Interferons are an

extraordinary group of proteins whose antiviral activity led to their discovery almost 50 years ago. Subsequent studies showed that interferons have other effects, including the capacity to induce cell differentiation, to inhibit proliferation by some cell types, to inhibit angiogene-sis, and to function in various immu-noregulatory roles. Their effects on the immune system are important and dramatic. Interferons induce increases in the expression of class I and class II MHC molecules, and augment NK-cell activity. Increased class I expression increases the display of antigen to CD8+ cells, a class that includes most of the TC population. This enhanced display of antigen not only makes the antigen-presenting cells more effective in inducing cytotoxic T-cell populations, it also makes them better targets for attack by TC cells. In addition to up-regulating class I MHC expression of many cell types, IFN-y increases the expression of class II MHC molecules on such antigen-presenting cells as macrophages and dendritic cells. This makes them better presenters of antigen to TH cells. IFN-y is also a potent inducer of macrophage activation and general promoter of inflammatory responses. Cloning of the genes that encode all three types of interferon, IFN-a, IFN-p, and IFN-y, has made it possible for the biotechnology industry to produce large amounts of all of these interferons at costs that make their clinical use practical. Some clinical uses of each type of interferon are described here:

IFN-a (also known by its trade names Roferon and Intron-A) has been used for the treatment of hepatitis C and hepatitis B. It has also found a number of different applications in cancer therapy. A type of B-cell leukemia known as hairy-cell leukemia (because the cells are covered with fine, hairlike cytoplasmic projections) responds well to IFN-a. Chronic myelogenous leukemia, a disease characterized by increased numbers of granulocytes, begins with a slowly developing chronic phase that changes to an accelerated phase and terminates in a blast phase, which is usually resistant to treatment. IFN-a is an effective treatment for this leukemia in the chronic phase (70% response rates have been reported) and some patients (as many as 20% in some studies) undergo complete remission. Kaposi's sarcoma, the cancer most often seen in American AIDS patients, also responds to treatment with IFN-a, and there are reports of a trend toward longer survival and fewer opportunistic infections in patients treated with this agent. IFN-y has also been used, with varying degrees of success, to treat a variety of malignancies that include non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, and multiple myeloma. Most of the effects mentioned above have been obtained in clinical studies that used

IFN-a alone. Future clinical trials in which IFN-a is used in combinations with other agents may improve the effectiveness of this interferon in cancer therapy.

■ IFN-p has emerged as the first drug capable of producing clinical improvement in multiple sclerosis (MS). Young adults are the primary target of this autoimmune neurologic disease, in which nerves in the central nervous system (CNS) undergo demyelination. This results in progressive neurologic dysfunction, which leads to significant and, in many cases, severe disability. This disease is often characterized by periods of nonprogression and remission alternating with periods of relapse. Treatment with IFN-p provides longer periods of remission and reduces the severity of relapses. Furthermore, magnetic-resonance-imaging studies of CNS damage in treated and untreated patients revealed that MS-induced damage was less in a group of IFN-p-treated patients than in untreated ones.

■ IFN-y has found application in the clinic as an agent for the treatment of chronic granulomatous disease (CGD). This disease is hereditary and quite rare. Its central feature is a serious impairment of the ability of phagocytic cells to kill ingested microbes. Patients with CGD are beset with recurring infections by a number of bacteria (Staphylococcus aureus, Klebsiella, Pseudomonas, and others) and fungi such as Aspergillus and Candida. Before interferon therapy, standard treatment for the disease was attempts to avoid infection, aggressive administration of characterized, erythropoietin, was isolated from the urine of anemic patients and shown to support the development of red blood cells. Subsequently, many cytokines have been shown to play essential roles in hematopoiesis (see

Table 12-5). During hematopoiesis, cytokines act as developmental signals that direct commitment of progenitor cells into and through particular lineages. As shown in Figure 12-16, a myeloid progenitor in the presence erythropoietin antibiotics, and surgical drainage of abscesses. A failure to generate microbicidal oxidants (H2O2, superoxide, and others) is the basis of CGD, and the administration of IFN-7 significantly reverses this defect. Therapy of CGD patients with IFN-7 significantly reduces the incidence of infections. Also, the infections that are contracted are less severe and the average number of days spent by patients in the hospital goes down.

■ IFN-7 has also been shown to be effective in the treatment of osteopetrosis, (not osteoporosis) a life-threatening congenital disorder characterized by overgrowth of bone which results in blindness and deafness. Another problem presented by this disease is that the buildup of bone reduces the amount of space available for bone marrow and the decrease in hematopoiesis results in fewer red blood cells and anemia. The decreased generation of white blood cells causes an increased susceptibility to infection.

