Biomedical Engineering Reference
In-Depth Information
tested for their efficacy or are under various phases of development. From
among these, antibodies to TNF-alpha are the only agents that have been
approved for clinical use. In addition, given the immuno-regulatory effects of
IL-10, much research has been focused on related agents for therapy. In the
following section we briefly highlight the evidence for biologic agents that
target these two key cytokines.
20.6 Anti-TNF
Monoclonal antibodies against TNF are the first line of biologic agents
advocated for the treatment of IBD. From among the various antibodies
Infliximab is registered for the treatment of steroid-refractory patients and
patients with perianal fistulizing disease. It is a chimeric IgG1 monoclonal
antibody comprising 75% human and 25% murine sequences. The mechanism of
action of infliximab is elusive. Efficacy is thought to be related to a combination
of effects including neutralization of TNF in the mucosa, antibody-dependent
cytotoxicity, lysis of TNF-producing cells by complement fixation or T-cell
apoptosis. Many large clinical trials have shown that Infliximab is efficacious
for induction of remission as well as maintenance of remission for up to 55
weeks. Evidence for its utility for long-term maintenance is currently limited.
14
Although well tolerated in the majority of patients, potential for mild and
severe side effects remains. Studies have indicated potential for the occurrence
of serious infections
15
demyelination, non-Hodgkin lymphomas, cardiac failure
and death. Among the infections, re-activation of latent tuberculosis is a severe
complication and evaluation and treatment of latent tuberculosis is a prerequisite
prior to initiation of therapy.
16
One of the main risks associated with Infliximab
is the potential for immunogenicity. Development of antibodies to Infliximab is
observed in a high proportion of treated subjects leading to infusion-reactions
and loss of response.
17
Concomitant use of immunosuppressive agents may be
an alternative.
16
About 30±50% of patients do not respond to Infliximab. The
underlying causes seem to be related to antibody formation, biological markers
such as C-reactive protein and genetic variation.
20.7 IL-10
IL-10 is an immunoregulatory cytokine produced by T-helper-2 (Th2) cells,
monocytes, macrophages, B cells, dendritic cells, mast cells, etc. Its myriad
biological actions are related to the regulation of the immune response by
blocking the secretion of pro-inflammatory cytokines such as IL-1-beta, TNF-
alpha, IL-6, IL-4, IL-5,
18,19
inhibiting the expression of inflammatory enzymes
inducible nitric oxide synthase (iNOS) and cyclooxgenase (COX-2), and
blocking allergen presentation by mononuclear and dendritic cells. Given its
wide immunoregulatory effects, and based on observations that IL-10 knock-out
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