Table of Contents
Page created on June 6, 2019. Last updated on December 18, 2024 at 16:57
Introduction
Immunosuppression refers to decreasing the activity of the immune system through cytotoxic effects or through bone marrow suppression. In other words, the activity of the immune system is decreased because there are fewer white bloods cells.
In contrast, immunomodulation refers to altering the immune response, without any bone marrow suppression or cytotoxic activity. It often involves inhibiting the function of certain WBCs or inhibiting certain cytokines, but it can also involve using drugs to stimulate the immune system in some way.
Immunosuppression
Immunosuppressants are used in the therapy of autoimmune disease and also to prevent transplant rejection. We can distinguish four types:
- Corticosteroids
- Drugs that inhibit lymphocyte signalling
- Cytotoxic drugs
- Antibodies with immunosuppressing effect
Corticosteroids
These drugs are glucocorticoid analogues and act on glucocorticoid receptors. They have immunosuppressive effect through many mechanisms.
The important drugs here are prednisone and dexamethasone.
Indications:
Autoimmune disorders like autoimmune haemolytic anaemia, inflammatory bowel disease, SLE.
Bronchial asthma (by local administration)
Organ transplant recipients.
Substitution therapy in adrenal insufficiency.
Mechanism of action:
Glucocorticoid drugs are lipophilic steroid drugs that diffuse into the nucleus of cells. Here it binds to the glucocorticoid receptor, a nuclear receptor. This regulates the expression of many genes. This has several effects on the immune system:
- Decreased transcription of IL-2, which inhibits the proliferation of T-helper cells
- Decreases transcription of many pro-inflammatory cytokines like TNF-α, IL-1
- Inhibition of monocyte and neutrophil chemotaxis
- Decreases the lymphocyte count (lymphopaenia)
They also decrease the synthesis of phospholipase A2.
Dosing:
Oral or IV.
Side effects:
Iatrogenic Cushing syndrome, adrenal suppression (through negative feedback on ACTH), serious bacterial and viral infections.
Drugs that inhibit lymphocyte signalling
By inhibiting the signalling between lymphocytes, we can decrease their proliferation and efficacy. By binding IL-2 to their IL-2 receptors T-cells are stimulated to proliferate. These drugs inhibit this mechanism.
The important drugs here are cyclosporin, tacrolimus and rapamycin (also known as sirolimus).
Indications:
Cyclosporin is used in organ transplantation, rheumatoid arthritis, psoriasis and certain autoimmune diseases.
Tacrolimus and rapamycin are used in organ transplantation.
Mechanism of action:
Cyclosporine and tacrolimus inhibit a protein called calcineurin. Calcineurin activates the transcription of IL-2 and IL-2 receptors on T-cells. By inhibiting calcineurin will these two drugs indirectly decrease the IL-2-mediated T-cell proliferation.
Rapamycin also interferes with IL-2 signalling, but by a different mechanism. It’s also a macrolide antibiotic, but it’s mechanism here is that it binds to an intracellular protein kinase called “molecular target of rapamycin”, or mTOR, which you might remember from biochemistry.
mTOR is involved in the intracellular signalling that occurs inside T-cells when their IL-2 receptor is activated. By inhibiting mTOR the signal from the IL-2 receptor is stopped, effectively blocking IL-2-mediated T-cell proliferation.
Side effects:
Cyclosporine is nephrotoxic and it may cause transient liver dysfunction.
Cytotoxic drugs
These drugs are cytotoxic, so they are immunosuppressive by killing WBCs.
The important drugs here are azathioprine, cyclophosphamide.
Indications:
Azathioprine is used in organ transplantation, acute glomerulonephritis and autoimmune diseases.
Cyclophosphamide are used in organ transplantation and autoimmune disorders.
Mechanism of action:
Azathioprine is a prodrug of mercaptopurine, a cytotoxic anticancer drug we saw in topic 13. This drug interferes with purine synthesis and is cytotoxic to all rapidly proliferating cells, but especially lymphocytes during the initial phase of the immune response.
Cyclophosphamide is also a cytotoxic anticancer drug from topic 13. It’s an alkylating agent that damages DNA by alkylating it. The result is the same as for azathioprine.
Contraindications:
Azathioprine is broken down by xanthine oxidase, so xanthine oxidase inhibitors like allopurinol should not be used together with azathioprine.
Side effects:
Azathioprine can cause bone marrow depression.
Antibodies with immunosuppressing effect
Antibodies can bind anything so there’s no surprise that they can be useful in immunosuppression as well.
