Untitled - D Ank Unlimited

CYNAP antibodies 206 CYNAP antibodies
(CH 3 ) 2 CHCH 2
H 3 C
(CH 3 ) 2 CHCH 2
H 3C
Rather than acting as a cytotoxic agent that defines the activity
of a number of currently available immmunosuppressive
drugs, cyclosporine (CSA) produces an immunomodulatory
effect principally on the helper/inducer (CD4) lymphocytes
that orchestrate the generation of an immune response. A
cyclic polypeptide, CSA blocks T cell help for both humoral
and cellular immunity. Functions at an early stage in the
antigen-receptor induced differentiation of T cells and
inhibits their activation. It binds to cyclophilin, a member of
the intracellular class termed immunophilins. Cyclosporine
and cyclophilin combine and inhibit cytoplasmic phosphatase,
calcineurin, which is requisite for a T cell-specific
transcription factor activation. This transcription factor,
NF-AT, participates in interleukin (e.g., IL-2) synthesis by
activated T cells. In vitro studies suggest that cyclosporine
inhibits gene transcription of IL-3, IFN-γ, and other products
of antigen-stimulated T cells. However, it fails to inhibit the
effects of these factors on primed T cells and does not block
interaction with antigen. A primary mechanism of action is
its ability to suppress interleukin-2 (IL2) synthesis. CSA fails
to block activation of antigen-specific suppressor T cells,
thereby assisting development of antigen-specific tolerance.
Side effects include nephrotoxicity and hepatotoxicity with
a possible increase in B cell lymphomas. Some individuals
may also develop hypertension. The mechanism of action
of CSA appears to include inhibition of the synthesis and
release of lymphokines and alteration of expression of major
histocompatibility complex (MHC) gene products on the cell
surface. CSA inhibits IL2 mRNA formation. This does not
affect IL2 receptor expression on the cell surface. Although
CSA may diminish the number of low affinity binding sites,
it does not appear to alter high affinity binding sites on cell
surfaces. CSA inhibits the early increase in cytosolic-free
calcium that occurs in beginning activation of normal T
lymphocytes. It appears to produce its effect in the cytoplasm
rather than on the cell surfaces of lymphocytes. It can reach
the cytoplasmic location because of its ability to dissolve
in the plasma membrane lipid bilayer. The cytosolic site of
action of CSA may involve calmodulin and/or cyclophilin, a
protein kinase. Although immunosuppressive action cannot
be explained based upon CSA–calmodulin interaction, this
association closely parallels the immunosuppressive effect.
CSA produces a greater suppressive effect upon class II than
N
N
O
O
N
HO
N
CH(CH 3 ) 2
CH 3
CH 3
CH3 O
H
O
H
N
N
N
N
O
H
CH3 O
CH3 O
CH(CH3 ) 2
O
N
CH 3
R
CH 2 CH(CH 3 ) 2
O
N
N
CH 3
O
CH 3
CH 2 CH(CH 3 ) 2
Structure of cyclosporine. Nuclear magnetic resonance (NMR) structure of cyclosporine A as bound to cyclophiline A.
upon class I antigen expression in at least some experiments.
While decreasing T helper lymphocytes, the T suppressor
cells appear to be spared following CSA therapy. Both
sparing and amplification of T lymphocyte suppression
have been reported during CSA therapy. CSA is a powerful
immunosuppressant that selectively affects CD4 + helper
T cells without altering the activity of suppressor T cells,
B cells, granulocytes, and macrophages. It alters lymphocyte
function, but it does not destroy the cells. Its principal
immunosuppressive action is to inhibit IL2 production and
secretion. Thus, the suppression of IL2 impairs the development
of suppressor and cytotoxic T lymphocytes that are
antigen-specific. It has a synergistic immunosuppressive
action with corticosteroids. Corticosteroids interfere with
IL2 synthesis by inhibiting IL1 release from monocytes and
macrophages. Cyclosporine, although water-insoluble, has
been successfully employed as a clinical immunosuppressive
agent principally in preventing rejection of organ and tissue
allotransplants including kidney, heart, lung, pancreas, and
bone marrow. It has also been successful in preventing graftvs.-host
reactions. The drug has some nephrotoxic properties
that may be kept to a minimum by dose reduction. As with
other long-term immunosuppressive agents, there may be
increased risk of lymphoma development such as Epstein–
Barr (EBV)-associated B cell lymphomas. Cyclosporine is
a potent immunosuppressive agent that prolongs survival of
allogeneic transplants of skin, kidney, liver, heart, pancreas,
bone marrow, small intestine, and lung. The primary effect
is on cell-mediated immune responses in allograft rejection,
but the compound has some suppressive effect on humoral
immunity. It also suppresses delayed type hypersensitivity.
The T helper cell is the principal target, although the T suppressor
cell may also be suppressed. It inhibits lymphokine
production and release, including IL2.
CYNAP antibodies
Cytotoxicity-negative but absorption-positive antibodies
that are concerned with human leukocyte antigen (HLA)
tissue typing. Most alloantibodies to public epitopes display
CYNAP when tested in complement-dependent cytotoxicity
assays. Most alloantisera contain public or CREG antibodies,
but they act operationally as “private” antibodies
because of their CYNAP phenomenon. For this reason, the
relative insensitivity of standard CDC, due to CYNAP, has