Page 151 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPTEr 9 Cytokines and Cytokine Receptors 133

similar defect may be responsible for disease in a subset of humans and contains binding sites for nuclear factor of activated T-cells
with this abnormality. (NFATs), AP-1, and NF-κB. IL-2 production is also regulated by
The production of GM-CSF can be induced by proinflam- stabilization of its messenger RNA (mRNA).
matory cytokines and LPS. GM-CSF is made by activated IL-2 is approved by the US Food and Drug Administration
lymphocytes and other stimulated cells and is an important driver (FDA) for the treatment of renal cancer; however, its clinical
of immune pathology in murine models of autoimmunity. 10,11 utility is limited by its toxicity, two important manifestations
GM-CSF is not ordinarily detectable in blood except under being hepatic dysfunction and the so-called capillary or vascular
pathological conditions, such as asthma. GM-CSF has been used leak syndrome. However, the anti–IL-2Rα mAbs daclizumab
clinically to treat chemotherapy-induced neutropenia, especially and basiliximab are used to prevent rejection of allotransplants
in the context of certain infections (e.g., fungal), and has been and, more recently, have been found to be effective in the treat-
18
tested in myelodysplastic syndrome and aplastic anemia. Mavrili- ment of multiple sclerosis (MS). Polymorphisms of IL-2Rα
mumab is an anti–GM-CSF antibody being studied in rheumatoid are also associated with MS.
arthritis. 12 Interleukin-4. Two classes of IL-4R appear to exist. The first
consists of the IL-4Rα subunit in conjunction with γc. It is
Cytokine Receptors Utilizing the γc Chain expressed on hematopoietic cells. The second, which is more
19
The cytokines IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 all bind to widely expressed, is a “type II” receptor. It consists of the IL-4Rα
receptors that share a common γc receptor subunit. The γc subunit subunit in associated with IL-13R α chain. Two IL-13R subunits
and the ligand-specific subunits are expressed predominantly have been cloned, so the exact composition of the type II IL-4R
on lymphocytes, although they can be found on other hemato- remains uncertain. The existence of two receptors helps explain
poietic cells as well. Mutation of the γc gene is responsible for why IL-4 has diverse actions on both hematopoietic and non-
X-linked severe combined immunodeficiency (SCID), character- hematopoietic cells. The loss of IL-4Rα would be predicted to
ized by a lack of T cells and natural killer (NK) cells, and poorly block the actions of both IL-4 and IL-13, which could explain
− +
13
functioning B cells (T B SCID) (Chapter 35). The lack of γc why gene targeting of IL-4Rα leads to a more severe phenotype
abrogates signaling by all cytokines that utilize this subunit (IL-2, than that observed in IL-4–deficient mice. Polymorphisms of
IL-4, IL-7, IL-9, IL-15, and IL-21). The lack of IL-7 and IL-15 IL-4Rα have been reported to be associated with a propensity
signaling is largely responsible for the lack of T and NK cells, to atopy. 20
respectively. In general, IL-4 promotes allergic responses and inhibits
Interleukin-2. The IL-2 receptor consists of three subunits, α, cell-mediated immune responses. Among the most important
β, and γc. The latter two are members of the type I cytokine roles of IL-4 is its ability to promote differentiation of naïve
21
receptor family. NK cells constitutively express these latter two CD4 T cells into a subset that produces IL-4 and IL-5, denoted
subunits and respond to high doses of IL-2, whereas in T cells as Th2 subset, as opposed to Th1 cells, which produce IFN-γ
the IL-2Rα subunit is induced upon activation, creating a high- (Chapter 16). In conjunction with CD40 activation, IL-4 also
affinity receptor for IL-2. IL-2Rα is also inducible in activated promotes B-cell proliferation and class switching, particularly
monocytes and B cells. IL-2Rα, however, is not a member of the to IgG1 and IgE in mice and to IgG4 and IgE in humans. Mice
type I cytokine receptor family. Rather, it resembles members deficient in IL-4 have normal B lymphopoiesis but marked
of the complement family and IL-15R (see below). reductions in IgG1 and IgE production in response to parasites.
IL-2, one of the first cytokines to be intensively studied, is These mice have residual Th2 responses because IL-13, which
produced principally by activated T cells. It is a prototypical also binds IL-4Rα, can partially compensate for the defect.
autocrine T-cell growth factor and is required for in vitro T-cell IL-4 upregulates the expression of surface IgM, major histo-
proliferation. It is an important factor in determining the compatibility complex (MHC) class II, and CD23 on B cells. In
magnitude of T-cell and NK-cell responses in vivo, although conjunction with GM-CSF, it is a growth factor for mast cells
other factors also contribute. It is thus redundant to some and basophils, as well as a potent inducer of DC differentia-
degree for this function. It augments the cytolytic activity of tion. IL-4 inhibits macrophage activation and the production of
T and NK cells and enhances IFN-γ secretion. IL-2 is also proinflammatory cytokines. It antagonizes the effects of IFN-γ,
important in programming CD8 memory T cells, which undergo blocks cytokine-induced proliferation of synoviocytes, down-
9
secondary expansion in viral infections. IL-2 is a growth factor regulates the expression of adhesion molecules, and antagonizes
for B cells and induces class switching. It also activates the induction of some acute-phase reactants in hepatocytes
macrophages. by IL-6.
+
+
IL-2–deficient mice develop massive enlargement of peripheral IL-4 is made by the Th2 subset of CD4 T cells, NK1.1 CD4
lymphoid organs, hemolytic anemia, inflammatory bowel disease T cells, basophils, and mast cells. A number of transcription
(IBD), and infiltrative granulopoiesis. In addition, the mice have factors appear to be important in regulating IL-4 production,
high levels of IgG1 and IgE. They succumb to widespread including NFAT, NF-IL6, C/EBP, c-MAF, and GATA-3. The IL4
autoimmune and lymphoproliferative disease, which points to gene has multiple signal transducer and activator of transcription
the nonredundant roles of IL-2 in promoting tolerance and 6 (STAT6) binding sites, consistent with the fact that IL-4 regulates
14
preventing autoimmunity. A similar phenotype is seen in humans its own expression. Epigenetic control and chromatin remodeling
with IL-2Rα mutations. are also important aspects. 22
Regulatory T cells (Tregs) in both mice and humans express Clinically, IL-4 has been tested in the treatment of malignancies
high levels of IL-2Rα. Maintenance of peripheral Treg numbers and some autoimmune disorders. The ability of IL-4 to generate
15
is dependent on IL-2. In addition, IL-2 inhibits Th17 and DCs is being exploited in the use of tumor vaccines. Conceivably,
T-follicular helper (Tfh) cell differentiation. 16,17 soluble IL-4R might also be useful in the treatment of allergic
IL-2 is produced by activated T cells but also myeloid cells, disease. Dupilumab is an anti-IL-4/13R mAb being studied in
including DCs. The IL2 gene has been extensively characterized severe atopic dermatitis. 23