We can group these drugs into two types:
- Polyclonal antibodies
- Hyperimmunoglobulin
- Rh(D) or anti-D immunoglobulin
- Monoclonal antibodies
- Monoclonal antibodies against TNF-α: infliximab, adalimumab
- Monoclonal antibodies against IL-12 and IL-23: ustekinumab
- Monoclonal antibodies against CD20: rituximab
- Monoclonal antibodies against IL-2 receptor: basiliximab
Hyperimmunoglobulin is the basis of passive immunization against diseases like rabies and tetanus. They are simply antibodies prepared from the plasma of people who have been exposed to the toxin or pathogen.
Indications:
Hyperimmunoglobulin is used for passive immunization in conditions like rabies and tetanus.
Rh(D) immunoglobulin is given to Rh- mothers who are pregnant with their second Rh+ child to prevent erythroblastosis foetalis.
Infliximab treats rheumatoid arthritis, inflammatory bowel disease and psoriasis.
Adalimumab treats rheumatoid arthritis.
Rituximab treats therapy-resistant rheumatoid arthritis.
Mechanism of action:
Hyperimmunoglobulins bind to and inactivate whatever their target is, like tetanus toxin or the rabies virus.
Rh(D) immunoglobulin bind to the D-antigen on the Rh+ foetus’ RBCs. This prevents the mother’s antibodies from binding to them.
Infliximab and adalimumab bind to the pro-inflammatory cytokine TNF-α and prevents it from activating the immune system.
Ustekinumab binds to a region found on both IL-12 and IL-23, so it binds these cytokines and prevent their action.
Rituximab binds to CD20, a cell surface receptor found on B-cells. This triggers the immune system to kill B-cells, causing B-cell depletion.
Basiliximab binds to the IL-2 receptor, preventing IL-2 from binding to and activating T-cells.
Immunomodulators
In this group we have both drugs that inhibit some parts of the immune system and drugs that stimulate the immune system:
- Immunostimulants
- Immune modulating interferons
Immunostimulants
Drugs like levamisole and isoprinosine may be useful in immunodeficiency disorders like AIDS.
BCG, the vaccine against tuberculosis, has immunostimulatory effects as well. More specifically it is injected into bladders with cancer to treat the cancer. The vaccine enhances the immune system’s response against the bladder cancer somehow. The mechanism is unknown.
Immune modulating interferons
Interferons are cytokines that have many immune-stimulatory functions. There exist multiple types of interferon. Interferon alpha (IFN-α) is the most pharmacologically used.
Indications:
Interferon alpha is used to treat chronic hepatitis B and C and certain leukaemias and lymphomas.
Treatment of rheumatoid arthritis
Rheumatoid arthritis (RA) is a chronic inflammatory joint disease that causes deformation of small joints. It is not curable, but pharmacological therapy can slow the progression, alleviate the symptoms and improve the physical condition of the patient.
Many drugs can be used in the treatment of RA. We can divide these drugs into two groups:
- Symptom-improving drugs
- NSAIDs
- Corticosteroids
- Disease-modifying antirheumatic drugs (DMARDs)
- Synthetic
- Methotrexate
- Cyclophosphamide
- Cyclosporine
- Biological
- Adalimumab
- Infliximab
- Rituximab
- Synthetic
Like the name implies, the symptom-improving drugs don’t actually affect the progression of the disease; they only improve the symptoms. They’re nevertheless an important part of RA treatment.
The disease-modifying antirheumatic drugs (the DMARDs) actually slow down the progression and induce clinical remission. Of the DMARDs, methotrexate is the first choice. Cyclophosphamide and cyclosporine are also included in this group. Methotrexate is here used in much lower doses than when used in cancer chemotherapy.
If standard DMARD therapy is not effective, biological DMARDs (monoclonal antibodies) can be used. This includes adalimumab, infliximab and rituximab.
“Rh(D) immunoglobulin bind to the D-antigen on the Rh+ foetus’ RBCs. This prevents the mother’s antibodies from binding to them”
Isn’t the therapy supposed to be anti-Rh(D), to bind to the mothers IgG antibodies to prevent them from crossing the placenta and binding to the foetus’ RBCs?
I can see why you’d think that, but no, the anti-Rh(D) antibodies bind to the D-antigen on the foetus’ RBCs. The text is correct.
With this therapy one would like to prevent that the mother forms antibodies against RH. This means that no immunization should take place from the beginning. For this reason, the blood groups of the mother and father are always asked during each pregnancy. If the mother forms Rhesus AK and the child is negative, his blood will be hemolyzed in the womb already early in the pregnancy.
A case study would look like this. Mother is Rh-, first baby +. The maternal immune system comes into contact with the child’s blood only at birth. (At this point we usually give the AK to prevent this. ) The first child is born and there were no problems. However, now the mother has Ak against the rhesus factor. If she gets pregnant again and the next child is Rh- again, the maternal IgG will pass through the placenta to the fetal blood. Depending on how many AK she makes, the symptoms can go from mild hemolytic anemia, to hydrops fetalis or abortion.