood circulation is established between the graft and the recipient, and the edges of the transplanted skin fuse with the host skin. Externally, within 4-5 days the transplant seems to have taken root. However, it is during this prosperous period that the effector mechanisms of rejection are formed.

By 6-7 days, swelling of the graft is observed, its blood supply stops, and hemorrhages develop. In the area where the transplant is located, cells of the inflammatory reaction accumulate, among which lymphocytes predominate. The process of graft destruction begins

On days 10-11, the graft dies, and its transplantation to the original donor does not restore viability. This is the picture of primary transplant rejection.

When a transplant is re-transplanted from the same donor, the rejection reaction develops approximately 2 times faster - in 6-8 days.

Immunogenicity of the graft 1. Peptide fragments derived from cytoplasmic proteins are formed in the proteasome and delivered by TAP transport proteins to the ER, where they bind to MHC molecules. squirrels

2) Recognition of the peptide associated with MHC I by the recipient's lymphocytes triggers the action of cellular and humoral immunity.

Peptides originating from other cellular compartments are also transported to the ER, bind to MHC I molecules and are presented on the cell surface. Non-MHC antigens produce a much weaker immune response and activate a limited number of T cell clones.

Conventional T-cell reaction to foreign protein antigens Immune response during transplantation Antigens are processed to form peptides that are presented on the surface of the recipient's APC in association with MHC. Foreign MHC molecules directly activate T lymphocytes MHC antigens

The role of T-lymphocytes in transplant rejection T-cells play a leading role in transplant rejection Congenital absence Thymectomized in the neonatal period Adult thymectomized rodents Deprived of T-cells and do not reject transplants

The molecular basis of the rejection reaction is the interaction of TCR and MHC. With the help of their TCR, T lymphocytes recognize donor peptides expressed on transplant cells in association with MHC antigens. T cells see only those antigens that are associated with MHC molecules

Comparison of the MHC of the donor and the recipient Relationship with the T-cell receptor The structure of the various MHC molecules is almost identical, but they differ in the structure of the peptide-binding region

The amino acid residues that determine the important differences between MHC molecules are mostly located inside the cavity formed by the α helices. Therefore, differences in the shape and surface charge of the peptide-binding cavity are of primary importance for T-cell recognition.

A different set of peptides is presented on the surface of the transplant cells, which is determined by differences in the shape and charge of the surface of the peptide-binding cavity of the transplant MHC molecules

Differences in MHC antigens between the transplant donor and recipient cause the graft to express an extremely large number of new foreign antigens that can be recognized by the recipient's T cells. Donor Recipient

Types of rejection reactions I. Hyperacute rejection. It occurs extremely quickly and is observed in patients whose blood serum already contains antibodies against the transplant. Antibodies to anti-HLA are formed as a result of: previous blood transfusions multiple pregnancies rejection of previously transplanted tissues

Antibodies Fix complement The vascular wall becomes permeable to plasma and cells, platelet aggregation occurs and the blood supply to the graft is disrupted Damage to the endothelium of blood vessels

Due to hyperacute rejection, it is impossible to transplant animal organs into patients, since humans have natural antibodies Ig M and Ig G to animal cellular antigens. Methods of prevention: Removal of antibodies Depletion of complement Using genetic engineering methods to obtain animals whose organs are less sensitive to rejection

Acute rejection Appears after several days or weeks and is primarily due to the activation of T cells with the subsequent launch of various effector mechanisms. If an antigenically identical graft is re-transplanted into a recipient, rejection develops very quickly (secondset phenomenon). This is an example of a secondary immune response.

Chronic rejection Cell-mediated sluggish rejection reaction Deposition of antibodies and antigen-antibody complexes in the transplanted tissue with damage or activation of vascular endothelial cells and subsequent inadequate regeneration.

1. Vascular obliteration (closing of the lumen of graft vessels by proliferating smooth muscle cells) 2. Interstitial fibrosis (diffuse formation of scar tissue in the graft)

The half-life of a transplanted kidney is still only 7-8 years, and over the past decade this period has not been increased, despite the use of a new drug - cyclosporine A - to eliminate acute rejection.

