SPECIFIC AGENTS USED IN SOLID ORGAN TRANSPLANT
Muromonab
Muromonab was the first monoclonal antibody used in solid organ
transplantation. Muromonab is a murine monoclonal antibody directed against
human CD3 receptor, which is situated on the T-cell antigen receptor of mature
T-cells, inducing apoptosis of the target cell (Bodziak, 2003; Wilde, 1996).
Cells which display the CD3 receptor include CD2, CD4, and CD8
positivelymphocytes (Ortho Biotech, 2004). Other investigators suggest that muromonab
may also induce CD3 com-plex shedding, lymphocyte adhesion molecule expres-sion
causing peripheral endothelial adhesion, and cell mediated cytolysis (Wilde,
1996; Ortho Biotech, 2004 Buysmann et al., 1996; Magnussen and Moller, 1994;
Wong et al., 1990). Muromonab is approved for the treatment of kidney allograft
rejection and steroid resistant rejection in heart transplant recipients (Ortho
Biotech, 2004). Muromonab was initially employed as an induction agent for
kidney transplant recipients, in conjunction with cyclosporine, azathioprine,
and corti-costeroids. Muromonab administration at the time of transplant
decreased the rate of acute rejection and prolonged the time to first acute
rejection when compared to no induction (Kahana, 1989). Liver recipients with
renal dysfunction at the time of transplant who received muromonab induction
were able to avoid cyclosporine without an increased incidence of acute
rejection and sustain renal function versus those who received cyclosporine
(Mills, 1989). Therefore administration of muromonab enabled pre-servation of
renal function in the setting of reduced calcineurin inhibitor exposure when
compared to those who did not receive muromonab (Wilde, 1996). The use of
muromonab as an induction agent is nearly extinct with the introduction of
newer agents that have more favorable side effect profiles.
Today, muromonab is reserved for treatment of refractory rejection.
Muromonab is extremely effective at halting most corticosteroid as well as
polyclonal antibody resistant rejections. These rejections are treated with 5
mg of muromonab given daily for 7 to 14 days (Ortho Biotech, 2004). The dose
and duration of therapy is often dependent on clinical or biopsy resolution of
rejection or may be correlated with circulating CD3 cell concentrations in the
serum.
Most patients who are exposed to muromonab will develop human against
mouse antibodies (HAMA) following initial exposure. These IgG anti-bodies may
lead to decreased efficacy of subsequent treatment courses, but pre-medication
with corticos-teroids or antiproliferative agents during initial ther-apy may
reduce their development (Wilde, 1996). Following administration, in vitro data
indicate that a serum concentration of 1000 mg/L is
required to inhibit cytotoxic T-cell function (Wilde, 1996). In vivo
concen-trations near the in vivo threshold immediately (1 hour) following
administration, but diminish significantly by 24 hours (Wilde, 1996).
Steady-state concentrations of 900 ng/mL can be achieved after three doses,
with a plasma elimination half life of 18 hours when used for treatment of
rejection and 36 hours when used for induction (Wilde, 1996; Ortho Biotech,
2004).
Muromonab administration is associated with significant acute and
chronic adverse effects.Immediately following administration, patients will
experience a characteristic OKT3 cytokine release syndrome. The etiology of
this syndrome is character-ized by the pharmacodynamic interaction the OKT3
molecule has at the CD3 receptor. Muromonab will stimulate the target cell
following its interaction with the CD3 receptor prior to inducing cell death.
Consequently, CD3 cell stimulation leads to cytokine production and release,
which is compounded by acute cellular apoptosis leading to cell lysis and release
of the intracellular contents. The cytokine release syndrome associated with
muromonab manifests as high fever, chills, rigors, diarrhea, capillary leak and
in some cases aseptic meningitis (Wilde, 1996). Capillary leak has been
correlated with increased tumor necrosis factor release leading to an initial
increase in cardiac output secondary to decreased peripheral vascular
resistance, followed by a reduction in right heart filling pressures (pulmonary
capillary wedge pressure) which leads to a decrease in stroke volume (Wilde,
1996). Sequelae of this cytokine release syndrome can occur immediately, within
30 to 60 minutes, and last up to 48 hours following administration (Ortho
Biotech, 2004). This syndrome appears to be the most severe following the initial
dose when the highest innoculum of cells is present in the patient’s serum or
when preformed antibodies against the mouse epitope exist. Subsequent doses
appear to be better tolerated, though cytokine release syndrome has been
reported after five doses, typically when the dose has been increased or the
CD3 positive cell population has rebounded from previous dose baseline (Wilde,
1996). Pre-treatment against the effects of this cytokine release is necessary
to minimize the host response. Specifically, corticoster-oids are to prevent
cellular response to cytokines, non-steroidal anti-inflammatory agents to
prevent sequelae of the arachidonic acid cascade, acetaminophen to halt the
effects of centrally acting prostaglandins, and diphenhydramine to attenuate
the recipient’s response to histamine.
In addition to immediate adverse effects, the potency of muromonab has
been associated with a high incidence of post-transplant lymphoprolifera-tive
disease and viral infections. For all patients, the 10-year cumulative
incidence of post-transplant lymphoproliferative disease is 1.6% (Opelz, 2004).
Review of large transplant databases, revealed that deceased donor kidney
transplant recipients who received muromonab for induction or treatment had a
cumulative incidence of post-transplant lympho-proliferative disease that was 3
times higher than those who did not received muromonab or other T-cell
depleting induction (Opelz, 2004). This ob-servation may be multifactorial. It
is well known that post-transplant lymphoproliferative disease may be induced
secondary to Epstein-Barr viral B-cell
malignant transformation. Muromonab’s potent in-hibition of
T-lymphocytes over a sustained period of time diminishes the immune system’s
normal sur-veillance and destruction of malignant cell lines, consequently
leading to unopposed transformed B-cell proliferation and subsequent
post-transplant lymphoma (Opelz, 2004).
Early use and development of muromonab in solid organ transplantation
was beneficial for the novel development and use of newer monoclonal agents.
The immunodepleting potency of muromo-nab, combined with the significant risk
for malig-nancy, has reduced its use in modern transplantation. However, this
agent is still a formidable option in the treatment of severe allograft
rejection.
Related Topics
Privacy Policy, Terms and Conditions, DMCA Policy and Compliant
Copyright © 2018-2023 BrainKart.com; All Rights Reserved. Developed by Therithal info, Chennai.