biological effect is to enhance general, lymphocyte-
mediated attack on the antigen-bearing cell.
Cytokines include the large and ever increasing
set of interleukins, various interferons, trophic
factors such as tumor necrosis factor and the
many growth factors. Granulocyte macrophage
colony stimulating factor (GMCSF; sargramostim,
Leukine;ImmunexCorp.) isusedfor myeloid recon-
stitution after bone marrow ablation, exploiting its
eponymous property, which was initially identified
in vitro. Interleukin-2 (aldesleukin, Proleukin,
Chiron Corp.) is approved in the United States for
the treatment of renal carcinoma and metastatic
melanoma. Platelet-derived growth factor can be
used to heal diabetic foot ulcers, presumably by
imitating normal physiology that is blunted in
patients with diabetes (gel becaplermin, Regranex;
Ortho-McNeil/Chiron, Inc.). Pegylated interferon
alpha has revolutionized the treatment of hepatitis
due to virus type C.
Because cytokines have nonspecific effects,
existing biological products often find additional
indications. Similarly, their adverse effects also
reflect their nonspecificity with symptoms such
as fever, myalgias, flu-like symptoms and rhabdo-
myolysis.
Immune adjuvants
Immune adjuvants can be classed as:
Nonspecific, for example BCG vaccine for blad-
der cancer
Specific, for example Salk vaccine for polio
prevention
Genetic, to elicit cytokine responses (see below)
Traditionally, vaccines have been directed against
the prevention of specific infectious diseases.Vacca
is the latin nominative for a cow, and vaccines have
been used widely in medicine since Jenner’s pio-
neering work. Live, live-attenuated and killed
microrganisms may all be used as antigens to elicit
cellular and humoral responses. They may be
viewed as adjuvants because it is the enhancement
of endogenous physiology which protects against
the pathogen, and not the vaccine itself.
The great scope for preventing infectious dis-
ease remains, and there is a continuing need for
worthwhile research programs. Current challenges
include malaria, sleeping sickness, HIVand prion-
mediated disease. The last of these may (contro-
versially) also be regarded as an ‘autoimmune’ or
‘congenital’disease, if it turns out to be truly due to
the derepression of prion genomes, which lurk
dormant in many normal mammals, including
human beings. Drug resistance, occurring in
numerous microorganisms ranging from staphylo-
coccus to malaria, is another field which could
conceivably be conquered by taking the biological
approach. A current ethical problem is that dis-
eases that plague tropical countries and the devel-
oping world are in great need for drug development
and research, but offer little financial incentive to
the traditional pharmaceutical industry.
Not surprisingly, there is considerable interest
in using adjuvant tactics for the prevention or
treatment of noninfectious disease. Spontaneous
tumor regression (although observed clinically
only very rarely) and the development of rare
tumors in immunocompromised patients (such as
Kaposi sarcoma in patients with AIDS) are both
consistent with the usefulness of endogenous host
mechanisms to either prevent or retard cancer.
Tumor-specific antigens may be used as therapeu-
tic targets for exogenous therapy.Antisense drugs
Antisense drugs are exogenous oligonucleotides
that bind to specific endogenous nucleic acid
sequences. Binding to mRNA prevents the con-
struction of proteins by ribosomes and similarly,
binding to specific gene sequences on DNA can
prevent transcription (i.e. inhibit mRNA synth-
esis). The application of antisense technology is
broad as this approach can be used to inhibit the
production of a wide range of proteins including
stimulatory and inhibitory molecules.
Although the synthesis of antisense molecules
using modern combinatorial chemical approaches is
easily automated, the delivery of these molecules to22.7 PEPTIDES 285