DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

1020 trials. Because they remain experimental, they are discussed
only briefly here.
Co-stimulatory Blockade. Induction of specific immune
responses by T lymphocytes requires two signals: an
antigen-specific signal via the T-cell receptor and a costimulatory
signal provided by the interaction of molecules
such as CD28 on the T lymphocyte and CD80 and
CD86 on the antigen-presenting cell (Figure 35–4;
Khoury et al., 1999).
SECTION IV
INFLAMMATION, IMMUNOMODULATION, AND HEMATOPOIESIS
In preclinical studies, inhibition of the co-stimulatory signal
has been shown to induce tolerance (Weaver et al., 2008).
Experimental approaches to inhibit co-stimulation include a
A
B
APC
MHC
Co-stimulatory
ligand
APC
MHC
MHC
TCR
TCR
T Cell
Co-stimulatory
receptor
T Cell
Co-stimulatory
receptor
TCR
CD154
TCR
Activated
T Cell
Inactivated
T Cell
recombinant fusion protein molecule, CTLA4-Ig, and anti-CD80
and/or anti-CD86 mAbs. The antibodies h1F1 and h3D1 are humanized
anti-CD80 and anti-CD86 mAbs, respectively. In vitro, h1F1
and h3D1 block CD28-dependent T-cell proliferation and decrease
mixed lymphocyte reactions. These mAbs must be used in tandem,
because either CD80 or CD86 is sufficient to stimulate T cells via
CD28. In nonhuman primates, anti-CD80 and anti-CD86 mAbs were
proven effective in renal transplantation, either as monotherapy or in
combination with steroids or cyclosporine (Weaver et al., 2008), but
did not induce durable tolerance. A phase I study of h1F1 and h3D1
in renal transplant recipients was performed in patients receiving
maintenance therapy consisting of cyclosporine, MMF, and steroids
(Vincenti, 2002). Although the results of this study showed that h1F1
and h3D1 are relatively safe and possibly effective, clinical development
was not further pursued.
CTLA4-Ig (abatacept) contains the binding region of
CTLA4, which is a CD28 homolog, and the constant region of the
human IgG 1
. CTLA4-Ig competitively inhibits CD28. Numerous
animal studies have confirmed the efficacy of CTLA4-Ig in inhibiting
alloimmune responses, resulting in successful organ transplantation.
More recently, CTLA4-Ig was shown to be effective in the
treatment of rheumatoid arthritis. However, CTLA4-Ig was less
effective when utilized in nonhuman primate models of renal
transplantation. Belatacept (LEA29Y) (Figure 35–5) is a secondgeneration
CTLA4-Ig with two amino acid substitutions. Belatacept
has higher affinity for CD80 (2-fold) and CD86 (4-fold), yielding a
10-fold increase in potency in vitro as compared to CTLA4-Ig.
Preclinical renal transplant studies in nonhuman primates showed
that belatacept did not induce tolerance but did prolong graft survival.
Extracellular
portion of CTLA4
(CD152)
APC
CD80/CD86
CD28
T Cell
CD28
CD152
Activated
T Cell
Mutations at
positions 29 and
105 confer
increased potency
Figure 35–4. Co-stimulation. A. Two signals are required for
T-cell activation. Signal 1 is via the T-cell receptor (TCR), and
signal 2 is via a co-stimulatory receptor–ligand pair. Both signals
are required for T-cell activation. Signal 1 in the absence of
signal 2 results in an inactivated T cell. B. One important costimulatory
pathway involves CD28 on the T cell and B7-1
(CD80) and B7-2 (CD86) on the antigen-presenting cell (APC).
After a T cell is activated, it expresses additional co-stimulatory
molecules. CD152 is CD40 ligand, which interacts with CD40 as
a co-stimulatory pair. CD154 (CTLA4) interacts with CD80 and
CD86 to dampen or downregulate an immune response.
Antibodies against CD80, CD86, and CD152 are being evaluated
as potential therapeutic agents. CTLA4-Ig, a chimeric protein
consisting of part of an immunoglobulin molecule and part
of CD154, also has been tested as a therapeutic agent. (Adapted
with permission from Clayberger, C., and Krensky, A.M.
Mechanisms of allograft rejection. In, Immunologic Renal
Diseases. (Nielson, E.G., and Couser, W.G., eds) Lippincott-
Raven, Philadelphia, 2001. (http://lww.com).)
Fragment of FC
domain of lgG1
Figure 35–5. Structure of belatacept, a CLTA4Ig congener. For
details, see the text and Figure 35–4.