Cytokines and Biologic Modifiers

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Cytokines and Biologic Modifiers

Learning Objectives

• Differentiate between a cytokine and an interleukin (IL)

• List the cells that produce IL-1

• Identify the three biologic functions of IL-1

• Identify the immunologic and genetic defects in patients with cryopyrin-associated periodic syndrome (CAPS)

• Design a treatment regimen for CAPS

• List the cells that produce IL-2

• Compare and contrast IL-2 receptors on activated and naïve T cells

• Compare the roles of IL-2 in autocrine and paracrine signaling

• Explain the relationship between natural killer (NK) cells, IL-2, and lymphokine-activated killer (LAK) cells

• Recognize the biologic role of aldesleukin

• Identify the biologic role(s) of IL-11 and the clinical usefulness of oprelvekin

• Compare and contrast type I and type II interferons (IFNs) and their biologic functions

• List the cellular sources of type I and type II IFNs

• Describe the role of IFNs in viral infections

• List the commercially available natural and synthetic IFNs

• Define tumor necrosis factor (TNF)

• Compare the functions of TNF at low and high concentrations

• Discuss the role of TNF in the pathophysiology of rheumatoid arthritis (RA)

• Identify the two monoclonal antibodies used in the treatment of RA

• Recognize the biologic target of etanercept

• Identify the biologic roles of IL-3, macrophage–colony-stimulating factor (M-CSF), granulocyte-macrophage–CSF (GM-CSF), and granulocyte-CSF (G-CSF)

• Differentiate between tumor-specific antigen (TSA) and tumor-associated antigen (TAA)

• Compare and contrast the structure of heat shock proteins (HSPs) from normal and malignant cells

• Compare and contrast normal and malignant carbohydrate tumor antigens

• Identify the two antigens present on germ-line tumor cells

• Discuss the advantages and disadvantages of whole-cell tumor vaccines

• Discuss the advantages and disadvantages of dendritic cell vaccines

• Identify the advantages and disadvantages of viral vector vaccines

• Explain the relationship between B cell receptors (BCRs), B cell malignancies, and idiotype vaccines

Key Terms

Colony-stimulating factor (CSF)

Cryopyrin-associated periodic syndrome (CAPS)

Cytokines

Dendritic cell cancer vaccine

Idiotypic cancer vaccine

Interferon (IFN)

Interleukin 1 (L-1)

Interleukin 2 (L-2)

Interleukin 11 (L-11)

Tumor-associated antigen (TAA)

Tumor necrosis factor (TNF)

Tumor-specific antigen (TSA)

Whole-cell cancer vaccine

Introduction

Biologic response modifiers (BRMs) are natural or synthetic substances that stimulate the immune system or restore normal numbers of immunocompetent cells in peripheral blood. BRMs include cytokines, interleukins (ILs), interferons (IFNs), and colony-stimulating factors (CSFs). In the broadest sense, human cancer vaccines are considered BRMs, since they modify the immune response to tumors.

Cytokines and Interleukins

Cytokines are a family of small-molecular-weight, soluble proteins that activate or inhibit the function of cells. Within the cytokine family are ILs, IFNs, and other factors that stimulate the differentiation of stem cells in bone marrow. ILs and IFNs facilitate cross-talk between immunocompetent cells, which results in an alteration of biologic function. Bone marrow–stimulating factors induce the differentiation of macrophages and granulocytes and their release into peripheral blood.

Interleukin 1

IL-1 is synthesized by macrophages, monocytes, dendritic cells, and keratinocytes. It comprises two different polypeptides (IL-1α and IL-1β), each having a molecular weight of 17 kilodaltons (kDa). The effects of IL-1 are wide ranging and concentration dependent. At low concentrations, IL-1 upregulates leukocyte adhesion factors, which facilitates the tethering of immunocompetent cells before their transmigration into tissue. As part of an innate immune response, IL-1 acts as an endogenous pyrogen, which raises the body temperature above 100.4o F (see Chapter 2). The temperature increase prevents microbial growth and accelerates lymphocyte division and the onset of an adaptive immune response.

Interleukin 1 and Disease

Cryopyrin-associated periodic syndrome (CAPS) comprises a group of inherited diseases that are characterized by the overproduction of IL-1β. CAPS is characterized by short, intense inflammatory reactions with rashes, fever or chills, redness of eyes, joint pain, and adolescent deafness. Included in the CAPS family are:

Individuals with CAPS have an autosomal dominant mutation in the NLRP3 gene that prevents the synthesis of cryopyrin (Table 23-1). Under normal conditions, cryopyrin interacts with apoptosis-associated Speck-like protein and caspase 1 to increase the synthesis of IL-1β (see Table 23-1).

