Acute and chronic rejection



The transplantation of organs and hematopoietic stem cells currently represents the therapy of choice, widely used, in severe organ failure (especially heart, liver, kidney and lung) and in numerous blood diseases such as, for example, leukemia and lymphomas.

In order to carry out a transplant it is necessary to have a donor who, in the case of organs, is mostly a deceased person, with the exception of kidney transplants and, to a lesser extent, liver transplants in which organs can be taken from a donor living.

The donation of hematopoietic stem cells, on the other hand, is always carried out by a living person.

One of the complications of transplantation, regardless of the type of organ and donor, is rejection.

We generally speak of rejection when the body's defense system (immune system) of the person undergoing a transplant (recipient) attacks the new organ, recognizing it as foreign (not really, from the English non-self). The better the compatibility between donor and recipient, the lower the possibility of rejection and mortality, early (early) and late, post transplant.

Rejection can occur at different times after the transplant. Based on the time in which it occurs, the following are distinguished:

  • hyperacute rejection (appears a few minutes to a few hours after the transplant)
  • acute rejection (occurs a few days to a few weeks after the transplant)
  • chronic rejection (occurs from a few months to several years after the transplant)

The mechanisms that determine the various types of rejection are different and can be linked to the presence / production of antibodies (humoral rejection) and / or the direct activation of cells of the immune system, lymphocytes (cell rejection). In the case of chronic rejection. the cause is probably multifactorial and is linked to immune and non-immune mechanisms (drug toxicity, chronic ischemia, repeated previous immune attacks of acute rejection).

In the case of hematopoietic stem cell transplantation there is also a particular form of rejection, called Graft Versus Host Disease (GVHD), in which the cells of the donor's immune system attack the organs and tissues of the recipient, recognizing it as a foreign body.

The introduction of therapy with immunosuppressive drugs has greatly increased survival after transplants by reducing the risk of rejection and the onset of GVHD. The use of these drugs, however, can lead to a condition of immunosuppression with a consequent increased susceptibility to infections.

Lung transplant

Rejection is the most fearful and frequent complication of lung transplantation. In fact, it occurs in 55% of people within the first year, in 50% within 5 years, in 80% within 10 years. It is linked to the activation of the recipient's immune system which recognizes the donor's organ as foreign. The ensuing chain of events includes several phases that end with the attack, by the recipient's organism, on the cells of the transplanted organ deemed foreign.

From the first hours after the transplant, to prevent rejection episodes, the person who has undergone it (recipient) is given a specific therapy (immunosuppressive) which must be continued throughout his life.

Different immunosuppressive drugs work by blocking the activation process of the immune system at different levels. The use of therapy with multiple drugs allows, in addition to obtaining a more complete immunosuppression, also the use of lower dosages than if each drug were used individually, thus minimizing the side effects of each.

Rejection is divided into acute and chronic depending on the time it appears and the underlying mechanism.

Acute rejection

It can occur within the first year of transplantation, most frequently between the first 3 and 6 months.

Disorders (symptoms) associated with rejection, which include fever, dyspnoea and cough, changes in the level of oxygenation of the blood (measured by blood gas analysis), chest x-rays and pulmonary function tests (spirometry), are very mild and the rejection is ascertained (diagnosed) only by biopsy performed during follow-up bronchoscopies after transplantation. The lung biopsy allows to evaluate the severity of the rejection and, consequently, to decide whether to undertake a specific therapy. It also makes it possible to distinguish rejection from infections since the disorders (symptoms) that appear in both cases are similar.

Damage from rejection occurs in the wall of the small arterial vessels that supply the lung and airways. Therapy consists of the administration of massive doses of cortisone for 3 consecutive days. In a second phase, the immunosuppressive therapy is modified. Usually, the disturbances disappear after the administration of cortisone; in some cases, however, a more aggressive therapy is required which involves the use of anti-lymphocyte antibodies (lymphocytes are the immune system cells responsible for rejection).

