Page 1230 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHAPTER 88 Protein Kinase Antagonists 1193

IL-12 and IL-23. Functionally, tofacitinib inhibits T-helper 1 (Th1) of kinases is exemplified by the fact that the mutations of BTK
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cells and Th2 differentiation, as well as pathogenic Th17 cells. underlie Bruton agammaglobulinemia a condition characterized
In addition to inhibiting adaptive immune responses, tofacitinib by the absence of all B cells (Chapter 34). Ibrutinib is the first
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appears to inhibit innate immune responses as well. Tofacitinib BTK inhibitor approved by the FDA in 2014 for the treatment
passed phase III trials for the treatment of methotrexate-resistant of mantle cell lymphoma and chronic lymphocytic leukemia
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rheumatoid arthritis (RA) and was FDA approved for this indica- (CLL). Recent work has identified ibrutinib as an inhibitor of
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tion in 2012. It completed phase III trials in both ulcerative Itk, which suggests it may have value as therapy in autoimmune
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colitis and psoriasis with successful results. Other diseases in disease. Antigen receptor activation of phospholipase C (PLC)γ1
which tofacitinib is being studied include ankylosing spondylitis appears to require Lck, Zap70, and Tec kinases working in concert.
and juvenile idiopathic arthritis. Tofacitinib has been used in the The action of PLCγ1 leads to elevation in intracellular calcium,
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treatment of alopecia areata, vitiligo, and atopic dermatitis. which in turn activates the phosphatase calcineurin. Calcineurin
A variety of additional inhibitors that target JAK3, including dephosphorylates and activates nuclear factor of activated T cells
decernotinib, peficitinib, and R-348 (Rigel), are under develop- (NFAT), which translocates to the nucleus and in cooperation
ment or in clinical trials (see Table 88.3). with activator protein-1 (AP-1) transcription factors induces
As gene targeting of Jak2 in mice was embryonically lethal, transcription of IL-2 and other key lymphocyte activation genes. A
it was initially thought that inhibition of JAK2 should be avoided. number of potent clinically successful immunosuppressive drugs
However, the discovery that gain-of-function mutations of JAK2 inhibit calcineurin, including cyclosporine and tacrolimus, drugs
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underlie primary polycythemia and myelofibrosis led to the idea that have revolutionized organ transplantation. Despite their
that pharmacologically targeting JAK2 could be useful. The JAK1/ success, long-term use of these drugs is limited, as they may
JAK2 inhibitor ruxolitinib was the first JAK inhibitor for the cause renal toxicity
treatment of myelofibrosis to be approved by the FDA in 2011
and was subsequently approved for the treatment of primary CLINICAL PEARLS
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polycythemia in 2014. As cγc cytokines employ both JAK1 and
JAK3 for signaling, it might be expected that ruxolitinib and Mutations Reveal Key Functions of Kinases in
tofacitinib might block some of the same cytokines. It is therefore Patients With Primary Immunodeficiencies
of interest to note that in a phase II study in RA, ruxolitinib was
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as efficacious as tofacitinib. A number of novel JAK1/JAK2 • Common γ-chain deficiency, JAK3 deficiency: severe combined
immunodeficiency
inhibitors under development both for the treatment of myelo- • ZAP70 deficiency: severe combined immunodeficiency
proliferative and inflammatory diseases. The JAK1/JAK2 inhibitors • TYK2 deficiency: rare cause of hyper-IgE syndrome
baricitinib, filgotinib, and AC-410 (Daiichi Sankyo, Tokyo, Japan)
all are in trials for the treatment of RA (see Table 88.3).
The side effects of JAK inhibitors include infection, including Protein Kinase C Family and NF-κB
serious infections, anemia, and leukopenia, presumably related TCR signaling also leads to the activation of members of the
to JAK2 inhibition and interference with cytokines, such eryth- PKC family, which, in turn, activate the transcription factor
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ropoietin, IL-11, and colony-stimulating factors. Little reduction complex nuclear factor (NF)-κB and the Ras guanyl nucleotide-
in CD4 T cells has been seen, but significant reduction in NK releasing proteins (RasGRPs). Genetic studies in mice have
cells and CD8 T cells does occur; just how significant this will identified the importance of one member, PKC-θ in TCR signal-
be in terms of infection risk remains to be determined. 11 ing. Recent work has identified PKC-θ as an inhibitor of regulatory
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T cell function. Regulatory T cells (Tregs), unlike conventional
TARGETING ANTIGEN RECEPTOR SIGNALING effector T cells, act to constrain the immune system. Enhancing
Treg numbers or function has been suggested as the treatment
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The first event in TCR signaling is the activation of the Src of a number of autoimmune diseases. For this reason, preserving
family kinase Lck (see Fig. 88.1), making it an attractive target or enhancing Treg function through the inhibition of PKC-θ is
as a therapy for autoimmune diseases and transplant rejection. an attractive strategy. Along with many other receptors, TCR
Several Lck inhibitors have been developed and showed promise signaling leads to the action of NF-κB family transcription factors,
in preclinical models of allograft rejection and autoimmunity, which control the genes involved in cellular activation and
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although at the cost of inducing progressive lymphopenia. This resistance to apoptosis. In T cells, PKC-θ is the main isoform
is consistent with the finding that induced deficiency of Lck in responsible for NF-κB activation. The novel PKC inhibitor
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mice leads to a progressive lymphopenia. Despite considerable Sotrastaurin, a potent inhibitor of the PKC-θ, β and α isoforms,
effort, the discovery of a selective Lck inhibitor suitable for use as is currently undergoing phase II trials for the treatment of diffuse
an immunosuppressive agent remains elusive. Lck activation leads large B-cell lymphoma. Early clinical testing on patients with
to the recruitment of a second round of tyrosine kinases to the psoriasis demonstrated that the drug is well tolerated and was
TCR complex; these include Zap70 or Syk. Deficiency of Zap70 able to inhibit T-cell proliferation, IL-2, and IFN-γ secretion.
causes SCID and preferential loss of CD8 T cells, but curiously, However, despite initial positive trial results, it was not effective
a successful Zap70 inhibitor has yet to be obtained. In contrast, in the treatment of psoriasis, ulcerative colitis, or liver transplanta-
Syk inhibitors have been generated; BIIB057 (Biogen, Cambridge, tion. Downstream of several inflammatory signaling pathways,
MA) is being investigated for the treatment of inflammatory including PKC, lies the nuclear factor kappa-light-chain-enhancer
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diseases, and a second, fostamatinib, is being investigated for the of activated B cells (NF-κB). NF-κB has been implicated as a
treatment of immune thrombocytopenia and immunoglobulin major mediator governing both cancer cell proliferation and
A (IgA) nephropathy. The recruitment of Zap70/Syk results in survival and governing chronic inflammation. It is held in an
activation of another class of PTKs, the Tec family kinases, Rlk inactive state by the binding of the inhibitor of κB (IκB). A
and Itk in T cells and Btk in B cells. The importance of this class cascade of protein kinases that include IκB kinases (IKK) and