DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

Immunosuppressants, Tolerogens,
and Immunostimulants
Alan M. Krensky, William M. Bennett,
and Flavio Vincenti
THE IMMUNE RESPONSE
The immune system evolved to discriminate self from
nonself. Multicellular organisms were faced with the
problem of destroying infectious invaders (microbes) or
dysregulated self (tumors) while leaving normal cells
intact. These organisms responded by developing a
robust array of receptor-mediated sensing and effector
mechanisms broadly described as innate and adaptive.
Innate, or natural, immunity is primitive, does not
require priming, and is of relatively low affinity, but is
broadly reactive. Adaptive, or 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
being 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 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 are important in the normal
immune response to infection and tumors but also
mediate transplant rejection and auto-immunity.
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 major histocompatibility complex (MHC) antigens
(called human leukocyte antigens [HLAs] in humans)
on the surface of antigen-presenting cells, such as dendritic
cells, macrophages, and other cell types expressing
MHC class I (HLA-A, -B, and -C) and class II
antigens (HLA-DR, -DP, and -DQ) in humans. Once
activated by specific antigen recognition via their
respective clonally restricted cell-surface receptors, both
B and T lymphocytes are triggered to differentiate and
divide, leading to release of soluble mediators
(cytokines, lymphokines) that perform as effectors and
regulators of the immune response.
The impact of the immune system in human disease
is enormous. Developing vaccines against emerging
infectious agents such as human immunodeficiency
virus (HIV) and Ebola virus is among the most critical
challenges facing the research community. Immune
system–mediated diseases are significant medical problems.
Immunological diseases are growing at epidemic
proportions that require aggressive and innovative
approaches to develop new treatments. These diseases
include a broad spectrum of auto-immune diseases, such
as rheumatoid arthritis, type I diabetes mellitus, systemic
lupus erythematosus, and multiple sclerosis (MS);
solid tumors and hematological malignancies; infectious
diseases; asthma; and various allergic conditions.
Furthermore, one of the great therapeutic opportunities
for the treatment of many disorders is organ transplantation.
However, immune system–mediated graft rejection
remains the single greatest barrier to widespread
use of this technology. An improved understanding of
the immune system has led to the development of new
therapies to treat immune system–mediated diseases.
This chapter briefly reviews drugs used to modulate
the immune response in three ways: immunosuppression,
tolerance, and immunostimulation. Four major
classes of immunosuppressive drugs are discussed: glucocorticoids
(Chapter 42), calcineurin inhibitors, antiproliferative
and antimetabolic agents (Chapter 61), and
antibodies. The “holy grail” of immunomodulation is