The Role of TNF-α in Immunity
Cell-Mediated Immunity
Cell-mediated immunity (CMI), also referred to
as delayed-type hypersensitivity, is an immune reaction
mediated by
CMI confers protection through multiple pathways and mechanisms:
-
Activating antigen-specific cytotoxic
T lymphocytes that are able to lyse endogenous cells displaying epitopes of foreign antigen on their surfaces, such as virus-infected cells, cells with intracellular bacteria, and cancer cells displaying tumor antigens -
Activating macrophages and NK cells, enabling them to destroy intracellular pathogens
-
Stimulating cells to secrete a variety of cytokines that influence the function of other cells involved in adaptive immune responses and innate immune responses
A cytokine is an intercellular regulatory protein
produced by one of many different cells within the immune system.
Cytokines function as regulatory messengers that control many aspects
of immune response and play critical roles in protective host responses,
including defense against microbial invasion and tumorigenesis. Cytokines
function by activating, deactivating, or altering the growth, development,
and function of immune system cells such as phagocytes. In addition,
certain cytokines can act on leukocytes or the endothelial cells of
the blood vessel wall to promote migration of leukocytes out of the
bloodstream and into inflamed tissue. Cytokines are mainly produced
by mononuclear phagocytes, such as macrophages and dendritic cells,
although they can also be produced by
In addition,
Granuloma Formation
A granuloma is one of a number of forms of localized inflammation found in tissues. It is composed of a group of epithelioid macrophages surrounded by a lymphocyte cuff. Granulomas are seen in a variety of diseases, including Crohn’s disease, tuberculosis, sarcoidosis, berylliosis, and syphilis. They are also a feature of Wegener granulomatosis and Churg-Strauss syndrome. Granulomas may be formed in response to a variety of biologic, chemical, and physical irritants of tissue and play an important role in the containment of infections that might otherwise disseminate.
The formation of granulomas in response to infections,
such as tuberculosis, leprosy, histoplasmosis, and coccidioidomycosis,
is a cytokine-mediated cellular response. Because macrophages have
difficulty removing microbes that cause these types of infections,
cytokines and chemokines are continuously secreted, which leads to
an accumulation of densely packed macrophages around the microbes.
The macrophages release fibrogenic cytokines, such as tumor necrosis
factor-α
Content on this page was last reviewed on May 21, 2010.
Content on this page was last changed on March 25, 2009.
References:| 1981. | Coico R, Sunshine S, Benjamini E. Cytokines. In: Coico R. Immunology: A Short Course . 5th ed. Hoboken, NJ: John Wiley and Sons; 2003:149-164. |
| 1982. | Coico R, Sunshine S, Benjamini E. Introduction and overview: elements of innate and acquired immunity. In: Coico R. Immunology: A Short Course . 5th ed. Hoboken, NJ: John Wiley and Sons; 2003:1-4;19-23. |
| 1986. | Flynn JL, Chan J. Immunology of tuberculosis. Annu Rev Immunol . 2001;19:93-129. |
| 1991. | Lukacs NW, Chensue SW, Strieter RM, Warmington K, Kunkel SL. Inflammatory granuloma formation is mediated by TNF-alpha-inducible intercellular adhesion molecule-1. J Immunol. 1994;152(12):5883-5889. |
| 1993. | Roach DR, Bean AG, Demangel C, France MP, Briscoe H, Britton WJ. TNF regulates chemokine induction essential for cell recruitment, granuloma formation, and clearance of mycobacterial infection. J Immunol. 2002;168(9):4620-4627. |
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Prescribing Information and Medication Guide
REMICADE® (infliximab) Indications and Important Safety Information
INDICATIONS AND USAGE
Crohn’s Disease
REMICADE is indicated for reducing signs and symptoms and inducing and maintaining clinical remission in adult and pediatric patients with moderately to severely active Crohn’s disease who have had an inadequate response to conventional therapy.
REMICADE is indicated for reducing the number of draining enterocutaneous and rectovaginal fistulas and maintaining fistula closure in adult patients with fistulizing Crohn’s disease.
