Transplant rejection (TR) is an immunological process directed against tissues foreign to the body, transplanted during the transplantation operation. It is accompanied by a complex of local (edema, inflammation) and general (intoxication phenomena, fever, weakness) manifestations, the severity and rate of development of which depend on the reaction variant. Diagnosis is made by studying the clinical picture, histological examination of transplanted tissues, a number of laboratory and instrumental methods, depending on the type of transplant. Treatment is reduced to immunosuppressive therapy, the use of cytotoxic drugs, some drugs are prescribed for life.
Immunological reactions of transplant rejection occur when using allogeneic (transplanted from human to human) or xenogenic (from animal to human) tissues and organs. Autografts, such as skin transplanted from the hip to the face, have the same antigenic structure as other tissues of the body, so they do not cause reactions. Rejection is extremely rare when transplanting non–vascular structures – the cornea, some cartilage – because in this case there is no contact of foreign tissues with immunocompetent cells. The condition was the most common complication at the dawn of transplantology, but in recent years it has become less common, despite the increase in the number of surgical operations of this type. This is due to the success in determining the histocompatibility of donor and recipient tissues, the development of more effective methods of immunosuppressive therapy.
Antigenic compatibility of tissues is due to the combination of a number of antigens – first of all, the main 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 usual immune response when foreign antigens enter the body or (in some cases) hypersensitivity reactions of the 2nd and 3rd types. 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 immunity, the magnitude of the antigenic difference in tissues.
The reason for the lightning-fast varieties of transplant rejection is the 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 reaction to transplanted tissues usually develop due to incompatibility with HCGS antigens, mainly cellular immune response is involved in pathogenesis. Chronic forms of TR are caused by both cellular and humoral reactions, their cause is often incorrect immunosuppressive therapy prescribed after surgery.
The processes of pathogenesis of the transplant rejection differ in different forms of this condition. Hyperacute or lightning-fast reactions are caused by the sensitization of the body to the antigens of the transplanted organ, therefore they proceed according to the type of intolerance or allergy. When allograft tissues come into contact with the recipient’s blood, the formation of immunocomplexes settling on the inner surface of the vessels is stimulated. They provoke the activation of the complement system, severely damaging the endometrium of the vascular network of the graft, which causes the formation of multiple microthrombs and embolization of blood vessels. This leads to ischemia of the transplanted tissues, their edema, 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 TR are based on the processes of cellular immune response, so such reactions develop somewhat more slowly – over several weeks. With antigenic incompatibility of graft and recipient tissues against the background of adequate or increased immunity activity, recognition of foreign cells by macrophages and T-lymphocytes (helpers or inducers) occurs. The latter activate T-killers, 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 connect humoral immunity factors with the synthesis of specific antibodies directed against graft antigens.
There are several forms of rejection reactions that differ in the rate of development and a number of clinical manifestations. The reason for this difference is different types of mouths, which have different rates of occurrence, as well as the predominant lesion of 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 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 “connection” of the transplanted organ to the recipient’s systemic blood flow, due to the sensitization of the latter’s body to the antigens of the transplant. It is characterized by massive microcirculatory disorders with ischemic phenomena in the allograft and the development of necrosis, while inflammation has a secondary character.
- Spicy. It is registered during the first three weeks after transplantation, the pathogenesis is based on the cellular immune response in case of incompatibility of the donor and recipient. The main manifestation is the development of inflammatory processes in the transplanted tissues, their severity depends on the activity of the immune system.
- Chronic. Occurs a few months after transplantation, may have a recurrent character, strongly depends on the immunosuppressive therapy regimen. It develops through both cellular and humoral mechanisms of the immune response.
Transplant rejection symptoms
All manifestations of allograft rejection are divided into systemic, depending only on the pathogenesis of the process and the reactivity of immunity, and local, directly related to the transplanted organ or tissue. Among the common symptoms, there is always an increase in temperature, chills, 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 increase with the development of necrosis processes in the graft, in severe cases, toxigenic shock may occur against this background.
Local manifestations of the TR are associated with the transplanted organ, therefore they may differ in different patients. When transplanting an entire organ, symptoms caused by a violation of its function come to the fore – for example, cardialgia, rhythm disturbances, heart failure during heart transplantation. Acute renal failure may be associated with a rejection reaction of the transplanted kidney, hepatic – liver. During allotransplantation of the skin flap, its swelling occurs, redness up to a purple hue, and the addition of a secondary bacterial infection is possible. The timing of the appearance of local and general symptoms of rejection depends on its form – the lightning type is characterized by a severe reaction within 2-3 hours after transplantation, whereas acute and chronic types can manifest themselves in a few weeks or even months.