The use of interferons in clinical practice is likely to expand as more is learned about their effects in combination with other therapeutic agents. Although, in common with other cytokines, interferons are powerful modifiers of biological responses, fortunately, the side effects accompanying their use are much milder. Typical side effects include flulike symptoms, such as headache, fever, chills, and fatigue. These symptoms can largely be managed with acetaminophen (Tylenol) and diminish in intensity during continued treatment. Although interferon toxicity is usually not severe, serious manifestations such as anemia and depressed platelet and white-blood-cell counts have been seen.

Cytokine-Based Therapies In Clinical Use

Agent

Nature of agent

Clinical application

Enbrel

Chimeric TNF-receptor/IgG constant region

Rheumatoid arthritis

Remicade

Monoclonal antibody against TNF-a receptor

Rheumatoid arthritis

Interferon a-2a

Antiviral cytokine

Hepatitis B Hairy cell leukemia Kaposi's sarcoma

Interferon a-2b

Antiviral cytokine

Hepatitis C Melanoma

Interferon ß

Antiviral cytokine

Multiple sclerosis

Actimmune

Interferon 7

Chronic granulomatous disease (CGD) Osteopetrosis

Neupogen

G-CSF (hematopoietic cytokine)

Stimulates production of neutrophils Reduction of infection in cancer patients treated with chemotherapy

Leukine

GM-CSF (hematopoietic cytokine)

Stimulates production of myeloid cells after bone-marrow transplantation

Neumega

Interleukin 11 (IL-11), a hematopoietic cytokine

Stimulates production of platelets

Epogen

Erythopoietin (hematopoietic cytokine)

Stimulates red-blood-cell production

would proceed down a pathway that leads to the production of erythrocytes; suitable concentrations of a group of cytokines including IL-3, GM-CSF, IL-1, and IL-6 will cause it to enter differentiation pathways that lead to the generation of monocytes, neutrophils, and other leukocytes of the myeloid group. The participation of leukocytes in immune responses often results in their death and removal. However, both adaptive and innate immune responses generate cytokines that

Haematopoietic cytokines

Haematopoietic growth factor Sites of production

Main functions

Erythropoietin G-CSF

Thrombopoietin M-CSF

SCF/c-kit ligand

Flt-3 ligand GM-CSF

IL-3

IL-11 IL-7

Kidney, liver

Endothelial cells, fibroblasts, macrophages Liver, kidney

Fibroblasts, endothelial cells, macrophages Bone marrow stromal cells, constitutively

Fibroblasts, endothelial cells

T cells (Th1 and TH2), macrophages, mast cells

T cells (Th1 and TH2), macrophages

Activated helper T cells -TH2 response only

Activated T cells monocytes, fibroblasts, endothelial cells

As above

Erythrocyte production Neutrophil production Platelet production

Macrophage and osteoclast production

Stem cell, progenitor cells survival/division; mast cell differentiation

Early progenitor cell expansion; pre-B cells

Macrophage, granulocyte production; dendritic cell maturation and activation

Stem cells and myeloid progenitor cell growth; mast cells

Eosinophil production murine B-cell growth

Progenitor cell stimulation; platelet production; immunoglobulin production in B cells

As LIF

T-cell survival

G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte-macrophage colony-stimulating factor; IL, interleukin; M-CSF, macrophage colony-stimulating factor; SCF, stem cell factor. Adapted from D. Thomas and A. Lopez, 2001. Encyclopedia of Life Sciences: Haematopoietic growth factors, Nature Publishing Group.

stimulate and support the production of leukocytes. The steps at which a number of cytokines participate in hema-topoiesis is shown in Figure 12-16.

SUMMARY

■ Cytokines are low-molecular-weight proteins that are produced and secreted by a variety of cell types. They play major roles in the induction and regulation of the cellular interactions involving cells of the immune, inflammatory and hematopoietic systems.

■ The biological activities of cytokines exhibit pleiotropy, redundancy, synergy, antagonism, and, in some instances, cascade induction.

■ There are over 200 different cytokines, most of which fall into one of the following families: hematopoietins, interferons, chemokines, and tumor necrosis factors.

■ Cytokines act by binding to cytokine receptors, most of which can be classified as immunoglobulin superfamily receptors, class I cytokine receptors, class II cytokine receptors, members of the TNF receptor family, and chemokine receptors.

■ A cytokine can only act on a cell that expresses a receptor for it. The activity of particular cytokines is directed to specific cells by regulation of the cell's profile of cytokine receptors.

■ Cytokine-induced multimerization of class I and class I cytokine receptors activates a JAK/STAT signal-transduction pathway.

■ Antigen stimulation of TH cells in the presence of certain cytokines can lead to the generation of subpopulations of helper T cells known as TH1 and TH2. Each subset displays characterisic and different profiles of cytokine secretion.

■ The cytokine profile of TH1 cells supports immune responses that involve the marshalling of phagocytes, CTLs, and NK cells to eliminate intracellular pathogens. TH2 cells produce cytokines that support production of particular immunoglobulin isotypes and IgE-mediated responses.

■ Therapies based on cytokines and cytokine receptors have entered clinical practice.

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