Immunosuppressants are drugs that can inhibit the immune response of the body, inhibit the proliferation and function of cells related to the immune response (macrophages such as T cells and B cells), and reduce the antibody immune response.Immunosuppressants are mainly used to fight organ transplantation rejection and autoimmune diseases such as rheumatoid arthritis, lupus erythematosus, dermatomycosis, membranous glomerulonephritis, inflammatory bowel disease and autoimmune hemolytic anemia.
Drug name
Immunosuppressant
Foreign name
Immunosuppressant
Prescription medicine or not
yes
Main indications
Autoimmune disease, allergic disease
Drug type
Chemical and biological agents
Adverse reactions
If cyclophosphamide is applied in the first trimester of pregnancy, it may lead to fetal malformation
n. Immunosuppressive agent; overview of immunosuppressor
Classification of immunosuppressants
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There are five main types of commonly used immunosuppressants: (1) glucocorticoids, such as cortisone and prednisone;(2) Microbial metabolites, such as cyclosporin and tenamycin;(3) Antimetabolites, such as azathioprine and 6-mercaptopurine;(4) Polyclonal and monoclonal anti lymphocyte antibodies, such as anti lymphocyte globulin and OKT3;(5) Alkanizing agents, such as cyclophosphamide, etc.
According to the synthetic method, immunosuppressants can be roughly divided into:
(1) Microbial fermentation products: cyclosporins CsA, tacrolimus (FK506), rapamycin (RPM) and its derivatives SDZ RAD, Mizorbine (MZ), etc;(2) Complete organic synthesis: most of them come from anti-tumor substances, mainly including alkylating agents and antimetabolic drugs.Including hormones (adrenocortical hormone, glucocorticoid), azathiopurine (Aza), methotrexate, Leflunomode, breqinar (BQR), etc;(3) Semi synthetic compounds: RS61443 (mycophenolate mofetil, MMF), SDZIMMl25, DeoxysPergualin (DSG), etc;(4) Biological agents: antithymocyte globulin (ATG), antithymocyte globulin (ALG), etc.
According to its development, immunosuppressants can be roughly divided into:
first generation
Represented by adrenocortical hormones (including adrenocortical hormones and glucocorticoids, drugs such as prednisone and methylprednisolone, tripterygium wilfordii polyglycoside tablets, azathioprine, anti lymphocyte globulin, i.e. anti lymphocyte immunoglobulin ALG), the main function is to dissolve immune active cells and block cell differentiation, which is characterized by non specificity,As a wide range of immunosuppressive agents, ALG has no inhibitory effect on bone marrow.The main side effects are metabolic disorder, hyperglycemia, hyperlipidemia and hypertension.At present, the general trend is to reduce its dosage or discontinue it as much as possible, but there is still controversy in the transplantation field;
Second generation
Cyclosporin (cyclosporin, cyclosporin A, Sandimine, Cespin, cyclosporin A, cyclosporin (Cy-A, Cs-A)Neoral and tacrolimus, as the representatives, are cytokines synthesis inhibitors, whose main role is to block the effect of interleukin-2 (IL-2) on immune active cells and interfere with cell activation. They are mainly lymphocytes and are relatively specific.CsA and FK506 have been approved by FDA for clinical use, while other drugs are still in clinical trials. Their main side effects are nephrotoxicity;
Third generation
Rapamycin and Mycophenolate Mofetil (MMF) were used as representatives to inhibit PI3K related signal pathways, thereby inhibiting the proliferation and expansion of immune cells, which had synergistic effects with the second generation preparations;
The fourth generation
Represented by anti IL-2 receptor monoclonal antibodies, FTYZO, etc., the main role is to change the Cytokine worm, such as inhibiting TH1 and enhancing TH2.
