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This chapter reviews the components of the immune response and drugs that modulate immunity via immunosuppression or tolerance. Four major classes of immunosuppressive drugs are discussed: glucocorticoids (see Chapter 46), calcineurin inhibitors, antiproliferative and antimetabolic agents (see Chapter 66), and antibodies. 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. Finally, the chapter ends with a brief case study of immunotherapy for the autoimmune disease MS.
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Abbreviations
ALG: antilymphocyte globulin
APC: antigen-presenting cell
ATG: antithymocyte globulin
AUC: area under the curve
CD: cluster of differentiation
CLL: chronic lymphocytic leukemia
CNS: central nervous system
CTL: cytotoxic T lymphocyte
CTLA4: cytotoxic T-lymphocyte–associated antigen 4
FKBP-12: FK506-binding protein 12
CYP: cytochrome P450
GVHD: graft-versus-host disease
HLA: human leukocyte antigen
HRPT: hypoxanthine–guanine phosphoribosyl transferase
IFN-β: interferon type I beta
Ig: immunoglobulin
IL: interleukin
IL-1RA: IL-1 receptor antagonist
IL-2R: interleukin 2 receptor
JCV: polyomavirus JC
LDL: low-density lipoprotein
LFA: lymphocyte function–associated antigen
mAb: monoclonal antibody
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
NHP: nonhuman primate
NK: natural killer
NSAID: nonsteroidal anti-inflammatory drug
PD1: programmed cell death protein 1
PD-L1: programmed death ligand 1
PML: progressive multifocal leukoencephalopathy
RA: rheumatoid arthritis
S1P-R: sphingosine-1-phosphate receptor
TCR: T-cell receptor
VZV: varicella zoster virus
WBC: white blood cell
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The immune system evolved to discriminate self from nonself. Innate immunity (natural immunity) is primitive, does not require priming, and is of relatively low affinity, but it is 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, NK 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) on the B-lymphocyte surface are receptors for a large variety of specific structural conformations. In contrast, T lymphocytes recognize antigens as peptide fragments in the context of self MHC antigens (called HLAs in humans) on the surface of APCs, such as dendritic cells, macrophages, and other cell types expressing MHC class I and class II antigens. Once activated by specific antigen recognition, both B and T lymphocytes are triggered to differentiate and divide, leading to release of ...