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INTRODUCTION

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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

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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 RESPONSE

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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 soluble mediators (cytokines, ...

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