According to its clinical application, immunosuppressants are classified as: (1) preventive drugs: CsAFK506、MMF、Aza、Prednisone；(2) Treatment/reversal of acute rejection (rescue drug): MP (methylprednisolone), ALG or ATG, Murononab-CD3 or CD4, MMF, FK506, etc.(3) Inducing drugs (patients with delayed renal function, high-risk patients, secondary transplantation, cyclosporine nephrotoxicity due to acute tubular necrosis): ATG or ALG, OKT3 or OKT4, Simulate or Zenapax, etc.
Main clinical immunosuppressants
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Cyclosporin
In the late 1970s, Borel in Switzerland discovered a circular polypeptide containing only 11 amino acids, named cyclosporine (CsA), which was extracted from the fermentation products of mold. It can effectively and specifically inhibit lymphocyte reaction and proliferation.It has a good selective inhibitory effect on T cells, especially TH cells, while it has a relatively weak inhibitory effect on other immune cells, so it has achieved a good effect in anti organ transplantation rejection;It is also used for the treatment of autoimmune diseases, so it is an immunosuppressant with high clinical value.After 10 years of clinical trials, it has been proved that its anti rejection effect is stronger than other drugs and its side effects are much smaller.Therefore, it was officially registered and put into market application at the end of 1980s.The clinical application of CsA in the past 20 years has shown miraculous effects, making the one-year survival rate of patients/grafts for liver, kidney, heart, heart/lung, and pancreas transplantation reach 70-85%, while only 30-50% before that.The incidence of CsA related neurotoxicity symptoms is about 10-28%, which is an important factor affecting the prognosis of patients.Headache, tremor of limbs and sensory disturbance are common in mild cases, and visual disturbance is the main in moderate cases.The incidence of severe manifestations of CsA related neurotoxicity is extremely low.[1-2]
Tacrolimus
Tacrolimus (FK506) is a macrolide antibiotic extracted from soil fungi. It has strong immunosuppressive properties. Its drug intensity is 10-100 times that of cyclosporine A. The effect of preventing rejection of various organ transplants is better than cyclosporine.
In 1984, Fujisawa isolated Streptomyces tsukuba in Tsukuba, Osaka, Japan, and the components of Tacrolimus were isolated through fermentation, purification and separation.
FK506 has only been used in clinic for more than ten years, and the time is relatively short.Therefore, the research on some aspects (pharmacology and toxicology) is not comprehensive enough.The main side effects of FK506 are nephrotoxicity, neurotoxicity and effects on the functions of circulatory system, digestive system, respiratory system and cardiovascular system.Tacrolimus can induce diabetes (the probability is about 10%~30%), and can cause ketoacidosis in severe cases.The incidence of FK506 related hypertension was significantly lower than that of CsA.Compared with FK506 and CsA, rapamycin is a new immunosuppressant that has no interaction with calmodulin and is considered to have no effect on blood pressure.
Macrolipid immunosuppressants (including FK506 and rapamycin) can not only be taken orally, but also be used externally, mainly for some skin diseases, such as atopic dermatitis, psoriasis, lichen planus, contact dermatitis and alopecia.In addition, the Journal of Arthritis and Rheumatology (Arthritis Rheum 2003; 48:3328-3337) published a report in December that the immunosuppressant tacrolimus alone at a dose of 2 or 3mg/day seems safe and effective in treating active rheumatoid arthritis (RA), but usually the dose is greater and the improvement is greater.[3-4]
Rapamycin is a kind of lipophilic triene nitrogen-containing macrolide antibiotic immunosuppressive drug produced by Streptomyces hygroscopicus isolated from soil samples of Easler Island in the Pacific Ocean by Vezina, Ayerst Laboratory, Canada, in 1975. It is an immunosuppressive agent used for solid organ transplantation rejection.The structure of rapamycin is similar to that of tacrolimus, but the mechanism of action is different.The interaction between rapamycin and tacrolimus has not been thoroughly studied.
