Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

12
Immunomodulatory therapy
Michael J Day
INTRODUCTION
In clinical veterinary medicine there are numerous
situations in which it would be advantageous to
either enhance the immune system (immunostimulatory
therapy) or downregulate it (immunosuppressive
therapy).
The form of immunomodulatory therapy most commonly
used in veterinary practice is immunosuppression
and currently this is achieved through the use of glucocorticoids,
given alone or in combination with a range
of adjunct drugs. These agents cause ‘blanket immunosuppression’
of both deleterious and beneficial immune
responses. Methods of inducing selective immunosuppression
of a specific pathological immune response that
leave general immunity intact are currently a major
research focus.
By contrast, immunostimulation is at present difficult
to achieve in the practice situation by pharmacological
means. Although some agents are advocated for their
immune-stimulatory properties, there have been few
studies of the effects of these drugs on immunological
parameters in companion animals.
This chapter will not address the application of the
glucocorticoids (which are reviewed in Chapter 11) but
will describe other agents with immunomodulatory
capacity that are currently available to veterinary practitioners.
Potential future developments in this important
area will also be addressed.
Relevant pathophysiology
The rational use of immunomodulatory agents requires
a working knowledge of the immune response. An overview
of the complex interactions that make up any
immune response is given in Figure 12.1. The key regulatory
cell of the immune system is the CD4 + T lymphocyte,
which is activated following molecular interactions with
an ‘antigen-presenting cell’ that has previously processed
native antigen to a form that can be recognized by the
antigen-specific T-cell receptor. The activated T cell in
turn induces the specific immunological effector mechanisms
that deal with the antigenic insult to the host.
There are several regulatory subsets of CD4 + T cells
that mediate different end-effects. The Th2 CD4 + T cell
induces B lymphocyte differentiation to antibodysecreting
plasma cells (humoral or type 2 immunity).
The Th1 CD4 + T cell activates a range of cytotoxic cell
populations, which can destroy neoplastic or infected
target cells, or enable phagocytes to destroy intracellular
pathogens (cell-mediated or type 1 immunity). By contrast,
the effector function of Th3 or Treg CD4 + T cells
inhibits or ‘suppresses’ the immune response rather than
amplifying it. All these regulatory functions are mediated
by cytokines – soluble factors released from cells
that initiate intracellular signaling pathways with resultant
gene transcription in effector cells expressing
appropriate cytokine receptors. There is intrinsic interconnection
between the immune and inflammatory
pathways and factors such as the complement cascade
provide a bridge between the systems.
Immunomodulatory agents have the ability to act
at different levels of these complex pathways. In some
instances, a drug has a selective and specific action on
one individual component (e.g. ciclosporin chiefly affects
T lymphocytes) but this may have broad effects on other
populations that are regulated by the target cell. By
contrast, the mechanism and target of many other
immunomodulatory agents are incompletely understood,
despite the clinical effects observed.
DRUGS WITH IMMUNOSUPPRESSIVE
EFFECTS
Azathioprine
Clinical applications
Although azathioprine is classified as a cytotoxic drug,
it is used almost exclusively in small animal practice in
the management of immune-mediated disease. Azathioprine
has been used successfully in a large range of
immune-mediated and inflammatory disorders in dogs
and to a lesser extent in cats. This drug is often administered
as an adjunct to immunomodulatory therapy
with corticosteroids as this combination may have
complementary immunological effects and concurrent
azathioprine treatment usually permits lower doses
of corticosteroids to be used in the maintenance phase
of therapy.
Disorders in which azathioprine has been used include
myasthenia gravis, immune-mediated hemolytic anemia,
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