Recognition of transplantation antigens occurs either directly on the cells of the transplant, or in the nearest (regional) lymphoid tissue, where the antigen detached from the cell surface arrives.

v Donor APCs (passenger leukocytes) migrate and directly activate host T cells, which become specific to the MHC molecules of the transplant. v Transplant Ags can undergo phagocytosis and be processed by host APCs. v Presentation on the recipient's MHC activates only those T cells that do not recognize the graft's MHC molecules.

q Activated T cells infiltrate perivascular tissues and areas around the APC. A population of Th 1 type cells is involved. q The release of cytokines has a direct toxic effect on surrounding tissues. q Cytokines induce the recruitment of T and B cells, macrophages and granulocytes. Activated effector cells release procoagulant factors, kinins and eicosanoids. q Under the influence of cytokines, adhesion molecules and MHC are strengthened in surrounding tissues.

3 stages of the rejection reaction At stage I, recognition of transplant antigens by the precursors of cytotoxic T lymphocytes and the precursors of helper and inflammatory T cells occurs. Once recognized, the cells migrate to the nearest (regional) lymphoid tissue.

q In the peripheral lymphoid tissue, the main events leading to the formation of the effectors of the rejection reaction develop (stage II). q TCD 8 are transformed into effector mature cytotoxic T cells (CD 8) q Free transplantation antigens entering the lymphoid tissue are captured by APCs and involve both TH 1 and TH 2 cells in the response.

q At stage III, reactions of rejection of foreign tissue develop. It is realized with the participation of mature CD 8 T cells, Ig-activated macrophages, Ab with the participation of NK, Ig and activated cytokines. q With the participation of TH 1, macrophages are attracted to the rejection zone, providing the inflammatory component of the rejection reaction.

Transplantation – second life

“I was tormented by attacks of suffocation so terrible that I did not know what to do with myself. Water stagnated in my lungs, and severe pneumonia developed; I don’t know how I survived. Constant bouts of vomiting. I was endlessly thirsty. But you can’t drink, so as not to increase the load on the heart,” this is how she described her condition before the heart transplant Alla Gridneva.

She had an operation in 2004, after which Anna returned to work as a journalist, got married, and gave birth to a child.

Transplantation is the most effective way to treat terminal conditions. It is carried out when other methods cannot save a person’s life. We can say that this is the last hope for many patients.

“People with transplanted hearts, kidneys, livers, and lungs live almost as long as those who did not. Moreover, the quality of life of these patients is quite decent: they work, start families, give birth to children,” said Marina Minina, head of the Moscow Coordination Center for Organ Donation of the State Clinical Hospital named after S.P. Botkin.

Prevent rejection

Mikhail Kaabak, head of the kidney transplantation department of the Russian Scientific Center for Surgery named after. B.V. Petrovsky RAMS. Photo from pochka.org

But the transplanted organ, like the entire body as a whole, requires special care - discipline of life. Otherwise, post-transplantation risks will exceed the initial benefits.

— As a rule, a person experiences a surge of health after an organ transplant. But a person’s life after a transplant is a balancing act between rejection of the transplanted organ, that is, insufficient suppression of the immune system, and excessive immunosuppression, leading to infections and cancer,” he told Miloserdiyu.ru Mikhail Kaabak, Head of the Kidney Transplantation Department of the Russian Scientific Center for Surgery named after. B.V. Petrovsky RAMS.

Rejection occurs because the body recognizes the new organ as “foreign,” and the immune system begins to slowly destroy it. Signs of donor heart rejection, for example, include high fever, asthma attacks, chest pain, increased fatigue, pressure surges, and “cold” symptoms.

To prevent organ loss, patients are prescribed immune-suppressing drugs. As a result, people may develop pneumonia, cytomegalovirus infection, candidiasis, lymphoma, melanoma, and carcinoma.

— 10 years after transplantation, cancer occurs in 10% of patients. This is much higher than the average population, but there is no hopelessness, notes Mikhail Kaabak.