Morris et al. used it for the first time to fight graft rejection in 1989. They found that the effective anti proliferation effect of peripheral blood mononuclear cells was 50~500 times stronger than cyclosporine (C17A), and the renal toxicity was lower than cyclosporine and tacrolimus.It was applied in clinical practice in 1999.From the current clinical application, RAPA has a good anti rejection effect, and has a good synergistic effect with immunosuppressants such as cyclosporine A (CsA) and FK506. It is a new immunosuppressant with good efficacy, low toxicity and no nephrotoxicity.
CsA and FK506 are related to drug-induced renal dysfunction, especially in the process of delayed recovery of transplanted renal function. Nephrotoxic drugs should be avoided as far as possible in treatment.So far, RAPA has not been found to have obvious nephrotoxicity.
The combination of RAPA with CsA, FK506, MMF, etc. has good synergistic effect. Its benefits lie in ① reducing the dosage of various immunosuppressants in the treatment scheme, ② reducing the side effects of immunosuppressants, and ③ enhancing the effect of immunosuppression.
RAPA has side effects similar to FK506.In a large number of clinical trials, it is found that the side effects are dose dependent and reversible. The therapeutic dose of RAPA has not been found to have obvious nephrotoxicity and no gingival hyperplasia.The main side effects include headache, nausea, dizziness, epistaxis and joint pain.
SDZ RAD is a derivative of rapamycin.There is a hydroxyethyl chain at the 40th position of SDZ RAD, which can enhance the polarity of the molecule, thus improving the oral bioavailability. Moreover, SDZ RAD can be administered simultaneously with CsA. Because its half-life is shorter than sirolimus, the phase III test compares it with the standard scheme consisting of CsA, hormone and mycophenolate, and has made some progress.
Mycophenolate
（Mycophenolate Mofetil，MMF，RS-61443）
Mycophenolate is an antimetabolic semi synthetic mycophenolic acid produced by penicillin fungi, which is synthesized by Nelson of Syntex Company in the United States, with the trade name of Cellcept.The active component of this drug is mycophenolic acid (MPA). Mycophenolate is a 2-ethyl ester derivative of mycophenolic acid, which has strong immunosuppressive effect.[5-6]
Imidazolidine
(mizoribine, MZ, bredinin, Bredinin)
Mizolibine is an imidazole antibiotic obtained by Asahi Kasei from the culture filtrate of soil mold Eupeniil liumbrefeldianum.As an immunosuppressant, it has been used in clinical renal transplantation in Japan since December 1991.Many clinical transplantation centers in Japan have used mizoribine as a routine immunosuppressive drug after kidney transplantation.In recent years, it has also been used as an anti rejection drug for kidney transplantation in China.Compared with azathioprine, mizoribine has less hepatotoxicity and bone marrow suppression. Its main adverse reactions are gastrointestinal reactions, blood system disorders and allergic symptoms. Bone marrow suppression and acute renal failure are occasionally seen.[7-8]
cyclophosphamide
（Cyclophosphamide）
Cyclophosphamide, also known as "Ai De San, Ai De Xing, An Dao Sheng, and cyclophosphamide nitrogen mustard", has no effect before being activated, so unlike nitrogen mustard, it has no local blistering and irritation, and does not cause local necrosis or phlebitis.Gastrointestinal reaction is lighter than nitrogen mustard, manifested as anorexia and nausea. Large dose injection can also cause vomiting, but not very serious.Hair loss is more common, generally occurring 3 to 4 weeks after medication, and renewable after drug withdrawal.Bone marrow suppression: the decrease of white blood cells is far more obvious than that of platelets.Although myelosuppression caused by this product is common, it is generally easy to recover.Toxic cystitis: It is a specific toxic reaction, which can be seen in large doses of injection.It is mainly due to the concentration of its hydrolysates in the bladder, causing bladder irritation symptoms and oliguria, hematuria, proteinuria, etc.Liver function damage is common and should be used with caution for patients with original liver disease.A few patients can still have dizziness, restlessness, hallucination and other adverse reactions.Long term use can cause male testicular atrophy, sperm deficiency, women's amenorrhea, ovarian fibrosis, and malformation.Not for pregnant women.Occasional gastric ulcer, bleeding, etc[9]。