Chronic rejection

Chronic rejection can occur after the first year after transplantation.Numerous episodes of acute rejection, as well as recurrent infections of the respiratory system, favor the onset of chronic rejection.

The symptoms of chronic rejection are very nuanced and progressive in some cases, and sudden and acute in others. They include cough and a feeling of lack of air (dyspnea) and, sometimes, fatigue (asthenia) and generalized malaise. Progressive reduction in lung function also occurs. Because often, the first abnormality is only evident in the lung function test (spirometry), it is important to do it frequently to monitor lung function (at least every 4 to 8 weeks). Therapy is effective when given in the shortest time possible (early stage) since the loss of lung function is often definitive.

The damage to the lung can consist of a simple inflammatory process up to actual fibrosis which causes a narrowing of the small airways of the lung. This set of alterations is called obliterative bronchiolitis.

Heart transplant

Acute rejection

Acute cellular rejection is the most common form of the immune system's response to the transplanted heart and usually occurs within the first week after the transplant. It is mainly caused by an inflammatory response of T lymphocytes that attack the transplanted muscle tissue of the heart (myocardium).

The frequency of acute cell rejection has been significantly reduced by advances in immunosuppressive therapy.

Acute humoral rejection, on the other hand, is linked to the presence of antibodies to HLA (human leucocyte antigen or human leukocyte antigen; particular molecules that are found on the surface of the cells of the transplanted organ and are recognized as foreign by the recipient's immune system) or antibodies directed against the inner lining (endothelium) of the coronary arteries of the transplanted heart.It usually appears in the first months after the transplant.

The disorders (symptoms) that indicate the presence of acute rejection are: general malaise, tachycardia, fever, nausea, vomiting and, in severe cases, clinical signs of heart failure.

The assessment (diagnosis) must, in any case, be confirmed by an ultrasound of the heart (echocardiographic examination) and by the removal of a small piece of myocardial tissue (endomyocardial biopsy) which allow an assessment of the severity of the rejection, of the changes heart function (systodiastolic dysfunction), increased myocardial mass and the possible presence of a pericardial effusion.

Endomyocardial biopsy is essential to ascertain (diagnose) cardiac rejection. It is performed under local anesthesia by introducing a catheter into the right internal jugular vein (the jugular veins are located on both sides of the neck) and continuing it to the right ventricle.

Currently, there are 4 degrees of acute cell rejection of the transplanted heart: the first two (absent and mild) do not generally imply a modification of immunosuppressive therapy, while moderate and severe degrees involve an increase.

Over time, the risk of rejection decreases as the body gets used to the new heart and, therefore, the number of biopsies can be reduced. Generally, for heart transplant monitoring, endomyocardial biopsy should be performed once a week for the first month, every two weeks for the second and third months, once a month until the sixth month, and finally every two months until the first. year from transplant.

The appearance of rejection does not lead to the loss of functionality of the transplanted organ, as long as it is promptly treated. Periodic myocardial biopsies have the purpose of highlighting rejection episodes in its early stages.

Chronic rejection

Chronic rejection limits the long-term success of the heart transplant and occurs one year after the transplant. It is thought to be caused by a combination of immune and non-immune responses directed against the vascular system of the transplanted heart.

It is characterized by the appearance of arteriosclerosis (deposition of fat and cholesterol on the inner walls of blood vessels) affecting the arteries that carry blood to the heart (coronary arteries). Since it is a serious coronary artery disease that extends to small vessels, it can cause myocardial infarction and is therefore instrumentally detected with a coronary arteriography.

In the most serious cases, the only chance of survival is the transplantation of a new heart.

Transplant people who do not have coronary heart disease are more likely to survive than coronary heart disease.

Liver transplantation

Acute rejection

The rejection of the transplanted liver consists of an "inflammation of the organ" induced by an antigenic incompatibility between donor and recipient that primarily affects the bile ducts and the tissue lining the inside of the blood vessels (vascular endothelium), including the veins portals, the hepatic venules and, occasionally, the hepatic artery and its branches.