Prevent amputation

Maya Sonina, director of the Oxygen Charitable Foundation. Photo: Pavel Smertin

Postoperative thrombosis can lead to gangrene of varying severity. Maya Sonina, director of the Oxygen Charitable Foundation, told Miloserdiy.ru about two cases of thrombosis after lung transplantation, which led to amputation of limbs. One woman lost both legs up to the knee joints. Now she has started walking with prosthetics and is learning to live again.

Another patient lost her legs up to her ankles and her fingers. Then she began to have transplant rejection, developed pulmonary hemorrhage, and died. The second case occurred six months after the operation, which is not typical. But, according to Maya Sonina, such situations have arisen in world practice.

After heart transplantation, 25-30% of patients develop myocardial ischemia and various pathologies of the coronary arteries (RCA) after 5-6 years. RCA can cause death, since there is no pain with a transplanted heart (it is “denervated”), and the person does not notice the seriousness of his condition.

Diabetes mellitus is detected in 35% of patients 2-5 years after heart transplantation. About 2-3% of people who have this type of surgery eventually need dialysis due to kidney failure. In addition, they may develop osteoporosis, hip necrosis and other diseases of the musculoskeletal system, as well as neurological disorders, epilepsy, according to one of the medical sites in an article entitled “Heart transplantation: a therapist’s view.”

The most complex organ is the lungs

“The average lifespan of a transplanted kidney received from a deceased person is about 8 years. The same kidney obtained from a living person lasts about 15 years. There are technologies that allow these periods to be doubled. That is, a kidney received from a relative can work for an average of 30 years,” said Mikhail Kaabak.

“The most complex organ is the lungs,” he continued. — Five-year survival does not exceed 50% for transplanted lungs. The heart and liver have the same 70% survival rate, and for the liver it makes no difference whether it comes from a living or deceased person. This is due to the fact that a whole liver is transplanted from a deceased person, but only a surgically damaged part of the liver is transplanted from a living person.”

“The transplanted organ will not work indefinitely,” the expert warns. — It all depends on the age category of the patient. In children, loss of organ function is much more common, but life expectancy is longer. In older people, exactly the opposite happens: they die more often than they lose an organ.”

If a transplanted organ fails, this is not the end. Secondary transplants are also carried out in Russia. “Regardless of the reason why the first organ died, one way or another, sensitization (increased sensitivity of the body to antigens, where antigen is a substance that the body perceives as foreign) of the body occurred,” explained Mikhail Kaabak. — That is, a secondary transplant is more complex immunologically.

And from a surgical point of view, transplanting a kidney a second time is no more difficult than the first time, because it can be transplanted to the side where there has not yet been surgery.

If we are talking about the liver or the heart, then surgical difficulties arise. It’s the same with the lungs, since the organ needs to be transplanted to the same place where it was before, and accordingly, surgeons are faced with scarring processes.”

“I’ve already had a kidney transplanted twice,” he told Mercy.ru DmitriyBabarin,

Deputy Chairman of the Interregional public organization of disabled people - nephrology and transplant patients "New Life". — The second transplant is more tedious. There is no such fear anymore, but there is an understanding that this routine - recovery after surgery - will drag on for a long time.”

“The smarter the patient, the longer he will live”

“The smarter the patient, the longer he will live,” he said earlier in an interview Sergey Gauthier, Director of the Federal State Budgetary Institution "National Medical Research Center for Transplantology and Artificial Organs named after Academician V. I. Shumakov."

“There are situations when people relax and lose their vigilance, and do not follow doctors’ orders,” noted Maya Sonina. “They begin to rejoice in the fact that after a lung transplant they began to breathe on their own, and, as they say, go all out. We have already lost patients for such reasons.”

“Transplantation is a complex technology. When a person neglects the doctor’s prescriptions, he violates this technology, and the resource embedded in the transplanted organ decreases,” noted Mikhail Kaabak.

