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INTRODUCTION

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.

ABBREVIATIONS

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

THE IMMUNE RESPONSE

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.

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.

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 ...

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