What Causes Transplant Rejection?

Transplant rejection (transplant rejection) means that after a recipient undergoes an allogeneic tissue or organ transplant, the transplant of foreign tissues or organs is recognized by the recipient's immune system as a "foreign component" which initiates Immunological response to attack, destruction and clearance. The mechanism of rejection mainly includes two aspects of cellular immunity and humoral immunity. The most common clinical acute rejection is mainly mediated by cellular immunity, while the superacute rejection and chronic rejection are mainly mediated by humoral immunity.

Transplant rejection

Transplant rejection (transplant rejection) refers to the recipient's allogeneic tissue or

The human immune system has a very complete

Cell-mediated rejection

Cellular immunity plays a leading role in the development of acute rejection. Donor in graft

There are two basic types of rejection in allografts:

Because it is difficult to find donors and recipients with exactly the same HLA in the population, in addition to identical twin organ transplants, rejection occurs in allogeneic tissues or organ transplants. The success of organ transplantation depends to a large extent on the prevention and treatment of transplant rejection. At present, clinically, it is mainly used to strictly prevent donors, suppress the recipient's immune response, induce transplant tolerance, and strengthen immune monitoring after transplantation. Rejection occurs.

Graft and recipient preconditioning

Graft pretreatment

When parenchymal organs are transplanted, as much as possible to remove the passing cells in the graft can help reduce or prevent transplant rejection. In the same kind of bone marrow transplantation, in order to prevent a possible graft-versus-host response, the bone marrow transplant can be pretreated. The principle is based on the removal of T cells from the bone marrow transplant. However, the use of allogeneic bone marrow from which T cells are removed for transplantation, the graft's anti-leukemia effect may also disappear, leading to an increased leukemia recurrence rate, which affects the prognosis of patients.

Recipient preprocessing

In the case of parenchymal organ transplantation, inconsistent ABO blood types between donor and recipient may lead to strong transplant rejection. In some cases, it is necessary to pretreat the recipient to perform a substantial organ transplant to cross the ABO barrier. Pretreatment methods include: transfusion of donor-specific platelets into the recipient before surgery, removal of natural anti-A or anti-B lectin in the recipient by means of plasma exchange, recipient splenectomy, immunosuppressive therapy, and the like.

Suppresses the recipient's immune response

If there is no intervention, rejection usually occurs after allogeneic transplantation, so the success or failure of clinical transplantation depends to a large extent on the moderate suppression of the recipient's immune response. The commonly used methods of suppressing the recipient's immune response are divided into the following categories:

Chemical immunosuppressive drugs

Glucocorticoids, representative drugs: methylprednisolone, prednisone. Mechanism of action: It mainly inhibits the activity of nuclear transcription factor KB. The immunological effects of glucocorticoids are mainly reduced in the production of cytokines by lymphocytes, which affects T cell activation and adhesion. However, in the case of shock treatment at large doses, it can also cause lymphocyte lysis and apoptosis through direct action to achieve rapid and effective To suppress the immune effect. Adverse reactions: As long-term application of glucocorticoids can induce and exacerbate infections, or cause adrenal cortex dysfunction, etc., in organ transplantation, the combined application of glucocorticoids and other immunosuppressants can produce a good synergy.

Cytotoxic drugs, representative drugs: azathioprine tablets, cyclophosphamide. Mechanism of action: Inhibition of DNA, RNA and protein synthesis in immune organs, thereby inhibiting lymphocyte proliferation response. Azathioprine is one of the earliest immunosuppressive drugs. Adverse reactions: The main adverse reactions of azathioprine are bone marrow suppression and drug-induced hepatitis. Monitor blood counts and liver function during medication.

Calmodulin inhibitors, representative drugs: cyclosporine A, tacrolimus. Mechanism of action: Inhibition of calcineurin activity, thereby inhibiting T lymphocyte activation and secretion of interleukin 2; meanwhile, it also inhibits the expression of interleukin 2 receptors of T lymphocytes, thereby effectively inhibiting the activation and proliferation of T lymphocytes. Adverse reactions: The adverse reactions of cyclosporine A are mainly manifested in the cardiovascular, kidney, and central nervous systems. Cyclosporine A also affects B lymphocytes to a certain extent, not only preventing the proliferation of B lymphocytes, but also inducing and promoting B lymphocyte procedures. Death. Long-term application can also cause reduction of spleen lymphocytes and cause spleen atrophy.

Drugs that inhibit cytokine proliferation response, representative drug: rapamycin. Mechanism of action: Inhibition of T cell proliferation induced by antigen and cytokines Interleukin 2, Interleukin 4, Interleukin 6 and B cell proliferation induced by lipopolysaccharide, the renal toxicity is very low, but it is dose dependent and is reversible. Adverse reactions: Can cause adverse reactions such as hypercholesterolemia and hypertriglyceridemia, infection, and damage to the blood system.