Table 23-1

Gene Abnormalities in Cryopyrin-Associated Periodic Syndrome (CAPS)

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Syndrome Gene and Locus Protein Mode of Inheritance
MWS NLRP3 (CIAS1), 1q44 Cryopyrin (NALP3/PYPAF1) Autosomal dominant
FCAS NLRP3 (CIAS1), 1q44 Cryopyrin (NALP3/PYPAF1) Autosomal dominant
NOMID NLRP3 (CIAS1), 1q44 Cryopyrin (NALP3/PYPAF1) Autosomal dominant

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IL-1 as a Biologic Response Modifier

Fusion proteins, receptor antagonists, and monoclonal antibodies are used to neutralize the physiologic effects of soluble IL-1 or block the interactions with the receptor. Rilonacept is a fusion protein that contains the IL-1 receptor coupled with the Fc portion of immunoglobulin G (IgG). It binds and neutralizes soluble IL-1 before it can interact with its receptor. Canakinumab is a humanized monoclonal antibody directed at IL-1β. It blocks the effects of IL-1β and has no cross-reactivity with IL-1α or the IL-1 receptor. Anakinra is an IL-1 receptor antagonist that downregulates or blocks intracellular signaling. Many of these BRMs are used to treat patients with CAPS (Table 23-2).

Table 23-2

Treatment for Cryopyrin-Associated Periodic Syndrome (CAPS)

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Product Description Disease
Rilonacept Fusion product of the interleukin 1 (IL-1) receptor and the Fc portion of immunoglobulin G (IgG)

Canakinumab Fully humanized monoclonal antibody directed at IL-1β Neonatal-onset multisystem inflammatory disease (NOMID)
Anakinra Nonglycosylated form of the human IL-1 receptor antagonist (IL-1Ra) Neonatal-onset multisystem inflammatory disease (NOMID)

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Interleukin 2

Interleukin 2 (or T cell growth factor) is a glycosylated protein synthesized by activated T cells. Synthesis is transient, with peak activity occurring 4 hours after T cell activation. Autocrine IL-2 stimulation of activated T cells is necessary for the activation and proliferation of CD8+ and CD4+ cells (see Chapter 7). By increasing the synthesis of perforin and granzymes, IL-2 transforms natural killer (NK) cells into lymphokine-activated killer (LAK) cells.

IL-2 as a Biologic Response Modifier

Administration of IL-2 can augment or inhibit immune function. Blocking the interaction between IL-2 and the high-affinity IL-2 receptor prevents autocrine stimulation of T cells and the initiation of an immune response. Two commercially available monoclonal antibodies block autocrine stimulation. Daclizumab is a humanized IgG1, and basiliximab is a chimeric (murine–human) antibody. Both antibodies are directed at the α-chain of the human high-affinity IL-2 receptor. They are administered in concert with cyclosporine and corticosteroid therapy to prevent the rejection of allografts.

Recombinant IL-2 is also used to stimulate the immune system. Aldesleukin is a recombinant human IL-2 produced in Escherichia coli. It is indicated for the treatment of metastatic renal cell carcinoma in adults.

Aldesleukin has serious side effects. In some patients, it induces capillary leak syndrome (CLS), which is characterized by leakage of fluid into tissue and the loss of vascular tone. The rapid drop in blood pressure results in reduced organ perfusion, hypotension, and death.

Interleukin 11

IL-11 is one of several uncharacterized proteins that stimulate the proliferation and differentiation of platelet progenitors.

IL-11 as a Biologic Response Modifier

Oprelvekin is a recombinant IL-11 produced in E. coli. It is indicated for the prevention of severe thrombocytopenia following immunosuppressive therapy in patients with nonmyeloid malignancies.

Interferons

IFNs, a group of proteins usually produced in response to viral infections, are divided into two broad groups: type I and type II. The two subclasses of type I interferons are known as IFN-α and IFN-β. Type I IFN-α is produced by lymphocytes. Type I IFN-β is produced by fibroblasts. IFN-γ is also produced by lymphocytes and is the only known type II IFN. IFN-γ has a unique role in immune responses. It directs immune responses by recruiting Th1 cells to the inflammatory site and by downregulating the activity of Th2 cells. At the site of the inflammatory reaction, IFN-γ upregulates the expression of vascular adhesion factors that tether immunocompetent cells to the vascular endothelium before diapedesis.

Interferons and Viral Infections

Containment of viral infections is the primary biologic role of type I IFNs. Infected cells secrete IFNs, which warn adjacent cells of the infection risk. Uninfected, IFN-stimulated cells produce a unique 2’5’ oligoadenylate synthetase that activates several nucleases and kinases. Nucleases cleave viral ribonucleic acid (RNA) preventing transcription and translation of viral proteins and the synthesis of new viral RNA. Kinases also inhibit the synthesis of viral proteins by downregulating protein elongation factors (ELF-2).

Synthetic and Natural Interferons and Biologic Modifiers