Acute rejection typically occurs 5 days to 6 weeks after transplantation. If the histological examination and tests for liver damage are positive, the rejection is considered clinically relevant and requires additional immunosuppressive therapy.

Clinically, acute rejection can occur without particular disturbances (generally, they are absent in mild to moderate rejection).

A single episode of acute rejection, of any magnitude, even if initially steroid resistant, does not impair long-term liver function.Conversely, episodes of acute rejection that occur more than twice can damage the transplanted organ, inducing detectable alterations through liver function measurement tests and histological analysis.

Disorders caused by rejection can include: fever, malaise, yellow discoloration of the muscles (sudden jaundice), enlarged liver (hepatomegaly).

The biochemical and clinical alterations, however, are not specific to rejection and to ascertain (diagnose) it requires confirmation from tissue (histological) analysis.

If the rejection does not create disturbances (clinically silent) or is of a mild degree, clinical observation and modification / adjustment of the immunosuppressive therapy already in place is recommended.

In the presence, on the other hand, of moderate-severe acute rejection, rapid intravenous administration of certain amounts of corticosteroids (intravenous boluses) is recommended according to well-defined clinical protocols.

Chronic rejection

Chronic rejection is defined as damage, on an immunological basis, of the transplanted liver which causes irreversible damage to the bile ducts, arteries and veins of the liver.

It can represent the evolution of an acute, severe or persistent rejection over time, or manifest spontaneously.

Chronic rejection can occur over a period ranging from 60 to 90 days after the transplant and cause loss of organ function within 4-12 months, or appear later.

The assessment (diagnosis) of rejection always derives from the combined evaluation of symptoms, laboratory tests, radiological and histopathological tests. It should always be suspected in a transplant person who has had multiple episodes of severe to moderate acute rejection.

There are three clinical pictures:

  • evolution from an episode of unresolved acute rejection
  • evolution after repeated episodes of acute rejection
  • late form without a clear diagnosis of acute episode (often associated with inadequate immunosuppressive therapy)

It is useful to establish the stage of severity (staging) of chronic rejection in order to differentiate rejection episodes that have just occurred (which can benefit from the increase in immunosuppressive therapy with possible healing and regression of the damage) from those that have been diagnosed late and are no longer reversible. The prerequisite for staging rejection is the existence of a certain diagnosis of chronic rejection based on the results of multiple tests (clinical, laboratory, instrumental and histological).

Some variables have been reported as risk factors for chronic rejection:

  • number of acute rejection episodes
  • severity of acute rejection episodes
  • acute late rejection
  • age of the person undergoing transplantation (recipient) since the lower the age, the greater the possibility of rejection (younger recipients = higher frequency of rejection)
  • age of the donor over 40 years

The therapy consists of a modification of the immunosuppressive therapy in progress.

Kidney transplant

Rejection is the main complication that can occur after a kidney transplant. At its base there is the immune system of the transplanted person which, coming into contact with particular molecules found on the surface of the cells of the transplanted organ (HLA, human leucocyte antigen), does not recognize the organ transplanted as belonging to the organism and considers it foreign, non-self.

Clinically, it manifests itself with a progressive increase in the amount of creatinine in the blood, in the amount of protein in the urine (proteinuria), with a decrease in the emission of urine (contraction of diuresis) and with fever.

On the basis of the times in which the rejection occurs, the following are distinguished:

  • hyperacute rejection: occurs within minutes, or at most hours, with arterial thrombosis and hemorrhage.It is due to the presence of pre-existing antibodies in the recipient against the blood group AB0 or ​​against the donor's HLA
  • accelerated acute rejection: occurs after a few hours or days (2nd - 4th day after transplantation). It manifests itself with arterial thrombosis and hemorrhage. Similar to hyperacute rejection, it is due to pre-sensitization caused by anti-HLA antibodies
  • acute rejection: occurs after a few days or weeks but can occur at any time. It is due to cellular immunity, linked to cells of the immune system called T lymphocytes and B lymphocytes, or to humoral immunity due to circulating molecules, antibodies
  • chronic rejection: occurs after months or years. It is due to the activation of cellular (T and B lymphocytes) and humoral (antibodies or immune complexes) mechanisms

The diagnosis of rejection is based on clinical suspicion and is confirmed by performing one or more kidney biopsies performed under local anesthesia.

