Immune Modulatiors

Inhibition of Immune Responses
Both the prevention of transplant rejection
and the treatment of autoimmune
disorders call for a suppression of immune
responses. However, immune
suppression also entails weakened defenses
against infectious pathogens and
a long-term increase in the risk of neoplasms.
A specific immune response begins
with the binding of antigen by lymphocytes
carrying specific receptors
with the appropriate antigen-binding
site. B-lymphocytes “recognize” antigen
surface structures by means of membrane
receptors that resemble the antibodies
formed subsequently. T-lymphocytes
(and naive B-cells) require the
antigen to be presented on the surface
of macrophages or other cells in conjunction
with the major histocompatibility
complex (MHC); the latter permits
recognition of antigenic structures
by means of the T-cell receptor. T-helper
cells carry adjacent CD-3 and CD-4
complexes, cytotoxic T-cells a CD-8
complex. The CD proteins assist in docking
to the MHC. In addition to recognition
of antigen, activation of lymphocytes
requires stimulation by cytokines.
Interleukin-1 is formed by macrophages,
and various interleukins (IL), including
IL-2, are made by T-helper cells. As
antigen-specific lymphocytes proliferate,
immune defenses are set into motion.
I. Interference with antigen recognition.
Muromonab CD3 is a monoclonal
antibody directed against mouse
CD-3 that blocks antigen recognition by
T-lymphocytes (use in graft rejection).
II. Inhibition of cytokine production
or action. Glucocorticoids modulate
the expression of numerous
genes; thus, the production of IL-1 and
IL-2 is inhibited, which explains the
suppression of T-cell-dependent immune
responses. Glucocorticoids are
used in organ transplantations, autoimmune
diseases, and allergic disorders.
Systemic use carries the risk of iatrogenic
Cushing’s syndrome .
Cyclosporin A is an antibiotic polypeptide
from fungi and consists of 11, in
part atypical, amino acids. Given orally,
it is absorbed, albeit incompletely. In
lymphocytes, it is bound by cyclophilin,
a cytosolic receptor that inhibits the
phosphatase calcineurin. The latter
plays a key role in T-cell signal transduction.
It contributes to the induction
of cytokine production, including that of
IL-2. The breakthroughs of modern
transplantation medicine are largely attributable
to the introduction of cyclosporin
A. Prominent among its adverse
effects are renal damage, hypertension,
and hyperkalemia.
Tacrolimus, a macrolide, derives
from a streptomyces species; pharmacologically
it resembles cyclosporin A,
but is more potent and efficacious.
The monoclonal antibodies daclizumab
and basiliximab bind to the α-
chain of the II-2 receptor of T-lymphocytes
and thus prevent their activation,
e.g., during transplant rejection.
III. Disruption of cell metabolism
with inhibition of proliferation. At
dosages below those needed to treat
malignancies, some cytostatics are also
employed for immunosuppression, e.g.,
azathioprine, methotrexate, and cyclophosphamide.
The antiproliferative
effect is not specific for lymphocytes
and involves both T- and Bcells.
Mycophenolate mofetil has a more
specific effect on lymphocytes than on
other cells. It inhibits inosine monophosphate
dehydrogenase, which catalyzes
purine synthesis in lymphocytes.
It is used in acute tissue rejection responses.
IV. Anti-T-cell immune serum is
obtained from animals immunized with
human T-lymphocytes. The antibodies
bind to and damage T-cells and can thus
be used to attenuate tissue rejection.