Drugs that interfere with metabolism represent drugs, which represent: mycophenolate mofetil, imidazoribine. Mechanism of action: Competitively inhibits the inosine-to-guanylate pathway in the purine synthesis system thereby inhibiting nucleotide synthesis. Adverse reactions: Adverse reactions of mycophenolate esters are mainly diarrhea, leukopenia, and opportunistic infections. The main adverse reactions of mizoribine include gastrointestinal reactions, hematological disorders and allergic symptoms, and occasionally bone marrow suppression and acute renal failure. Mizoribine is not metabolized in the liver, and it has been shown that there is no obvious hepatotoxicity and bone marrow suppression, and the immunosuppressive effect is similar to azathioprine, so it is used as a substitute for azathioprine.

FTY720 can reduce the number of T and B lymphocytes in peripheral blood, thereby reducing the attack on the graft. Because FTY720 has a high degree of cell selectivity and low toxicity, it avoids liver and kidney toxicity that may be caused by cyclosporine A overdose.

The biological agents currently used in the clinic are mainly antibodies against immune cell membrane antigens, such as anti-lymphocyte globulin (ALG), anti-thymocyte globulin (ATG), anti-CD3, CD4, CD8 monoclonal antibodies, and high affinity ID2R monoclonal antibody, anti-TCR monoclonal antibody, anti-adhesion molecule (1CAM-1, LAF-1) antibodies, etc. These antibodies, by binding to corresponding membrane antigens and removing complement-dependent cytotoxicity, clear T cells or thymus cells in vivo, respectively. Fusion proteins composed of certain cytokines and toxins, anti-cytokine antibodies, fusion proteins composed of certain adhesion molecules and immunoglobulins (such as CFLA-4-Ig), etc. also have anti-rejection effects.

Some Chinese herbal medicines have significant immunomodulatory or immunosuppressive effects. Domestic literature has reported that certain Chinese medicines such as Cordyceps sinensis can be used to treat rejection after organ transplantation.

Clear pre-existing antibodies

Plasma exchange before transplantation can remove specific antibodies pre-stored in the recipient's blood to prevent ultra-acute rejection.

Other immunosuppressive methods

Clinical application of splenectomy, radiation irradiation of grafts or recipient lymph nodes, plasma exchange, plasma lymphocyte replacement and other techniques to prevent and reject rejection has achieved certain effects. In bone marrow transplantation, in order to completely lose the recipient's ability to respond to bone marrow transplantation, high-dose radiation or chemical drugs are often used before surgery to destroy the patient's own hematopoietic tissue.

Post-immunity surveillance

In clinical work, immune monitoring after transplantation is extremely important. Early detection and diagnosis of rejection have important guiding significance for timely prevention and treatment measures.

The clinical judgment of rejection mainly depends on comprehensive indicators such as symptoms and signs, graft functional status, and laboratory testing. Superacute rejection is easy to diagnose. The clinical manifestations of acute rejection and graft-versus-host response are more obvious. Chronic rejection usually has no typical clinical manifestations. The functional measurement of the transplanted organ varies depending on the graft, and a large number of biochemical measurements and hematological indicators are required. Some auxiliary tests such as B-mode ultrasound and color Doppler are necessary to understand the morphology, vascular patency, and blood of the transplanted organ Traffic etc. can also help. Immunological monitoring is to examine the changes in the immune cells and some immune molecules involved in the response of the recipient before the rejection occurs, which has important reference significance for judging whether the patient will have rejection ^[3] .

Peripheral blood T cell count

T cells and their subpopulations can be determined by monoclonal antibody immunofluorescence or flow cytometry. One to five days before the onset of clinical symptoms of acute rejection, the total number of T cells and the ratio of CD4 / CD8 increased, and the ratio decreased during cytomegalovirus infection. It is generally believed that when the ratio is greater than 1.2, it indicates that acute rejection is imminent; if the ratio is less than 1.08, the possibility of infection is very high. If dynamic monitoring can be performed, the differential diagnosis of acute rejection and infection will be of great value. In addition, the lymphocyte transformation test has certain significance for measuring the total number and functional status of T cells.

Killer cell activity assay

After transplantation, the activity of killer cells is suppressed due to the application of immunosuppressants, but it will be significantly increased before acute rejection. Donor lymphocytes were used as stimulation cells after isolation, and patient lymphocytes were used as reactive cells. The two types of cells were mixed and directly used as CML. The measured results are the result of the combined action of Tc cells and NK cells. Bigger.

Determination of serum IL-2R

After activation of T cells, IL-2R can be released. The serum level of IL-2R increases during acute rejection and viral infection. The increase is most pronounced in cytomegalovirus infection. Cyclosporine A nephrotoxic renal dysfunction increased serum creatinine value while IL-2R decreased significantly. The simultaneous increase of serum creatinine and IL-2R is significant for the diagnosis of acute rejection. However, there are significant differences in serum IL-2R content among individuals, and there is no recognized diagnostic standard, which limits its clinical application. Dynamic determination can overcome this shortcoming.

Detection of anti-donor HLA antibodies

Cross-fit test was used to detect the presence of anti-donor HLA antibodies in the patient's serum, and the presence of antibodies heralded the possibility of rejection.

Other methods, such as serum complement measurement, have also been reported, but their significance is uncertain. It must be pointed out that the above indicators have certain reference values, but they all have problems such as low specificity and low sensitivity. How to establish a set of immunological monitoring methods that can guide clinical organ transplantation is an important subject to be further studied.