Ulcerative Colitis
REMICADE is indicated for reducing signs and symptoms, inducing and maintaining clinical remission and mucosal healing, and eliminating corticosteroid use in patients with moderately to severely active ulcerative colitis who have had an inadequate response to conventional therapy.
Rheumatoid Arthritis
REMICADE, in combination with methotrexate, is indicated for reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in patients with moderately to severely active rheumatoid arthritis.
Ankylosing Spondylitis
REMICADE is indicated for reducing signs and symptoms in patients with active ankylosing spondylitis.
Psoriatic Arthritis
REMICADE is indicated for reducing signs and symptoms of active arthritis, inhibiting the progression of structural damage, and improving physical function in patients with psoriatic arthritis.
Plaque Psoriasis
REMICADE is indicated for the treatment of adult patients with chronic severe (i.e., extensive and /or disabling) plaque psoriasis who are candidates for systemic therapy and when other systemic therapies are medically less appropriate. REMICADE should only be administered to patients who will be closely monitored and have regular follow-up visits with a physician.
IMPORTANT SAFETY INFORMATION
RISK OF INFECTIONS
Patients treated with REMICADE® (infliximab) are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids. Discontinue REMICADE® if a patient develops a serious infection or sepsis.
Reported infections include:
- Active tuberculosis (TB), including reactivation of latent TB. Patients frequently presented with disseminated or extrapulmonary disease. Patients should be tested for latent TB before and during treatment with REMICADE®. 1,2 Treatment for latent infection should be initiated prior to treatment with REMICADE®.
- Invasive fungal infections, including histoplasmosis, coccidioidomycosis, candidiasis, aspergillosis, and pneumocystosis. Patients may present with disseminated, rather than localized, disease. Empiric anti-fungal therapy should be considered in patients at risk for invasive fungal infections who develop severe systemic illness.
- Bacterial, viral, and other infections due to opportunistic pathogens.
The risks and benefits of treatment with REMICADE® should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection. Closely monitor patients for the development of signs and symptoms of infection during and after treatment with REMICADE®, including the possible development of TB in patients who tested negative for latent TB infection prior to initiating therapy.
In clinical trials, other serious infections observed in patients treated with REMICADE® included pneumonia, cellulitis, abscess, and skin ulceration.
MALIGNANCIES
Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF blockers, including REMICADE®. Approximately half of these cases were lymphomas, including Hodgkin's and non-Hodgkin's lymphoma. The other cases represented a variety of malignancies, including rare malignancies that are usually associated with immunosuppression and malignancies that are not usually observed in children and adolescents. The malignancies occurred after a median of 30 months after the first dose of therapy. Most of the patients were receiving concomitant immunosuppressants.
Postmarketing cases of hepatosplenic T-cell lymphoma, a rare type of T-cell lymphoma, have been reported in patients treated with TNF blockers including REMICADE®. These cases have had a very aggressive disease course and have been fatal. All reported REMICADE® cases have occurred in patients with Crohn’s disease or ulcerative colitis and the majority were in adolescent and young adult males. All of these patients had received treatment with azathioprine or 6-mercaptopurine concomitantly with REMICADE® at or prior to diagnosis. Carefully assess the risks and benefits of treatment with REMICADE®, especially in these patient types.
In clinical trials of all TNF inhibitors, more cases of lymphoma were observed compared with controls and the expected rate in the general population. However, patients with Crohn’s disease, rheumatoid arthritis, or plaque psoriasis may be at higher risk for developing lymphoma. In clinical trials of some TNF inhibitors, including REMICADE®, more cases of other malignancies were observed compared with controls. The rate of these malignancies among patients treated with REMICADE® was similar to that expected in the general population whereas the rate in control patients was lower than expected. Cases of acute and chronic leukemia have been reported with postmarketing TNF-blocker use. As the potential role of TNF inhibitors in the development of malignancies is not known, caution should be exercised when considering treatment of patients with a current or a past history of malignancy or other risk factors such as chronic obstructive pulmonary disease (COPD).
