Immunotherapy is a treatment that functions by triggering, improving, or suppressing the body’s immune response.
Immunotherapies that induce or amplify an immune response are referred to as activation immunotherapies and are often used in vaccines or anti-cancer agents. Comparatively, immunotherapies that reduce an immune response are referred to as suppression immunotherapies and are often used to treat allergies or autoimmune diseases. Suppression immunotherapy may also be used to prevent tissue/organ rejection in patients who receive a transplant.
Immunotherapy for allergies
When the body is exposed to an allergen, mast cells release histamine within seconds, along with serine proteases and proteoglycans. This triggers allergic symptoms that peak within 15 to 30 minutes and cause irritation in the eyes, skin, and respiratory system.
Mast cells also release proinflammatory mediators and cytokines, which leads to increased vascular permeability and recruitment of other effector cells. Approximately 6 to 12 hours after the initial exposure to an allergen, a second or late phase of inflammation can occur as a result of activated CD4+ T cells, basophils, eosinophils and neutrophils leaving the bloodstream to enter local tissue upon exposure to allergens. Important allergy mediators are contained within each of these cell types. For example, whereas basophils contain histamine, eosinophils contain leukotrienes and neutrophils secrete lipids, cytokines, and proteases that damage tissues directly, including mucosal membranes.
Allergen immunotherapy works by suppressing this second phase response and by reducing the first phase response by preventing allergen-driven Th2 responses, which includes a fall in the levels of interleukin (IL)-4, IL-5, IL-9, and IL-13. This decreased Th2 response is accompanied by a shift in the immune response to one that favors protective Th1 pathways. The therapy activates IL-10 and T regulatory cells that secrete transforming growth factor–β (TGF-β), which appears to suppress Th2 responses. IL-10 also helps immunoglobulin isotypes switch to IgG4, while TGF-β mediates switching to IgA.
Suppression of the immune response in patients receiving allergen immunotherapy is attributed to increases in immunoglobulin A (IgA), IgG1, and IgG4, as well as a fall in IgE. The number of infiltrating T cells, eosinophils, basophils, and neutrophils is also significantly reduced.
Allergen immunotherapy results in a long-term reduction in serum allergen-specific IgE levels and it has also been shown that the early phase response is significantly reduced.
Immunotherapy for transplant patients
Almost all patients who receive an organ or tissue transplant (allograft) need to take immunosuppressive agents to prevent the body from recognizing the tissue or organ as foreign and subsequently launching an immune response to attack it.
An allogeneic transplant will not be successful unless the patient’s immune system is downregulated; in fact, it is crucial that this downregulation is maintained for the long-term. Immunosuppressive therapy must downregulate the immune system in such a way that all other responses, aside from those to the allograft, remain intact.
Three main aspects, therefore, need to be considered when deciding on an immunosuppressive regimen, of which include:
- Immunosuppression must be sufficient to prevent the allogeneic response from damaging the transplanted organ.
- The overall immunosuppressive load needs to be sufficiently low to enable the immune system to still fight infection and check for tumor cells.
- To increase efficacy and reduce toxic effects, immunosuppressants with complementary mechanisms of action should be used.
Aside from corticosteroids, all immunosuppressive agents that are currently used for mainstay regimens to prevent allograft rejection disrupt discrete points in the T and B cell activation cascades. Cyclosporin A and tacrolimus, for example, prevent the transcription of cytokines, whereas azathioprine and mycophenolate mofetil prevent nucleotide synthesis. Additionally, daclizumab and basiliximab block stimulation of T cell IL-2 receptors by IL-2, whereas sirolimus blocks growth factor signal transduction.
Corticosteroids
Corticosteroids have a wide range of effects on nearly every phase of the inflammatory and immune responses seen in humans. They can disrupt various stages of immune activation due to the ubiquitous expression of corticosteroid receptors.
Corticosteroids can disrupt antigen presentation, prevent cytokine production and inhibit lymphocyte proliferation. Their administration results in a fall in the lymphocyte, monocyte and basophil counts, but an increase in neutrophil count.
Immunotherapy for autoimmune disease
Disorders of the immune system cause this system to become either overactive or underactive. In cases where the immune system is overactive, an autoimmune disease arises, during which the immune system produces antibodies that attack and damage the body’s own tissues instead of fighting infection. Some examples of autoimmune disorders that can be treated with immunosuppressant therapies include rheumatoid arthritis (RA) and inflammatory bowel disease (IBD).
RA
In RA, antibodies that are produced by the immune system attack the linings in the joints. Initially, a doctor may prescribe a non-steroidal anti-inflammatory drug (NSAID), which can reduce pain and inflammation, but does not slow or prevent disease progression.
People with moderate to severe RA therefore usually need to take another medication. In some cases, this may be the disease-modifying antirheumatic drug (DMARD) methotrexate. If this drug fails to work, an alternative DMARD such as hydroxychloroquine or sulfasalazine may be prescribed.
In cases where DMARDs fail to relieve symptoms, suppressive immunotherapy may be recommended. These engineered proteins block particular parts of the immune response that lead to inflammation and may slow or halt the progression of RA. Some examples of these agents include abatacept, rituximab and etanercept.
IBD
The most common pharmaceutical agents used in the initial treatment of IBD are typically aminosalicylates such as sulfasalazine, olsalazine or mesalamine. These drugs can be effective at alleviating symptoms of ulcerative colitis and sometimes Crohn's disease that is confined to the colon.
Despite their utility, aminosalicylates are associated with a number of side effects such as headache and digestive distress. Corticosteroids may also be used to relieve inflammation and symptoms of IBD; however, they are not typically given in the long-term as they can eventually cause severe side effects such as diabetes, osteoporosis, and high blood pressure.
The treating clinician may eventually prescribe an immunosuppressive therapy, to suppress the immune response that releases chemicals in the intestinal lining that cause the inflammation in IBD. Some individuals may benefit more from a combination of these drugs rather than one agent alone. Examples of these immunosuppressive agents include cyclosporine, azathioprine, infliximab, methotrexate, natalizumab and vedolizumab.
References
Further Reading
Patient-derived organoids: Transforming cancer research and personalized medicine