Dmitry Babarin explained how a patient with a transplanted kidney should behave: “For the first time after transplantation, physical activity must be very limited. Follow the diet strictly. Many people start eating salty foods (foods containing potassium) to celebrate. But the transplanted kidney is supported only by pills that prevent the body from destroying it; it is very weak.

Again, alcohol. Here, your own kidneys don’t always hurt, but the transplant doesn’t hurt at all, and you may not notice the danger. In addition, after the transplant you have to take a lot of medications, and the liver is hit.

In winter, be sure to dress warmly. You can’t sit in clinics too much; doctors even advise wearing a mask, because for a transplanted patient any “sneeze” is dangerous due to immunosuppression.”

But after a heart transplant, on the contrary, physical activity is recommended to reduce the risk of weight gain, and the main thing in the diet is to reduce the consumption of foods high in fat.

However, not everything depends on the patient.

Availability of drugs will reduce risks

“The main problem of transplanted patients is the availability of medicines,” noted Dmitry Babarin.

The selection of a medicine is the basis of transplantology, says Mikhail Kaabak. But the reality is that, as part of the preferential provision, the patient is replaced with one drug for another, depending on what is available in a given region. In Moscow, for example, according to Maya Sonina, people with lung transplants are often given generics.

“Even original drugs act differently on each patient, and it is impossible to mechanically replace one with another. With generics it’s even more difficult,” emphasized Mikhail Kaabak.

It is no coincidence that the European Society of Transplantation (ESOT) previously advocated that the transfer of a patient from one drug to another should only be carried out by a transplantologist, since when changing a drug it is necessary to review all dosages. In most European countries, organ transplant patients have the opportunity to receive the same medicine for life.

Another problem for patients is the lack of infrastructure. For example, in Moscow, half of the tests must be done in one place, one third of the tests must be done in another place, a quarter must be done somewhere else, and one tenth must be done at one’s own expense in private laboratories. For one drug you need to go to one clinic, for another - to another, and look for the third and fourth in pharmacies.

“For example, patients after a kidney transplant have, in addition to clinical and biochemical blood tests, regularly undergo tests for drug concentrations, antibodies, PCR viruses, hepatitis (HBV, HCV), post-vaccination immunity (anti-HBs antibodies, antibodies against measles, rubella , mumps, etc.), coagulogram, etc. In addition, regular urine tests and ultrasound of the graft are required every three months.

For a person who leads an ordinary life, works, studies, and also has traffic jams in Moscow, implementing these recommendations is a huge difficulty,” said Mikhail Kaabak.

Why is it harmful to reduce your disability group after a transplant?

“For many patients after transplantation, medical and social examination is trying to reduce the disability group,” said Dmitry Babarin. “They believe that after a kidney transplant a person becomes healthy. But this is not a new kidney; the person constantly takes pills to make the transplant work.

And as the disability group decreases, the volume of medical care is also cut. For example, in case of complications, a person will not be able to walk. A disabled person of the first group will receive a wheelchair free of charge from the state, and it will be easier for him to move, but with the second and third groups it is very difficult. The same is true with drug provision.

Even when calling an ambulance, disability matters.

I remember from myself that when calling an ambulance, simply saying that you have a high temperature is one thing. And if you add: “I have a transplant, I am a disabled person of the first group,” then the ambulance arrives immediately.”

“The condition after organ and tissue transplantation is a serious disease that essentially requires palliative treatment. A lung transplant prolongs life, but this does not mean that the person has recovered,” Maya Sonina emphasized.

— Transplantation is not a panacea. This is a serious, high-tech treatment that improves the prognosis and prolongs life, but under certain conditions. Before him, a person must calculate all the risks, without hesitating to ask doctors.”

World's first heart transplant made in 1967 by Christian Bernard in South Africa. In Russia, such an operation was first performed in 1987 by Valery Shumakov. In 2016, the National Medical Research Center for Transplantology and Artificial Organs performed 132 heart transplants, placing it first in the world.

First successful kidney transplant took place in 1954, the liver - in 1956, and the lung - in 1963. Nowadays, organ transplantation has become a fairly routine and well-studied method of treating complex diseases. She saves hundreds of lives of adults and children.