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Chapter 18
Antibiotics
The most important of the drugs employed in helping the body
to resist microbes, mainly bacteria, are antibiotics. An
antibi-
otic
is any molecule or substance that kills bacteria. Antibiotics
may be produced by one strain of bacteria to defend against
other strains. Since the mid-twentieth century, commercial
manufacture of antibiotics such as
penicillin
has revolution-
ized our ability to treat disease.
Antibiotics exert a wide variety of effects, including
inhibition of bacterial cell-wall synthesis, protein synthe-
sis, and DNA replication. Fortunately, a number of the reac-
tions involved in the synthesis of protein by bacteria, and the
proteins themselves, are suffi ciently different from those in
human cells that certain antibiotics can inhibit them without
interfering with the body’s own protein synthesis. For exam-
ple, the antibiotic
erythromycin
blocks the movement of ribo-
somes along bacterial messenger RNA.
Antibiotics, however, must not be used indiscriminately.
For one thing, they may exert allergic reactions, and they may
exert toxic effects on the
body’s
cells. A second reason for judi-
cious use is the escalating and very serious problem of drug resis-
tance. Most large bacterial populations contain a few mutants
that are resistant to the drug, and these few may be capable of
multiplying into large populations resistant to the effects of that
particular antibiotic. Alternatively, the antibiotic can induce the
expression of a latent gene that confers resistance. Finally, resis-
tance can be transferred from one resistant microbe directly
to another previously nonresistant microbe by means of DNA
passed between them. (One example of how drug resistance
can spread by these phenomena is that many bacterial strains
that were once highly susceptible to penicillin now produce an
enzyme that cleaves the penicillin molecule.) A third reason for
the judicious use of antibiotics is that these agents may actually
contribute to a new infection by eliminating certain species of
relatively harmless bacteria that ordinarily prevent the growth
of more dangerous ones. One site in which this may occur is the
large intestine, where the loss of harmless bacteria may account
for the symptoms of cramps and diarrhea that occur in some
individuals taking certain types of antibiotics.
Harmful Immune Responses
Until now, we have focused on the mechanisms of immune
responses and their protective effects. The following section
discusses how immune responses can sometimes actually be
harmful or unwanted.
Graft Rejection
The major obstacle to successful transplantation of tissues and
organs is that the immune system recognizes the transplants,
called grafts, as foreign and launches an attack against them.
This is called
graft rejection
.
Although B cells and macro-
phages play some role, cytotoxic T cells and helper T cells are
mainly responsible for graft rejection.
Except in the case of identical twins, the class I MHC
proteins on the cells of a graft differ from the recipient’s. So
do the class II molecules present on the macrophages in the
graft (recall that virtually all organs and tissues have macro-
phages). Consequently, the MHC proteins of both classes are
recognized as foreign by the recipient’s T cells, and the cells
bearing these proteins are destroyed by the recipient’s cyto-
toxic T cells with the aid of helper T cells.
Some of the tools aimed at reducing graft rejection are
radiation and drugs that kill actively dividing lymphocytes
and thereby decrease the recipient’s T-cell population. A very
effective drug, however, is
cyclosporin
,
which does not kill
lymphocytes but rather blocks the production of IL-2 and
other cytokines by helper T cells. This eliminates a critical sig-
nal for proliferation of both the helper T cells themselves and
the cytotoxic T cells. Synthetic adrenal corticosteroids in large
doses are also used to reduce the rejection.
There are several problems with the use of drugs like cyclo-
sporin and potent synthetic adrenal corticosteroids: (1) immu-
nosuppression with them is nonspecifi c, so patients taking them
are at increased risk for infections and cancer; (2) they exert
other toxic side effects; and (3) they must be used continu-
ously to inhibit rejection. An important new kind of therapy,
one that may be able to avoid these problems, is under study.
Recall that immune tolerance for self proteins is achieved by
clonal deletion and/or inactivation, and that the mechanism
for this is absence of a nonantigenic costimulus at the time the
antigen is fi rst encountered. The hope is that, at the time of
graft surgery, treatment with drugs that block the complemen-
tary proteins constituting the costimulus may induce a perma-
nent state of immune tolerance toward the graft.
The Fetus as a Graft
During pregnancy, the fetal trophoblast cells of the placenta lie
in direct contact with maternal immune cells. Because half of
the fetal genes are paternal, all proteins coded for by these genes
are foreign to the mother. Why does the mother’s immune sys-
tem refrain from attacking the trophoblast cells, which express
such proteins, and thus fail to reject the placenta? This issue is
far from solved, but one critical mechanism (there are certainly
others) is as follows: Trophoblast cells, unlike virtually all other
nucleated cells, do not express the usual class I MHC proteins.
Instead, they express a unique class I MHC protein that mater-
nal immune cells do not recognize as foreign.
Transfusion Reactions
Transfusion reactions
,
the illness caused when erythrocytes
are destroyed during blood transfusion, are a special example
of tissue rejection, one that illustrates the fact that antibod-
ies rather than cytotoxic T cells can sometimes be the major
factor in rejection. Erythrocytes do not have MHC proteins,
but they do have plasma membrane proteins and carbohydrates
(the latter linked to the membrane by lipids) that can function
as antigens when exposed to another person’s blood. There are
more than 400 erythrocyte antigens, but the ABO system of
carbohydrates is the most important for transfusion reactions.
Some people have the gene that results in synthesis of
the A antigen, some have the gene for the B antigen, some
have both genes, and some have neither gene. (Genes cannot
code for the carbohydrates that function as antigens; rather,
they code for the particular enzymes that catalyze the forma-
tion of the carbohydrates.) The erythrocytes of those with nei-
ther gene are said to have O-type erythrocytes. Consequently,
the possible blood types are A, B, AB, and O (
Table 18–9
).
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