Page 994 - Basic _ Clinical Pharmacology ( PDFDrive )

980 SECTION VIII Chemotherapeutic Drugs

unresponsive (anergic) or undergo apoptosis. The second signal disease, rheumatoid arthritis, and multiple sclerosis. In fact, new
involves binding of costimulatory molecules (CD40, CD80 [also Mabs for some of these diseases that neutralize IL-17 by binding
known as B7-1], and CD86 [also known as B7-2]) on the APC to the cytokine itself or to its receptor (see Mab section below)
to their respective ligands (CD40L for CD40, CD28 for CD80 have recently been FDA-approved.
or CD86). Activation of T cells is regulated via a negative feed- Regulatory T (Treg) cells constitute a population of CD4
back loop involving another molecule known as T-lymphocyte– T cells that is essential for preventing autoimmunity and allergy
associated antigen 4 (CTLA-4). Following engagement of CD28 as well as maintaining homeostasis and tolerance to self antigens.
with CD80 or CD86, CTLA-4 in the cytoplasm is mobilized to This cell population exists as natural Treg (nTreg), derived directly
the cell surface where, because of its higher affinity of binding to from the thymus, and induced (adaptive) Treg (iTreg), generated
CD80 and CD86, it outcompetes or displaces CD28 resulting from naïve CD4 T cells in the periphery. Both populations have
in suppression of T-cell activation and proliferation. This prop- also been shown to inhibit antitumor immune responses and are
erty of CTLA-4 has been exploited as a strategy for sustaining a implicated in fostering tumor growth and progression. Recent
desirable immune response such as that directed against cancer. attempts to distinguish both populations have resulted in the
A recombinant humanized antibody (ipilimumab) that binds discovery of a transcription factor, Helios, in nTreg but not in
CTLA-4 prevents its association with CD80/CD86. In so doing, iTreg cells.
the activated state of T cells is sustained. Programmed cell death CD8 T lymphocytes recognize endogenously processed pep-
protein-1 (PD-1) is another negative regulator of T cells. Ligation tides presented by virus-infected cells or tumor cells. These pep-
of PD-1 with its ligands (PD-L1 or PD-L2) suppresses T-cell tides are usually nine-amino-acid fragments derived from virus
activity. Like CTLA-4, Mabs have been developed to block the or protein tumor antigens in the cytoplasm and are loaded onto
interaction of PD-1 with PD-L1, having the effect of sustained MHC class I molecules (Figure 55–2) in the endoplasmic reticu-
T cell activation. Mabs to CTLA-4 and PD-1/PD-L1 are immune lum. In contrast, class II MHC molecules present peptides (usu-
checkpoint inhibitors. They have been associated in some patients ally 11–22 amino acids) derived from extracellular (exogenous)
with the development of autoimmune toxicity that subsides upon pathogens to CD4 T helper cells. In some instances, exogenous
discontinuation of Mab therapy. antigens, upon ingestion by APCs, can be presented on class I
T lymphocytes develop and learn to recognize self and non-self MHC molecules to CD8 T cells. This phenomenon, referred to as
antigens in the thymus; those T cells that bind with high affinity “cross-presentation,” involves retro-translocation of antigens from
to self antigens in the thymus undergo apoptosis (negative selec- the endosome to the cytosol for peptide generation in the proteo-
tion), while those that are capable of recognizing foreign antigens some and is thought to be useful in generating effective immune
in the presence of self MHC molecules are retained and expanded responses against infected host cells that are incapable of priming
(positive selection) for export to the periphery (lymph nodes, T lymphocytes. Upon activation, CD8 T cells induce target cell
spleen, mucosa-associated lymphoid tissue, peripheral blood), death via lytic granule enzymes (“granzymes”), perforin, and the
where they become activated after encountering MHC-presented Fas-Fas ligand (Fas-FasL) apoptosis pathways.
peptides (Figures 55–2 and 55–3). B lymphocytes undergo selection in the bone marrow, during
Studies using murine T-cell clones have demonstrated the which self-reactive B lymphocytes are clonally deleted while B-cell
presence of two subsets of T helper lymphocytes (Th1 and Th2) clones specific for foreign antigens are retained and expanded.
based on the cytokines they secrete after activation. The Th1 sub- The repertoire of antigen specificities by T cells is genetically
set characteristically produces IFN-γ, IL-2, and IL-12 and induces determined and arises from T-cell receptor gene rearrangement
cell-mediated immunity by activation of macrophages, cytotoxic while the specificities of B cells arise from immunoglobulin gene
T cells (CTLs), and NK cells. The Th2 subset produces IL-4, rearrangement; for both types of cells, these determinations occur
IL-5, IL-6, and IL-10 (and sometimes IL-13), which induce B-cell prior to encounters with antigen. Upon an encounter with anti-
proliferation and differentiation into antibody-secreting plasma gen, a mature B cell binds the antigen, internalizes and processes
cells. IL-10 produced by Th2 cells inhibits cytokine production it, and presents its peptide—bound to class II MHC—to CD4
by Th1 cells via the downregulation of MHC expression by APCs. helper cells, which in turn secrete IL-4 and IL-5. These inter-
Conversely, IFN-γ produced by Th1 cells inhibits the proliferation leukins stimulate B-cell proliferation and differentiation into
of Th2 cells (Figure 55–3). Although these subsets have been memory B cells and antibody-secreting plasma cells. The primary
well described in vitro, the nature of the antigenic challenge that antibody response consists mostly of IgM-class immunoglobulins.
elicits a Th1 or Th2 phenotype is less clear. Extracellular bacteria Subsequent antigenic stimulation results in a vigorous “booster”
typically cause the elaboration of Th2 cytokines, culminating in response accompanied by class (isotype) switching to produce
the production of neutralizing or opsonic antibodies. In contrast, IgG, IgA, and IgE antibodies with diverse effector functions
intracellular organisms (eg, mycobacteria) elicit the production of (Figure 55–3). These antibodies also undergo affinity matura-
Th1 cytokines, which lead to the activation of effector cells such tion, which allows them to bind more efficiently to the antigen.
as macrophages. With the passage of time, this results in accelerated elimination
Another subset of CD4 T cells that secrete IL-17 (Th17) of microorganisms in subsequent infections. Antibodies mediate
is important in leukocyte recruitment to sites of bacterial and their functions by acting as opsonins to enhance phagocytosis and
fungal pathogens. Th17 cells also contribute to the pathogenesis cellular cytotoxicity and by activating complement to elicit an
of autoimmune diseases such as psoriasis, inflammatory bowel inflammatory response and induce bacterial lysis (Figure 55–4).