Pharmacological treatment varies according to the type of rejection. However, it should be emphasized that in chronic rejection there is no specific and always decisive therapy and, often, a new transplant must be rescheduled.

Hematopoietic stem cell transplantation

The transplantation of hematopoietic stem cells consists in destroying the diseased cells of the person who undergoes them, through the use of chemo and / or radiotherapy, and in replacing them with those obtained from a healthy donor. The goal is to restore the recipient's hematopoietic and immune system.

The replacement of the diseased cells with those of the healthy donor determines the coexistence in the same individual of the genetic patrimony of two different subjects; a condition called chimera, a term that derives from the mythological figure formed by parts of the body of different animals.

Healing, or the success of the transplant, depends on the realization of three main factors:

  • the total disappearance of diseased cells through the use of high-dose chemotherapy, a phase called "conditioning regimen", which is essential for eliminating the disease, for the immunosuppression necessary for the graft to take root and for the release of the so-called medullary niches, in which the new cells will implant
  • the overcoming, for the purpose of engraftment, of the immunological barrier of the transplanted person represented by the immunocompetent cells responsible for rejection (i.e. the disappearance of the recipient's non-diseased immunological cells)
  • overcoming the immunological barrier, responsible for graft versus host disease (GVHD), represented by the donor's active immunocompetent cells present in the suspension of stem cells infused into the recipient

Therefore, in the transplantation of stem cells from a donor (allogeneic), unlike any other type of transplant, the immunological barrier to be overcome is double: that of the recipient towards the donor (rejection) and that of the donor towards the recipient (GVHD) .

The phenomenon of rejection occurs when the donor's immune cells, recognized as non-self (non-self) or foreign, are attacked and destroyed by the cells of the body's defense system (immune system) of the transplanted person (recipient).

The incidence of rejection in bone marrow transplantation (OMT) from an HLA compatible donor is a rather rare event (1-2%) due to the profound immunosuppression induced by the high doses of radio-chemotherapy administered before the transplant. Rejection is a major problem in transplants from donors not belonging to the recipient's family or in incompatible transplants.

Graft versus host disease (GVHD) is the reaction exerted by the cells of the donor's immune system towards the recipient's tissues and is one of the main causes of failure in patients undergoing donor (allogeneic) transplantation. Its frequency and severity increase with the degree of HLA incompatibility.

There is an acute form and a chronic form of GVHD, in relation to the time when it occurs and its clinical characteristics.

Acute GVHD is observed in the first 100 days from the date of transplant. Its main clinical manifestations are represented by skin rash, diarrhea, hepatic dysfunction (cholestatic jaundice). Not necessarily all three manifestations are present, but in relation to the severity of the damage, the organs affected and the clinical manifestations, acute GVHD has a degree of severity ranging from I to IV.

Chronic GVHD has a time to onset after the first 100 days of allogeneic bone marrow transplantation and can follow acute GVHD or occur spontaneously.

It can affect the same sites as acute GVHD but, usually, its extension is greater (systemic) and can involve many organs and systems (skin, eyes, oral or esophageal mucosa, liver, lung, neuromuscular system, intestine; characteristics of scleroderma, biliary cirrhosis or obliterative bronchiolitis).

Based on the damage it causes to affected organs, chronic GVHD can be classified as limited or extensive.
Both forms increase the risk of complications of an infectious nature, both for their immunosuppressive nature and for the depressive effect of the immune system exerted by the therapies used to block it.

The primary therapy for GVHD is the administration of immunosuppressive drugs that reduce the immune response of donor cells.The therapy of first choice is represented by corticosteroids.
Preventive treatment with immunosuppressive drugs can reduce the risk of GVHD after transplantation; therapy is usually started before the transplant itself.

Editor'S Choice 2022