Cytokine inhibitor
Afinitor
Evimox is a mammalian rapamycin target protein inhibitor first developed by Novartis. It is mainly used clinically to prevent rejection after kidney transplantation and heart transplantation. In 2003, Evimox was approved in Europe to treat rejection after organ transplantation and was launched to the market.Ivimox is a sirolimus derivative, which is effectively used to prevent organ transplantation rejection.Its anti proliferation and immunosuppressive effect is to interfere with the formation of regulatory proteins that control cell metabolism and proliferation by forming complexes with immune binding proteins.Evimox is rapidly absorbed in local tissues, has long residual time in cells and intracellular activity, and can significantly reduce the proliferation of new intima.Evimox has a wide range of applications, and can be used to treat rejection after kidney and heart surgery in adults, advanced renal cancer, subependymal giant cell astrocytoma with nodular cerebral sclerosis, and advanced pancreatic neuroendocrine tumors that cannot be removed by surgery or have spread to other parts of the body.The most common adverse reactions include upper respiratory tract infection, sinus and ear infection, oral ulcer, etc.[10]
DNA synthesis inhibitor
Azathiopurine (AZA)
In 1960, it was found that 6-mercaptopurine could delay the rejection of skin transplantation.In the following years, azathioprine has been found to delay organ transplantation rejection, including human kidney transplantation rejection.AZA metabolized into the active product 6-mercaptopurine can inhibit purine biosynthesis, inhibit DNA, RNA and protein synthesis, and inhibit lymphocyte proliferation.AZA is classified as the first generation immunosuppressant because it non selectively inhibits the synthesis of purine nucleotides in body cells. It is well absorbed orally and completely metabolized in the body.The synthesis of purine nucleotides in a variety of cells is inhibited to a considerable extent. The adverse reactions of AZA include bone marrow suppression, hepatotoxicity, gastrointestinal toxicity, tumor risk, granulocytopenia, and decrease in the number of platelets.[11]
Immunosuppressive active ingredients of Chinese herbal medicine
Tripterygium wilfordii
Tripterygium wilfordii is a perennial vine belonging to the genus Tripterygium wilfordii of Weimao family. It has the effects of heat clearing, detoxification, detumescence, deconcentration, insecticidal, hemostasis, etc. It is one of the most reliable traditional Chinese medicines with immunosuppressive effects so far.The active ingredients are mostly diterpenoids and triterpenoids, such as triptolide, triptolide ketone, triptolide, etc.Because of its remarkable immunosuppressive activity and special chemical structure, scholars at home and abroad have synthesized hundreds of derivatives in order to develop new immunosuppressants with high efficiency and low toxicity.At present, tripterygium wilfordii polyglycoside has been mainly used in clinic in China. It is a kind of Chinese medicine immunosuppressant with good effect, which can significantly inhibit the cellular and humoral immune functions of mice, without obvious adverse reactions[12]。
other
Fingolimod
Fingomod is a new synthetic compound jointly developed by Japanese scholars in 1994 after structural modification of the effective components of Cordyceps sinensis extract [7].Its chemical structure and mechanism of action are different from those of immunosuppressants currently used. It can reduce the number of T and B lymphocytes in the peripheral blood, thus weakening the attack on the graft, without affecting the functions of natural killer cells, granulocytes and monocytes.The animal experiment and clinical phase III experiment of organ transplantation show that its strong immunosuppressive activity and unique pharmacological effect can not only prevent the occurrence of rejection, but also reverse the rejection that has occurred.In addition to its own immunosuppressive activity, combined use with other immunosuppressants (such as cyclosporine A, sirolimus and tacrolimus) has good synergistic effect, small adverse reactions and high bioavailability[13]。
