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This chapter reviews the components of the immune response and drugs that modulate immunity via immunosuppression, tolerance, or neutralization of cytokine signaling. Four major classes of immunosuppressive drugs are discussed: glucocorticoids, calcineurin inhibitors, antiproliferative and antimetabolic agents, and antibodies or small molecules that target cytokine signaling. While there are similarities, the approach to the use of immunosuppressant drugs in transplant rejection has evolved separately from the approaches used to treat autoimmune disease and thus is presented separately.
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Abbreviations
ALG: antilymphocyte globulin
APC: antigen-presenting cell
ATG: antithymocyte globulin
AUC: area under the plasma concentration–time curve
CAPS: cryopyrin-associated periodic syndromes
CLL: chronic lymphocytic leukemia
CTLA-4: cytotoxic T-lymphocyte–associated antigen 4
CYP: cytochrome P450
GA: glatiramer acetate
GI: gastrointestinal
GM-CSF: granulocyte-macrophage colony-stimulating factor
GVHD: graft-versus-host disease
HLA: human leukocyte antigen
HSC: hematopoietic stem cell
IFN: interferon
Ig: immunoglobulin
IL: interleukin
IL-1RA: IL-1 receptor antagonist
IL-2R: interleukin 2 receptor
JAK: Janus kinase
JAKinib: Janus kinase inhibitor
JCV: John Cunningham virus
LDL: low-density lipoprotein
LFA: lymphocyte function–associated antigen
mAb: monoclonal antibody
MAO: monoamine oxidase
MHC: histocompatibility complex
MMF: mycophenolate mofetil
6-MP: 6-mercaptopurine
MPA: mycophenolic acid
MPAG: MPA glucuronide
MS: multiple sclerosis
mTOR: mammalian target of rapamycin
NFAT: nuclear factor of activated T lymphocytes
NK: natural killer
PD-1: programmed cell death protein 1
PD-L1: programmed death ligand 1
PML: progressive multifocal leukoencephalopathy
S1P: sphingosine-1-phosphate
S1PR: sphingosine-1-phosphate receptor
STAT: signal transducer and activator of transcription
TCR: T-cell receptor
TNF: tumor necrosis factor
TYK2: tyrosine kinase 2
VZV: varicella-zoster virus
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The immune system evolved to discriminate self from non-self. Innate immunity (natural immunity) is primitive, based on the recognition of conserved molecular patterns of microorganisms and, as such, broadly reactive. Adaptive immunity (learned immunity) is antigen specific, depends on antigen exposure or priming, and can be of very high affinity. The two arms of immunity work closely together, with the innate immune system most active early in an immune response and adaptive immunity becoming progressively dominant over time.
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The major effectors of innate immunity are complement, granulocytes, monocytes/macrophages, natural killer (NK) cells, innate lymphoid cells, mast cells, and basophils. The major effectors of adaptive immunity are B and T lymphocytes. B lymphocytes make antibodies; T lymphocytes function as helper, cytolytic, and regulatory (suppressor) cells. These cells not only are important in the normal immune response to infection and tumors but also mediate transplant rejection and autoimmunity.
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Immunoglobulins (antibodies) produced by B lymphocytes can recognize a large variety of specific structural conformations. In contrast, T lymphocytes recognize antigens as peptide fragments in the context of major histocompatibility complex II (MHC II) proteins (called human leukocyte antigens [HLAs] in humans) on the surface of antigen-presenting cells (APCs), such as dendritic cells and macrophages, or on MHC I, which is expressed by all nucleated cells. Once activated by specific antigen recognition, both B and T lymphocytes are ...