miércoles, 19 de diciembre de 2018

Suppression Immunotherapies

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Immunotherapy is treatment that works by triggering, improving or suppressing the body’s immune response. Therapies that induce or amplify an immune response are referred to as activation immunotherapies and these are used in vaccines or to treat cancer. Therapies that reduce an immune response to treat allergy or autoimmune disease, for example, are referred to as suppression immunotherapies. Suppression immunotherapy may also be used to prevent tissue/organ rejection in patients who receive a transplant.

Immunotherapy for allergy

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 later, 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. 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 seems 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 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 and IgG4 antibodies prevent IgE-dependent histamine release by basophils.

Allergen immunotherapy results in a long-term decrease 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 therapies to prevent the body recognizing the organ as foreign and launching an immune response to attack it. Allogeneic transplant will not be successful unless the patient’s immune system is downregulated and this downregulation must also be maintained in 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.

Immunosuppression must be sufficient to prevent the allogeneic response 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 currently used for mainstay regimens to prevent allograft rejection disrupt discrete points in the T and B cell activation cascades.

Cyclosporin A and tacrolimus prevent the transcription of cytokines
Azathioprine and mycophenolate mofetil prevent nucleotide synthesis
Daclizumab and basiliximab block stimulation of T cell IL-2 receptors by IL-2
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. These agents 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 the immune system to become either overactive or underactive. In cases where the immune system is overactive, it produces antibodies that attack and damage the body’s own tissues instead of fighting infection (autoimmune disease). Examples of autoimmune disorders that can be treated with immunosuppressant therapies include rheumatoid arthritis and inflammatory bowel disease.

Rheumatoid arthritis

In rheumatoid arthritis, antibodies are produced by the immune system that attack the linings in joints. Initially, a doctor may prescribe a non-steroidal anti-inflammatory drug, which can reduce pain and inflammation, but does not slow or prevent disease progression. People with moderate to severe rheumatoid arthritis therefore usually need to take another medication. In some cases, this may be the disease modifying antirheumatic drug (DMARD) methotrexate and if that fails to work, an alternative DMARD such as hydroxychloroquine or sulfasalazine may be prescribed. In cases where DMARDs fail to relieve symptoms, a suppressive immunotherapy may be recommended. These engineered proteins block particular parts of the immune response that leads to inflammation and may slow or halt the progression of rheumatoid arthritis. Examples of these agents include abatacept, rituximab and etanercept.

Inflammatory bowel disease

The first step to treating inflammatory bowel disease is usually to use aminosalicylates such as sulfasalazine, olsalazine or mesalamine. These can be effective at alleviating symptoms of ulcerative colitis and sometimes Chron’s disease that is confined to the colon. However, these agents 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 irritable bowel syndrome, but these are not usually given in the long-term because they can eventually cause severe side effects such as diabetes, osteoporosis and high blood pressure.

A doctor may eventually prescribe an immunosuppressive therapy, to suppress the immune response that releases chemicals in the intestinal lining that cause inflammation. 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.