The earliest and most severe complication of the rejection reaction of transplanted tissues is the development of shock associated with immunological processes or due to intoxication of the body. Necrosis and tissue damage of the transplanted organ, the work of which is vital for the body (for example, the heart), often leads to death. Some specialists also include infectious diseases caused by enhanced immunosuppressive therapy as TR complications. In the long term, against the background of an artificial decrease in the activity of cellular immunity, the development of oncological diseases is possible.
A feature of the diagnosis of the transplant rejection reaction is the need for its fastest possible implementation, which allows not only to improve the patient’s condition, but also to preserve the transplanted organ. Some researchers refer to the diagnosis of TR a number of immunological studies performed before surgery at the stage of donor selection – typing the spectrum of transplant antigens, determining the biological compatibility of tissues. High-quality performance of these analyses avoids the development of an over-acute reaction and significantly reduces the likelihood of other forms of rejection. Among the diagnostic procedures performed after transplantation, the following are the most informative:
- Laboratory tests. During the rejection process, signs of nonspecific inflammation will be detected in the general blood test – lymphocytosis, an increase in ESR. The study of the immune status allows you to detect immune complexes, an increase in the level of complement components (with lightning-fast forms), immunoglobulins. Under the influence of immunosuppressive therapy, the test results may be distorted, which must be taken into account when interpreting them.
- Instrumental research. Instrumental diagnostic methods (radiography, ultrasound, CT, MRI) are used to assess the functional activity and structure of the transplant – kidney, liver, heart, lung. In general, the transplant rejection is manifested by edema of the organ, disruption of its work, the presence of circulatory disorders (ischemia, heart attacks, necrosis). With chronic and recurrent types of reaction, areas of sclerosis can be determined in the graft structure.
- Histological studies. Biopsy of allograft tissues, their subsequent histological and histochemical examination is the gold standard in determining the mouth. With a lightning-fast type of reaction, damaged capillaries, perivascular edema, signs of ischemia and tissue necrosis are detected in the biopsy, biochemical studies determine immune complexes on the surface of the endometrium. In chronic or acute types of rejection, lymphocytic infiltration of graft tissues, the presence of ischemia and sclerosis sites are detected.
Approaches to the diagnosis of rejection reactions may vary depending on the specific transplanted organ. For example, during kidney transplantation, general and biochemical urine analysis, ultrasound and other ultrasound examinations of the organ are shown, with caution – excretory urography. In the case of a heart transplant, electrocardiography, EchoCG, coronary angiography is necessary.
Transplant rejection treatment
Treatment of transplant rejection is to reduce the activity of the immune response, the development of the most effective methods is still ongoing. An immunologist in cooperation with a transplant specialist is engaged in the preparation of a therapy 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, almost the only method of treatment and prevention of rejection is non-specific immunosuppressive therapy carried out by several groups of drugs:
- Steroid drugs. This group includes prednisone 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, the course use of these drugs after transplantation is prescribed for life.
- Analogues 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 prevention purposes, they are used shortly after organ transplantation.
- Alkylating agents. A group of drugs that can attach to the DNA of cells and block their division. Medications are used in acute forms of this condition due to the rapid and reliable cytotoxic effect.
- Antagonists of folic acid. Vitamin B9 is involved in the synthesis of some nitrogenous bases and the proliferation of lymphocytes, its antagonists slow down the development of the immune response in oral. The funds are used for chronic forms of reaction as part of complex therapy.
- Antibiotics. Some drugs of this group (cyclosporine, chloramphenicol) block the synthesis of RNA, inhibiting both cellular and humoral immune responses. Sometimes they are used for life after transplantation to prevent rejection.
According to the indications, other medications may be prescribed to improve the patient’s condition – detoxification drugs, diuretics, cardiac stimulants, anti-inflammatory and antipyretic agents. In case of severe complications (shock, acute cardiac or renal failure), resuscitation measures, hemodialysis are necessary. When an infection is attached against the background of immunosuppression, timely administration of antibiotics, antifungal or antiviral (taking into account the nature of the pathogen) means is required.
Prognosis and prevention
The prognosis for lightning–fast transplant rejection is unfavorable in almost 100% of cases – surgery to remove the transplanted organ, selection of a new donor and re-transplantation is required. At the same time, the risk of developing a mouth during a secondary transplant increases several times. Timely initiated immunosuppression in acute or chronic variants of the condition often allows you to save the allograft, but increases the risk of infectious complications and the likelihood of cancer in the future. An effective prevention of rejection is a careful selection of a donor for transplantation, checking compatibility for all possible antigenic systems – especially for GCs, at least 4 of the 6 main alleles should be compatible. The presence of a direct blood relationship between the donor and the recipient dramatically reduces the likelihood of developing pathology.