CONTRAINDICATIONS
REMICADE® is contraindicated in patients with moderate to severe (NYHA Class III/IV) congestive heart failure (CHF) at doses greater than 5 mg/kg. Higher mortality rates at the 10 mg/kg dose and higher rates of cardiovascular events at the 5 mg/kg dose have been observed in these patients. REMICADE® should be used with caution and only after consideration of other treatment options. Patients should be monitored closely. Discontinue REMICADE® if new or worsening CHF symptoms appear. REMICADE® should not be (re)administered to patients who have experienced a severe hypersensitivity reaction or to patients with hypersensitivity to murine proteins or other components of the product.
HEPATITIS B REACTIVATION
TNF inhibitors, including REMICADE®, have been associated with reactivation of hepatitis B virus (HBV) in patients who are chronic carriers. Some cases were fatal. Patients at risk for HBV infection should be evaluated for prior evidence of HBV infection before initiating REMICADE®. Exercise caution when prescribing REMICADE® for patients identified as carriers of HBV and monitor closely for active HBV infection during and following termination of therapy with REMICADE®. Discontinue REMICADE® in patients who develop HBV reactivation and initiate antiviral therapy with appropriate supportive treatment. Exercise caution when considering resumption of REMICADE® and monitor patients closely.
HEPATOTOXICITY
Severe hepatic reactions, including acute liver failure, jaundice, hepatitis, and cholestasis have been reported rarely in patients receiving REMICADE® postmarketing. Some cases were fatal or required liver transplant. Aminotransferase elevations were not noted prior to discovery of liver injury in many cases. Patients with symptoms or signs of liver dysfunction should be evaluated for evidence of liver injury. If jaundice and/or marked liver enzyme elevations (e.g., ≥ 5 times the upper limit of normal) develop, REMICADE® should be discontinued, and a thorough investigation of the abnormality should be undertaken.
HEMATOLOGIC EVENTS
Cases of leukopenia, neutropenia, thrombocytopenia, and pancytopenia (some fatal) have been reported. The causal relationship to REMICADE® therapy remains unclear. Exercise caution in patients who have ongoing or a history of significant hematologic abnormalities. Advise patients to seek immediate medical attention if they develop signs and symptoms of blood dyscrasias or infection. Consider discontinuation of REMICADE® in patients who develop significant hematologic abnormalities.
HYPERSENSITIVITY
REMICADE® has been associated with hypersensitivity reactions that differ in their time of onset. Acute urticaria, dyspnea, and hypotension have occurred in association with infusions of REMICADE®. Serious infusion reactions including anaphylaxis were infrequent. Medications for the treatment of hypersensitivity reactions should be available.
NEUROLOGIC EVENTS
TNF inhibitors, including REMICADE®, have been associated with rare cases of new or exacerbated symptoms of demyelinating disorders including multiple sclerosis, optic neuritis, and Guillain-Barré syndrome, seizure, and CNS manifestations of systemic vasculitis. Exercise caution when considering REMICADE® in all patients with these disorders. Consider discontinuation for significant CNS adverse reactions.
AUTOIMMUNITY
Treatment with REMICADE® may result in the formation of autoantibodies and, rarely, in development of a lupus-like syndrome. Discontinue treatment if symptoms of a lupus-like syndrome develop.
ADVERSE REACTIONS
In clinical trials, the most common REMICADE® adverse reactions occurring in >10% of patients included infections (e.g. upper respiratory, sinusitis, and pharyngitis), infusion-related reactions, headache, and abdominal pain.
USE WITH OTHER DRUGS
The concomitant use of a TNF blocker and anakinra was associated with a higher risk of serious infections, therefore the use of REMICADE® in combination with anakinra is not recommended. Live vaccines should not be given with REMICADE®. Bring pediatric Crohn's patients up to date with all vaccinations prior to initiating REMICADE®.
Please see full Prescribing Information and Medication Guide for REMICADE®. Provide the Medication Guide to your patients and encourage discussion.
References: 1. American Thoracic Society, Centers for Disease Control and Prevention. Targeted tuberculin testing and treatment of latent tuberculosis infection. Am J Respir Crit Care Med. 2000;161:S221–S247. 2. See latest Centers for Disease Control guidelines and recommendations for tuberculosis testing in immunocompromised patients.